REVIEWER FOR REMOVAL EXAMS 1.

Correlate the composition of the cell membrane with the mode of transport of polar and nonpolar substances into the cell. Diffusion through the cell membrane is divided into two subtypes called simple and facilitated diffusion. Simple diffusion means that kinetic movement of molecules or ions occurs through the cell membrane by two pathways: (1) through the interstices of the lipid bilayer if the diffusing substance is lipid soluble, and (2) through watery channels that penetrate all the way through some of the large transport proteins. Facilitated diffusion is also called carrier-mediated diffusion because a substance transported in this manner diffuses through the membrane using a specific carrier protein to help. That is, the carrier facilitates diffusion of the substance to the other side. Enough water ordinarily diffuses in each direction through the red cell membrane per second to equal about 100 times the volume of the cell itself. Yet, normally, the amount that diffuses in the two directions is balanced so precisely that zero net movement of water occurs. Therefore, the volume of the cell remains constant. However, under certain conditions, a concentration difference for water can develop across a membrane, just as concentration differences for other substances can occur. When this happens, net movement of water does occur across the cell membrane, causing the cell either to swell or to shrink, depending on the direction of the water movement. This process of net movement of water caused by a concentration difference of water is called osmosis. Active transport is divided into two types according to the source of the energy used to cause the transport: primary active transport and secondary active transport. In primary active transport, the energy is derived directly from breakdown of adenosine triphosphate (ATP) or of some other highenergy phosphate compound. In secondary active transport, the energy is derived secondarily from energy that has been stored in the form of ionic concentration differences of secondary molecular or ionic substances between the two sides of a cell membrane, created originally by primary active transport. In both instances, transport depends on carrier proteins that penetrate through the cell membrane, as is true for facilitated diffusion. However, in active transport, the carrier protein functions differently from the carrier in facilitated diffusion because it is capable of imparting energy to the transported substance to move it against the electrochemical gradient. Following are some examples of primary active transport and secondary active transport, with more detailed explanations of their principles of function. Different substances that are actively transported through at least some cell membranes include sodium ions, potassium ions, calcium ions, iron ions, hydrogen ions, chloride ions, iodide ions, urate ions, several different sugars, and most of the amino acids.

2. Describe the events and pathways from initial antigen contact to eventual antibody production and T-cell activation. Within minutes after inflammation begins, the macrophages already present in the tissues, whether histiocytes in the subcutaneous tissues, alveolar macrophages in the lungs, microglia in the brain, or others, immediately begin their phagocytic actions. When activated by the products of infection and inflammation, the first effect is rapid enlargement of each of these cells. Next, many of the previously sessile macrophages break loose from their attachments and become mobile, forming the first line of defense against infection during the first hour or so. Within the first hour or so after inflammation begins, large numbers of neutrophils begin to invade the inflamed area from the blood. This is caused by products from the inflamed tissues that initiate the following reactions: (1) They alter the inside surface of the capillary endothelium, causing neutrophils to stick to the capillary walls in the inflamed area. This effect is called margination. (2) They cause the

intercellular attachments between the endothelial cells of the capillaries and small venules to loosen, allowing openings large enough for neutrophils to pass by diapedesis directly from the blood into the tissue spaces. (3) Other products of inflammation then cause chemotaxis of the neutrophils toward the injured tissues, as explained earlier. Thus, within several hours after tissue damage begins, the area becomes well supplied with neutrophils. Because the blood neutrophils are already mature cells, they are ready to immediately begin their scavenger functions for killing bacteria and removing foreign matter. Also within a few hours after the onset of acute, severe inflammation, the number of neutrophils in the blood sometimes increases fourfold to fivefold from a normal of 4000 to 5000 to 15,000 to 25,000 neutrophils per microliter. This is called neutrophilia, which means an increase in the number of neutrophils in the blood. Along with the invasion of neutrophils, monocytes from the blood enter the inflamed tissue and enlarge to become macrophages. However, the number of monocytes in the circulating blood is low: also, the storage pool of monocytes in the bone marrow is much less than that of neutrophils. Therefore, the buildup of macrophages in the inflamed tissue area is much slower than that of neutrophils, requiring several days to become effective. Furthermore, even after invading the inflamed tissue, monocytes are still immature cells, requiring 8 hours or more to swell to much larger sizes and develop tremendous quantities of lysosomes; only then do they acquire the full capacity of tissue macrophages for phagocytosis. Yet, after several days to several weeks, the macrophages finally come to dominate the phagocytic cells of the inflamed area because of greatly increased bone marrow production of new monocytes, as explained later. As already pointed out, macrophages can phagocytize far more bacteria (about five times as many) and far larger particles, including even neutrophils themselves and large quantities of necrotic tissue, than can neutrophils. The fourth line of defense is greatly increased production of both granulocytes and monocytes by the bone marrow. This results from stimulation of the granulocytic and monocytic progenitor cells of the marrow. However, it takes 3 to 4 days before newly formed granulocytes and monocytes reach the stage of leaving the bone marrow. If the stimulus from the inflamed tissue continues, the bone marrow can continue to produce these cells in tremendous quantities for months and even years, sometimes at a rate 20 to 50 times normal. Although more than two dozen factors have been implicated in control of the macrophage response to inflammation, five of these are believed to play dominant roles. They consist of (1) tumor necrosis factor (TNF), (2) interleukin-1 (IL-1), (3) granulocyte-monocyte colony-stimulating factor (GM-CSF), (4) granulocyte colony-stimulating factor (G-CSF), and (5) monocyte colony-stimulating factor (MCSF).These factors are formed by activated macrophage cells in the inflamed tissues and in smaller quantities by other inflamed tissue cells. The cause of the increased production of granulocytes and monocytes by the bone marrow is mainly the three colony-stimulating factors, one of which, GM-CSF, stimulates both granulocyte and monocyte production; the other two, G-CSF and M-CSF, stimulate granulocyte and monocyte production, respectively. This combination of TNF, IL-1, and colonystimulating factors provides a powerful feedback mechanism that begins with tissue inflammation and proceeds to formation of large numbers of defensive white blood cells that help remove the cause of the inflammation. When neutrophils and macrophages engulf large numbers of bacteria and necrotic tissue, essentially all the neutrophils and many, if not most, of the macrophages eventually die. After several days, a cavity is often excavated in the inflamed tissues that contains varying portions of necrotic tissue, dead neutrophils, dead macrophages, and tissue fluid. This mixture is commonly known as pus. After the

infection has been suppressed, the dead cells and necrotic tissue in the pus gradually autolyze over a period of days, and the end products are eventually absorbed into the surrounding tissues and lymph until most of the evidence of tissue damage is gone.

3. Describe the volume and pressure changes in the different thoracic compartments during inspiration and expiration. Pleural pressure is the pressure of the fluid in the thin space between the lung pleura and the chest wall pleura. The normal pleural pressure at the beginning of inspiration is about 5 centimeters of water, which is the amount of suction required to hold the lungs open to their resting level. Then, during normal inspiration, expansion of the chest cage pulls outward on the lungs with greater force and creates more negative pressure, to an average of about 7.5 centimeters of water. Alveolar pressure is the pressure of the air inside the lung alveoli. during normal inspiration, alveolar pressure decreases to about 1 centimeter of water. This slight negative pressure is enough to pull 0.5 liter of air into the lungs in the 2 seconds required for normal quiet inspiration. During expiration, opposite pressures occur: The alveolar pressure rises to about +1 centimeter of water, and this forces the 0.5 liter of inspired air out of the lungs during the 2 to 3 seconds of expiration. The transpulmonary pressure is the pressure difference between that in the alveoli and that on the outer surfaces of the lungs, and it is a measure of the elastic forces in the lungs that tend to collapse the lungs at each instant of respiration, called the recoil pressure. The extent to which the lungs will expand for each unit increase in transpulmonary pressure (if enough time is allowed to reach equilibrium) is called the lung compliance. The total compliance of both lungs together in the normal adult human being averages about 200 milliliters of air per centimeter of water transpulmonary pressure. That is, every time the transpulmonary pressure increases 1 centimeter of water, the lung volume, after 10 to 20 seconds, will expand 200 milliliters.

4. Define the different lung volumes. Give the approximate values in adults for Tidal Volume, Residual Volume, Vital Capacity and anatomic dead space. The air in the lungs has been subdivided into four volumes and four capacities, which are average for a young adult man. The four listed pulmonary lung volumes, when added together equal the maximum volume to which the lungs can be expanded. The Tidal volume is the volume of air inspired or expired with each normal breath; it amounts to 500 milliliters in the adult male. The Inspiratory reserve volume is the extra volume of air that can be inspired over and above the normal tidal volume when the person inspires with full force. The Expiratory reserve volume is the maximum extra volume of air that can be expired by forceful expiration after the end of a normal tidal expiration after the end of a normal tidal expiration. The residual volume is the volume of air remaining in the lungs after the most forceful expiration; this volume averages about 1200 milliliters. When two or more volumes are considered, such combinations are called pulmonary capacities. These can be described as Inspiratory capacity which equals the tidal volume plus the inspiratory reserve volume; Functional residual capacity which equals the expiratory reserve volume plus residual volume; Vital capacity, which equals the inspiratory reserve volume plus the tidal volume plus the expiratory reserve volume, is about 4600 molliliters; and Total lung capacity, which is the maximum volume which lungs can be expanded with the greatest effort, is equal to the vital capacity plus the residual volume. The anatomic dead space is the volume of all the space of the respiratory system other than the alveoli and their other closely related gas exchange areas. This space equals 1 to 2 liters.

5. Define compliance in the lungs and correlate it with surfactant. Compliance refers to the extent to which the lungs will expand for each unit increase in transpulmonary pressure. If there is an increase in volume there would also be an increase in pressure. Transpulmonary pressure refers to the difference in pressure between the alveoli and the outer surface of the lings and is measured by the elastic forces in the lungs. There are two elastic forces in lungs: (1) elastic forces of the lung tissue and (2) the elastic forces caused by the surface tension of the fluid that lines the inside walls of the alveoli and other lungs spaces. When the lungs are fillled with air, there is an interface between the alveolar fluid and the air in the alveoli. Surface tension is formed when the water forms a surface in with air, the water molecules will exert strong attraction for one another causing these molecules to contract for them to hold together. In the case of the surface tension in the alveoli, the walls of the alveoli are coated with thin film of water. These water molecules are more attracted with each other than to air creating a surface tension. This tension increases as the water molecules come closer together which what happens when we exhale wherein our alveoli become smaller (like a deflating balloon). The water molecules will contract forcing the air out thus causing the alveoli to collapse. If this occurs the lungs would have difficulty to re-expand when you inhale. The role of surfactants in the lungs is to reduce the fluid-air surface tension to allow the lungs to expand fully when we inhale. Surfactants are produced by the type II alveolar epithelial cells, this is a surface active agent which functions to reduce the surface tension of water. It is composed of several phospholipids with hydrophobic tails. The hydrophobic tails comes closer together during expiration causing a decrease in surface tension (stage 3-5 in the picture). They move further apart when the alveoli expand. When you exhale, they prevent the water molecules (phospholipids= not soluble to water) to come closer thus decreasing the surface tension.

Remenber in the law of laplace (see formula below) states that the pressure within a sphecial structure with surface tesion is inversely proportional to the radius of the sphere. Hence, small radius (smaller alveoli) will generate bigger pressures with them than that of larger alveoli. Smaller alveoli would therefore be expected to empty into larger alveoli as lung volume decreases. This does not occur, however, because surfactant differentially reduces surface tension, more at lower volumes and less at higher volumes, leading to alveolar stability and reducing the likelihood of alveolar collapse. Smaller alveoli would therefore be expected to empty into larger alveoli as lung volume decreases. This does not occur, however, because surfactant differentiallyreduces surface tension, more at lower volumes and less at higher volumes, leading to alveolar stability and reducing the likelihood of alveolar collapse.

6. Describe how oxygen and carbon dioxide are transported in the lungs and in tissues. Oxygen is not very soluble in plasma. Most oxygen (about 97% of it) is transported via hemoglobin, which has special oxygen-binding capabilities. You would want it to bind to significant quantities of oxygen at the alveolar level, even when oxygen concentration in the alveoli is relatively low. You would, on the other hand, also like hemoglobin to release oxygen easily at the tissue level, but in just the right amounts, since too much can cause oxygen toxicity, and too little will not provide enough for the respiratory needs of the tissue. You would like hemoglobin to release large quantities of oxygen when the tissues really need it. Considering the oxygen dissociation curve, however, note that if alveolar pO2 levels fall really low, particularly below 40 (example at an altitude of 20,000ft or in condition where adequate amounts of oxygen do not reach the alveoli) hemoglobin will falter in trapping o2 and the patient will go downhill. Hemoglobin does not transport most of the carbon dioxide. Rather, CO2 combines with water in the RBC to form H2CO3 (the enzyme carbonic anhydrase in the RBC catalyzes this reaction). The H from the H2CO3 combines with the hemoglobin; HCO3 leaves the call and floats around in the blood until the blood reaches the lungs. Then the hemoglobin releases the H, which combines with bicarbonate ion to reform CO2, which is then expelled by the lungs. Some CO2 does, however, combine directly with hemoglobin (about 25%) to form carbaminohemoglobin, which releases its CO2 in the lungs. Additionally, a small amount of CO2 (about 5%) dissolves directly in the plasma.

7. Explain how breathing is regulated by pO2 and pCO2 Moderate increase of pCo2 stimulates respiration much more than does a moderate decrease in pO2. Moderate increases in pCO2 results in increased respiratory rate, without requiring much assistance from the stimulus of decreased O2. However, in severe pulmonary disease, in which there is poor exchange in both o2 and CO2, the CO2 effect is not enough. The large drop in PO2 then comes into play having a marked effect in increasing the rate of respiration when the PO2 falls to the 30-60mmHg range.

8. Compare the changes in membrane potential associated with an associated in a nodal pacemaker cell with those in a myocardial cell. What (mechanism/s) is/are responsible for such changes in membrane potential? Cardiac Action Potential The resting membrane potential is determined by the conductance to potassium and approaches the potassium equilibrium potential. Inward current brings positive charge into the cell and depolarizes the membrane potential. Outward current takes positive charge out of the cell and hyperpolarizes the membrane potential. The role of the sodium-potassium ATPase is to maintain ion gradients across the cell membrane

Mechanism of Ca extrusion Na-Ca Exchanger Na in then Ca out; 3Na:1Ca, higher concentration Na-K-ATPase pump lower concentration, Na concentration gradient outside the cell goes inside Ca pump strength of the muscular contraction is determined by the amount of Ca which interacts with the myofilament, Ca remains in the cell Increase Ca=Increase contraction = Increase cardiac performance

9. Discuss how a ventricular action potential develops. What changes occur in terms of: 1) membrane permeability, 2) ionic fluxes and 3) membrane potential? How do these changes come about? How is the development of a pacemaker potential any different from the development of a ventricular action potential? SLOW-RESPONSE ACTION POTENTIAL -SA node (normally the pacemaker of the heart) -does not have a constant resting potential -exhibits phase 4 depolarization of automatically due to: --gradual decrease in the permeability of membrane to potassium, therefore sodium is prevented from leaking out --increase in the permeability to sodium, therefore sodium moves into the cell; Na-K permeability ratio increases; membrane potential approaches a more positive value --increase permeability to calcium; net movement it towards the cell PHASES: Phase 0-upstroke of action potential = increase Ca Phase 3-repolarization = increase in K Phase 4-slow depolarization = increase Na Phases 1&2 are not present FAST-RESPONSE ACTION POTENTIAL -atrial muscle, purkinje fibers, ventricular muscle -have a stab;e resting membrane potential of about 90mV which approaches the potassium equilibrium potential -action potential are of long duration (200-300 milliseconds) PHASES: Phase 0-rapid upstroke = influx Na Phase 1-initial repolarization = efflux K Phase 2-plateau = slow Ca channels are opened so influx Ca Phase 3-repolarization = Ca channels close but permeable to sodium so influx of Na Phase 4-resting membrane potential = inward and outward currents are equal

*questions 8 & 9 is a bit confusing. If you find it wrong, please catch my attention and feel free to correct it. -bebe

10. CARDIAC CYCLE - Initiated by the action potential in the sinus node, traveling rapidly through both atria and then through the AV bundle into the ventricles. - Total duration of the cardiac cycle is reciprocal of heart rate ex: HR= 72 beats/min; Cardiac cycle=1/72 beats/min therefore, an increase in heart rate, is a decrease in Cardiac cycle

PERIOD I: FILLING OF VENTRICLES DURING DIASTOLE Ventricular Systole AV valves are closed that will give large amounts of blood accumulating in both atria P wave (depolarization in atria) Slight rise in ATRIAL PRESSURE will push AV valves open VENTRICULAR PRESSURE will fall Rapid blood flow to ventricles will increase VENTRICULAR VOLUME PERIOD II: PERIOD OF ISOVOLUMIC (ISOMETRIC) CONTRACTION Increase in tension but no shortening of muscle fiber Period of contraction but no emptying QRS wave (depolarization in ventricles) and 1st Heart Sound (low pitch, long lasting) Ventricles contract

Increase VENTRICULAR PRESSURE AV valves close Semilunar valves open PERIOD III: EJECTION Blood pours out of ventricles 1st (Rapid ejection) Decrease in VOLUME 2nd (Slow ejection)

PERIOD IV: PERIOD OF ISOVOLUMIC (ISOMETRIC) RELAXATION T wave (Repolarization of Ventricles) and Ventricular Diastole Decrease in VENTRICULAR PRESSURE VOLUME is same 2nd Heart Sound Pulmonary valves close AV valves open

11. FACTORS AFFECTING MYOCARDIAL OXYGEN CONSUMPTION (MVO2). A. Increase MVO2: Increase in Heart Rate, Inotropy, Afterload, Preload. HR = because myocytes are generating twice the number of tension cycles per minute. INOTROPY = because both the rate of tension development and the magnitude of tension are increased, and they both are associated with increased ATP hydrolysis and oxygen consumption. AFTERLOAD = because it increases the tension that must be developed by myocytes. PRELOAD = Increasing stroke volume by increasing preload (end-diastolic volume) B. IN A NORMAL HEART, HOW WOULD CHANGES IN THESE FACTORS AFFECT CORONARY BLOOD FLOW? Coronary blood flow is phasic as determined by systole and diastole. Left coronary flow decreases during systole and reaches a peak early in diastole. Under resting conditions, coronary venous blood contains little oxygen, and increased myocardial oxygen consumption must be met by increased coronary blood flow.

12. WHY IS TETANUS OF CARDIAC MUSCLE IMPOSSIBLE? WHY IS THIS ADVANTAGEOUS? A long refractory period prevents tetanus in cardiac muscle. The long refractory period means that cardiac muscle cannot be restimulated until contraction is almost over & this makes summation (& tetanus) of cardiac muscle impossible. This is a valuable protective mechanism because pumping requires alternate periods of contraction & relaxation; prolonged tetanus would prove fatal.

13. What are the factors that affect cardiac output? Before we talk about that, let's define what cardiac output is. Cardiac output is the volume of blood ejected by the left and right ventricle.

STROKE VOLUME x HEART RATE = CARDIAC OUTPUT / (SV x HR = CO) STROKE VOLUME - measuring the volume of blood present within the left ventricle just prior to contraction and measuring the volume of blood present after the full contraction is complete

The factors that affect the cardiac output are the following:

1. Contractility - the more the heart contracts, the more blood gets pumped per beat, increasing stroke volume and cardiac output; higher contractility will result to an increase in cardiac output

2. Preload- filling of the heart chambers with a certain amount of blood right BEFORE it contracts; "end diastolic volume"; An increase in the filling of heart chambers with blood would increase the stretching of the cardiac muscle fibers as well as the stroke volume

3. Afterload - pressure the heart must overcome to eject the blood into the rest of the body; "mean arterial pressure". A change in pressure could affect the cardiac performance so when the aortic pressure increases, the stroke volume decreases.

14. Discuss the short-term regulation of blood pressure. BLOOD PRESSURE = CARDIAC OUTPUT x PERIPHERAL RESISTANCE Short term control of Blood pressure is mediated by the nervous system, chemicals and hormones that control blood pressure by changing peripheral resistance. ( = in sec / minutes) a. Nervous system: Control blood pressure by changing blood distribution in the body and by changing blood vessel diameter. ANS sympathetic veins, arteries, heart control HR and force of contraction Parasympathetic The vasomotor center is a cluster of sympathetic neurons found in the medulla. It sends efferent motor fibers that innervate smooth muscle of blood vessels. Any increase in sympathetic activity causes vasoconstriction and any decreased sympathetic activity leads to vasodilation. Baroreceptors are stretch receptors found in the carotid body, aortic body and the wall of all large arteries of the neck and thorax. When BP activation of baroreceptors send impulses (APs) to the vasomotor center inhibition of vasomotor center

parasympathetic activity HR

sympathetic activity force of contraction and HR vasodilation of arteries and veins peripheral resistance and vessel diameter

CO and PR Blood Pressure

 When BP inhibition of baroreceptors send impulses (APs) to the vasomotor center activation of vasomotor center

parasympathetic activity HR

sympathetic activity force of contraction and HR vasoconstriction of arteries and veins peripheral resistance and vessel diameter

CO and PR Blood Pressure

There is dual regulation by both sympathetic and parasympathetic to control a rise in BP. The baroreflex is the fastest regulation method for blood pressure.

b. Chemoreceptors: these respond to changes in pCO2 and pO2 and PH levels. When pO2 and PH and pCO2 Stimulation of vasomotor center CO and HR and vasoconstriction BP (speeding return of blood to the heart and lungs) c. Hormones: bloodborne chemicals Adrenal Medulla Hormones (epinephrine & norepinephrine) When the body is stressed, adrenal medulla releases NE and E into the blood enhance sympathetic activity. NE vasoconstriction E CO and HR (it also promotes generalized vasoconstriction except in skeletal and cardiac muscle where it causes vasodilation) Atrial Natriuretic Peptide (ANP) Produced by heart atrium Natri release of Na+ Uretic excretion of urine It promotes the excretion of Na+ from the body water also is excreted Blood Volume Blood Pressure. Antidiuretic Hormone (ADH) Decrease the excretion of water Leads to blood volume BP. Endothelial factors Local system in the blood vessel endothelium

Release of endothelin vasoconstriction NO Nitric Oxide vasodilation NO works for a small time only because it is quickly destroyed. Represents fine minute regulation at the tissue level

15. Discuss the factors that affect fluid flow in rigid tubes. The factors that affect fluid flow are distensibility of the blood vessels, pressure and constant flow. Flow Flow is more likely to be turbulent if: Velocity is high Viscosity of blood is low Blood vessel diameter is high The conditions for turbulence are summarised in the Reynolds Number Note that turbulent flow is noisy and will give rise to sounds or murmurs In turbulent flow, the resistance to flow is increased Turbulent flow results in damage to endothelium

Distensibility and Pressure Blood Vessels are not rigid They are distensible especially so with veins They have blood inside them under pressure They may have external pressures acting on them Transmural pressure = Pintravascular Pextravascular With a rigid tube, resistance is constant. With a distensible tube, an increase in pressure stretches walls lowering resistance: tendency for resistance to fall with increasing pressure 16. DISCUSS THE LOCAL AND EXTRINSIC CONTROLS THAT REGULATE ARTERIOLAR PRESSURE. Local Control temperature; Heat application will dilate arterioles and cold application constricts them. Extrinsic sympathetic control is important in regulating blood pressure Increased sympathetic activity will lead to vasoconstriction, while decreased sympathetic activity will lead to arteriolar vasodilation. If vasodilated decrease in pressure, and vice-versa if vasoconstricted.

17. Discuss the factors the determine mean arterial pressure a. Total Peripheral Resistance (TPA) Blood vessels provide resistance to the flow of blood because of friction between moving blood and the wall of the vessel. The TPA refers to the sum total of vascular resistance to the flow of blood in the systemic circulation. Because of their small radii, arterioles provide the greatest resistance to blood flow in the arterial system. Adjustments in the radii of arterioles has a significant effect on TPA, which in turn has a significant effect on MAP. Resistance and pressure are directly proportional to each other. If resistance increases, then pressure increases. When the radii of arterioles decrease with vasoconstriction, TPA increases, which causes MAP to increase. b. Cardiac Output Cardiac output refers to the volume of blood pumped by the heart each minute. Put another way, the cardiac output is a measure of blood flow into the arterial system. Blood flow is directly proportional to pressure (Flow = pressure/resistance), therefore an increase in flow (cardiac output) will cause an increase in pressure (MAP). c. Blood Volume Blood volume is directly related to blood pressure. If the blood volume is increased, then venous return of blood to the heart will increase. An increase in venous return will, by Starling's Law, cause stroke volume to increase. As stroke volume goes up the cardiac output goes up and the blood pressure rises. Thus one way to control blood pressure over the long term is to control blood volume.

18. Describe the extrinsic and intrinsic innervation of the gastrointestina tract and explain their effects on GI motility and secretion. a. Intrinsic innervation: Myenteric Plexus/Auerbachs Plexus an outer plexus lyins between the longitudinal and circular muscle layers - not considered as excitatory since some of the neurons are INHIBITORY; its inhiboitory signals are used for inhibiting the intestinal sphincter muscles that impede food between segments of the g.i. tract, such as the pyloric sphincter, which controls emptying of the stomach into the duodenum, and the sphincter of the ileocecal valve, which controls emptying of the small intestine into the cecum. Submucosal Plexus/Meissners Plexus an inner place that lies in the submucosa - mainly concerned with controlling function within the inner wall of each minute segment of the intestine; helps control local intestinal secretion, local absorption, and local contraction of the submucosal muscle that cause various degrees of infolding of the g.i. mucosa. b. Extrinsic Innervation Sympathetic the sympathetic nerve endings secrete mostly norepinephrine; stimulation inhibits activity of the g.i. tract and exerts its effect in two ways: one, to a slight extent by direct effect of the secreted norepinephrine to inhibit the smooth muscle and two, to a major extent

by the inhibitory effect of the norepinephrine on the neurons of the enteric nervous system. Hence, when sympathetic nerve fibers are stimulated, it can inhibit motor movements of the gut to a point that it can block movement of food through the gastrointestinal tract. Parasympathetic the parasympathetic supply is divided into cranial and sacral divisions. The cranial divisions are transmitted almost entirely in the vagus nerves which provide innervations to the esophagus, stomach and pancreas, while the sacral divisions originate in the second, third, and fourth sacral segments of the spinal cord and pass through the pelvic nerves to the distal half of the large intestine.

19) Describe how peristalsis in the GI propels content analward. Reflexes occur over considerable distances (1) intestinointestinal overdistention in one segment causes relaxation in other (2) ileogastric distention of ileum decreases gastric motility (3) gastroileal gastric motility stimulates movement through ileocecal sphincter Obstructions occur from cancer, ulcers, hernia, or paralytic ileus (loss of motility following abdominal trauma or surgery) *type of vomit indicates location above pylorus is acidic, below pylorus is basic high obstruction produces intense vomiting, low obstruction leads to constipation and delayed vomiting Emptying ileocecal sphincter is relaxed by ileal peristalsis, distention of terminal ileum, or gastroileal reflex Motility of the Colon The colon absorbs water and electrolytes (in ascending colon), stores fecal matter, and eliminates waste. Longitundinal muscle is gathered into three narrow bands (teniae coli) two anal sphincters internal consists of smooth muscle, external of striated Innervation parasymp. innervation is from the vagus nerve above transverse colon and from the pelvic nerve below. Sympathetic decreases motility, parasymp. increases segmental movements and produces sustained contractions *external anal sphincter is innervated by somatic motor fibers both voluntary and reflex control Haustration segments (haustra) mix and knead contents Mass Movement periodic (1-3 per day) sustained contractions that move material forward can be triggered by reflex from stomach (gastrocolic reflex) or duodenum (duodenalcolic reflex) Defecation mass movement of feces into rectum causes internal sphincter relaxation and external sphincter contraction

*voluntary relaxation of external sphincter initiates defecation control of muscle is learned behavior *if no motor nerves to external sphincter (babies or lower spinal damage), defecation is automatic upon filling of rectum

20) Describe the regulation of gastric acid secretion. Gastric acid is produced by parietal cells (oxyntic cells) in the stomach. The canaliculi, which is an extensive secretory network of parietal cells (part of the epithelial fundic glands in the gastric mucosa), secretes acid into the lumen of the stomach. The acidity is maintained by the H+/K+ ATPase proton pump which allows parietal cells to release bicarbonate into the blood stream, which causes a temporary rise in pH (alkaline tide). The resulting highly acidic environment in the stomach lumen causes proteins from food to lose their characteristic folded structure (or denature). This exposes the protein's peptide bonds. The chief cells of the stomach secrete enzymes for protein breakdown (inactive pepsinogen and rennin). HCl activates pepsinogen into the enzyme pepsin, which then helps digestion by breaking the bonds linking amino acids, a process known as proteolysis. Gastric acid production is regulated by both the autonomic nervous system and several hormones. The parasympathetic nervous system, via the vagus nerve, and the hormone gastrin stimulate the parietal cell to produce gastric acid, both directly acting on parietal cells and indirectly, through the stimulation of the secretion of the hormone histamine from enterochromaffine-like cells (ECL). Vasoactive intestinal peptide, cholecystokinin, and secretin all inhibit production. The production of gastric acid in the stomach is tightly regulated by positive regulators and negative feedback mechanisms. Four types of cells are involved in this process: parietal cells, G cells, D cells and enterochromaffine-like cells. Besides this, the endings of the vagus nerve (CN X) and the intramural nervous plexus in the digestive tract influence the secretion significantly. Nerve endings in the stomach secrete two stimulatory neurotransmitters: acetylcholine and gastrin-releasing peptide. Their action is both direct on parietal cells and mediated through the secretion of gastrin from G cells and histamine from enterochromaffine-like cells. Gastrin acts on parietal cells directly and indirectly too, by stimulating the release of histamine. The release of histamine is the most important positive regulation mechanism of the secretion of gastric acid in the stomach. Its release is stimulated by gastrin and acetylcholine and inhibited by somatostatin.

21) Explain how the gastric mucosal barrier protects the stomach. Gastric Mucosal Barrier The gastric mucosal barrier is the property of the stomach that allows it to contain acid.

If the barrier is broken, as by acetylsalicylic acid (ASS, aspirin) in acid solution, acid diffuses back into the mucosa where it can cause damage to the stomach itself. The barrier consists of three protective components [1]. These provide the additional resistance for the mucosal surface of the stomach. The three components include: a compact epithelial cell lining o Cells in the epithelium of the stomach are bound by tight junctions that repel harsh fluids that may injure the stomach lining. a special mucus covering o The mucus covering is derived from mucus secreted by surface epithelial cells and mucosal neck cells. This insoluble mucus forms a protective gel-like coating over the entire surface of the gastric mucosa. The mucus protects the gastric mucosa from autodigestion by e.g. pepsin and from erosion by acids and other caustic materials that are ingested. bicarbonate ions o The bicarbonate ions are secreted by the surface epithelial cells. The bicarbonate ions act to neutralize harsh acids.

Diagram of alkaline Mucous layer in stomach with mucosal defense mechanisms

22) Describe the disgestion of carbohydrates, proteins and lipids along the length of the GIT. Digestion can occur at many levels in the body; generally, it refers to the breakdown of macro-molecules or a matrix of cells, or tissues, into smaller molecules and component parts. This

particular section will focus on digestion of food in the gastrointestinal tract: the process that is required to obtain essential nutrients from the food we eat. The gastrointestinal tract (GIT) is a highly specialized organ system that allows humans to consume food in discrete meals as well as in a very diverse array of foodstuffs to meet nutrient needs. Figure 1 contains a schematic of the GIT and illustrates the organs of the body with which food comes into contact during its digestion. These organs include the mouth, esophagus, stomach, small intestine, and large intestine; in addition, the pancreas and liver secrete into the intestine. The system is connected to the vascular, lymphatic, and nervous systems; however, the function of these systems in gastrointestinal physiology is beyond the scope of this article, which focuses primarily on the process of breaking down macromolecules and the matrix of food. Mechanical Aspects of Digestion Food is masticated in the mouth. Chewing breaks food into smaller particles that can mix more readily with the GIT secretions. In the mouth, saliva lubricates the food bolus so that it passes readily through the esophagus to the stomach. The sensory aspects of food stimulate the flow of saliva, which not only lubricates the bolus of food but is protective and contains digestive enzymes. Swallowing is regulated by sphincter actions to move the bolus of food into the stomach. The motility of the stomach continues the process of mixing food with the digestive secretions, now including gastric juice, which contains acid and some digestive enzymes. The action of the stomach continues to break down food into smaller particles prior to passage to the intestine. The mixture of food and digestive juices is referred to as digesta, or chyme. The stomach, which after a meal may contain more than a liter of material, regulates the rate of digestion by metering chyme into the small intestine over several hours. Several factors can slow the rate of gastric emptying; for example, solids take longer to empty than liquids, mixtures relatively high in lipid take longer to empty, and viscous, or thick, mixtures take longer to empty than watery, liquid contents. In the upper part of the small intestine, the duodenum, receptors appear to influence the rate of gastric emptying either through hormonal or neural signals. Peristaltic motor activity in the small intestine propels chyme along the length of the intestine, and segmentation allows mixing with digestive juices in the intestine, which include pancreatic enzymes, bile acids, and sloughed intestinal cells. Digestion of macronutrients, which began in the mouth, continues in the small intestine, where the intestinal surface provides an immense absorptive surface to allow absorption of digested molecules into circulation. While the intestine from the outside appears to be a tube, the lining of the inner surface contains tissue folds and villi that are lined with intestinal cells, each with microvilli, or a brush border, which greatly amplify the absorptive surface. The intestinal cells can absorb compounds by several cell membraneediated transport mechanisms and then transform them into compounds, or complexes, that can enter circulation through the blood, or lymphatic, system. What is not digested and absorbed passes into the large intestine. In this organ, water and electrolytes are reabsorbed, and the movements of the large intestine allow mixing of the contents with the microflora of bacteria and other microbes that are naturally present in the large intestine. These microbes continue the process of digesting the chyme. Eventually the residue enters the rectum and the anal canal, and stool is formed, which is defecated. Transit time of a non-digestible marker from mouth

to elimination in the stool varies considerably: normal transit time is typically twenty-four to thirty-six hours, but can be as long as seventy-two hours in otherwise healthy individuals. Breakdown of Macromolecules in Foods Foods are derived from the tissues of plants and animals as well as from various microorganisms. For absorption of nutrients from the gut to occur, the cellular and molecular structure of these tissues must be broken down. The mechanical actions of the GIT help disrupt the matrix of foods, and the macromolecules, including proteins, carbohydrates and lipids, are digested through the action of digestive enzymes. This digestion produces smaller, lower molecular weight molecules that can be transported into the intestinal cells to be processed for transport in blood, or lymph. Proteins are polymers of amino acids that in their native structure are three-dimensional. Many cooking or processing methods denature proteins, disrupting their tertiary structure. Denaturation, which makes the peptide linkages more available to digestive enzymes, is continued in the stomach with exposure to gastric acid. In addition, digestion of the peptide chain begins in the stomach with the enzyme pepsin. Once food enters the small intestine, enzymes secreted by the pancreas continue the process of hydrolyzing the peptide chain either by cleaving amino acids from the C-terminal end, or by hydrolyzing certain peptide bonds along the protein molecule. The active forms of the pancreatic enzymes include trypsin, chymotrypsin, elastase, and carboxypeptidase A and B. This process of protein digestion produces small peptide fragments and free amino acids. The brush border surface of the small intestine contains peptidases, which continue the digestion of peptides, either to smaller peptide fragments or free amino acids, and these products are absorbed by the intestinal cells. Carbohydrates are categorized as digestible or non-digestible. Digestible carbohydrates are the various sugar-containing molecules that can be digested by amylase or the saccharidases of the small intestine to sugars that can be absorbed from the intestine. The predominant digestible carbohydrates in foods are starch, sucrose, lactose (milk sugar), and maltose. Glycogen is a glucose polymer found in some animal tissue; its structure is similar to some forms of starch. Foods may also contain simple sugars such as glucose or fructose that do not need to be digested before absorption by the gut. Alpha amylase, which hydrolyzes the alpha one to four linkages in starch, is secreted in the mouth from salivary glands and from the pancreas into the small intestine. The action of amylase produces smaller carbohydrate segments that can be further hydrolyzed to sugars by enzymes at the brush border of the intestinal cells. This hydrolysis step is closely linked with absorption of sugars into the intestinal cells. Non-digestible carbohydrates cannot be digested by the enzymes in the small intestine and are the primary component of dietary fiber. The most abundant polysaccharide in plant tissue is cellulose, which is a glucose polymer with beta one to four links between the sugars. Amylase, the starch-digesting enzyme of the small intestine, can only hydrolyze alpha links. The non-digestible carbohydrates also include hemicelluloses, pectins, gums, oligofructose, and inulin. While non-digestible, they do affect the digestive process because they provide bulk in the intestinal contents, hold water, can become viscous, or thick, in the intestinal contents, and delay gastric emptying. In addition, non-starch polysaccharides are the primary substrate for growth of the microorganisms in the large intestine and contribute to stool formation and laxation. Products of microbial action include ammonia, gas, and short-chain fatty acids (SCFA). SCFA are used by cells in the large intestine for energy and some appear in the circulation and

can be used by other cells in the body for energy as well. Thus, while dietary fiber is classified as nondigestible carbohydrate, the eventual digestion of these polysaccharides by microbes does provide energy to the body. Current research is focused on the potential effect of SCFA on the health of the intestine and their possible role in prevention of gastrointestinal diseases. For dietary lipids to be digested and absorbed, they must be emulsified in the aqueous environment of the intestinal contents; thus bile salts are as important as lipolytic enzymes for fat digestion and absorption. Dietary lipids include fatty acids esterified to a glycerol backbone (mono-, di-or triglycerides); phospholipids; sterols, which may be esterified; waxes; and the fat-soluble vitamins, A, D, E, and K. Digestion of triglycerides (TG), phospholipids (PL), and sterols illustrate the key factors in digestion of lipids. Lipases hydrolyze ester bonds and release fatty acids. In TG and PL, the fatty acids are esterified to a glycerol backbone, and in sterols, to a sterol nucleus such as cholesterol. Lipases that digest lipids are found in food, and are secreted in the mouth and stomach and from the pancreas into the small intestine. Lipases in food are not essential for normal fat digestion; however, lipase associated with breast milk is especially important for newborn infants. In adults the pancreatic lipase system is the most important for lipid digestion. This system involves an interaction between lipase, colipase, and bile salts that leads to rapid hydrolysis of fatty acids from TG. An important step in the process is formation of micelles, which allows the lipid aggregates to be miscible in the aqueous environment of the intestine. In mixed micelles, bile salts and PL function as emulsifying agents and are located on the surface of these spherical particles. Lipophilic compounds such as MG, DG, free sterols, and fatty acids, as well as fat-soluble vitamins, are in the core of the particle. Micelles can move lipids to the intestinal cell surface, where the lipids can be transported through the cell membrane and eventually packaged by the intestinal cells for transport in blood or lymph. Most absorbed lipid is carried in chylomicrons, large lipoproteins that appear in the blood after a meal and which are cleared rapidly in healthy individuals. Bile salts are absorbed from the lower part of the small intestine, returned to the liver, and resecreted into the intestine, a process referred to as enterohepatic circulation. It is important to note that bile salts are made from cholesterol, and drugs such as cholestyramine or diet components such as fiber that decrease the amount of bile salt reabsorbed from the intestine help to lower plasma cholesterol concentrations. Regulation of Gastrointestinal Function Regulation of the gastrointestinal response to a meal involves a complex set of hormone and neural interactions. The complexity of this system derives from the fact that part of the response is directed at preparing the GIT to digest and absorb the meal that has been consumed in an efficient manner and also at signaling short-term satiety so that feeding is terminated at an appropriate point. Traditionally, physiologists have viewed the regulation in three phases: cephalic, gastric, and intestinal. In the cephalic phase, the sight, smell, and taste of foods stimulates the secretion of digestive juices into the mouth, stomach, and intestine, essentially preparing these organs to digest the foods to be consumed. Experiments in which animals are sham fed so that food consumed does not actually enter the stomach or intestine demonstrate that the cephalic phase accounts for a significant portion of the secretion into the gut. The gastric and intestinal phases occur when food and its components are in direct contact with

the stomach or intestine, respectively. During these phases, the distension of the organs with food as well as the specific composition of the food can stimulate a GIT response. The GIT, the richest endocrine organ in the body, contains a vast array of peptides; however, the exact physiological function of each of these compounds has not been established. Five peptides, gastrin, cholecystokinin (CCK), secretin, gastric inhibitory peptide (GIP), and motilin are established as regulatory hormones in the GIT. Multiple aspects have been investigated to understand their release and action. For example, CCK is located in the upper small intestine; protein and fat stimulate its release from the intestine, while acid inhibits its secretion. Once released, it can inhibit gastric emptying and stimulate secretion of acid and pancreatic juice and contraction of the gall bladder. In addition, it stimulates motility and growth in the GIT and regulates food intake and insulin release. Among the other established gastrointestinal peptides, secretin stimulates secretion of fluid and bicarbonate from the pancreas, gastrin stimulates secretion in the stomach, GIP inhibits gastric acid secretion, and motilin stimulates the motility of the upper GIT. In addition to investigating the various factors causing release of these hormones and the response to them, physiologists are also interested in the interactions among hormones as well as those with the nervous system, since the response to a meal involves release of many factors. Obtaining food and digesting it efficiently are paramount to survival. The human GIT system most likely evolved during the period when the species acquired its food primarily through hunting and gathering. The over-lapping regulatory systems, combined with an elevated capacity to digest food and absorb nutrients, insured that humans used food efficiently during periods in which scarcity might occur.

23) Describe the defacation reflex and explainhoe defacation occurs in individuals with spinal cord injury. It is a synchronized sequence of events associated with neural influences. There are several reflexes that are related to the physiology of defecation. The rectum is innervated with nerves that initiate reflex contractions upon its distention. These contractions altogether constitute the desire to defecate. The human rectum has two sphincters: the external anal sphincter, and the internal anal sphincter. In the internal anal sphincter, the sympathetic nerve supply towards it is excitatory, while the parasympathetic nerve supply is inhibitory. Thus, this sphincter relaxes when the rectum is being distended. On the other hand, the external anal sphincter, which is a skeletal muscle, is innervated by a branch of the pudendal nerve, and this is maintained in a state of contraction. Even a slight increase or slight distention of the rectum allows it to increase several-fold the force of its contraction. When this rectal pressure rises to approximately 18 mmHg, the urge to defecate arises. However when this reaches 55 mmHg, this means bad news since both the external and internal anal sphincter will relax and therefore, there will be a reflex expulsion of fecal matter! This will explain why in animals, expulsion of rectal contents is not an atypical sight.

Prior to reaching this seemingly embarrassing pressure point of 55 mmHg, defecation can be made voluntarily through straining. Defecation is hence a spinal reflex that can be managed through keeping the external sphincter in its contracted state, or it can be induced through sphincter muscle relaxation and contracting the muscles of the abdomen. Ever wondered why at times the urge to defecate happens after a hearty meal? This is because the stomach, upon distention by food, initiates contraction of the rectum. This is called the gastrocolic reflex, and there are recent studies that it is a function of gastrin on the colon, and not due to any neural influence. That is why in children, it is already a given rule that defecation should occur after meals. In abnormalities involving the colon, these reflexes may be impaired, but not necessarily. It is important to have quite a little bit of knowledge as to how the mechanism of defecation works, so it would be easier to understand the abnormal conditions. Function of the Bowel Following a Spinal Cord Injury Following a spinal cord injury, damage to the spinal cord may result in the loss of the ability to control the bowel reflex when the rectum is full, or the reflex to empty the rectum may be lost altogether. The function of the bowel is maintained by the nerves entering the spinal cord at the sacral levels of S2 - S4. Due to the voluntary action of the bowel being communicated so low in the spinal cord, any spinal cord injury will usually have some impact on the defecation process. The Reflex Bowel or Upper Motor Neuron Bowel If the spinal cord injury is above T12, the sensation of a full bowel may no longer be detectable by the injured person. In such cases, the anal sphincter will remain closed, however, it will open on a reflex basis when the rectum becomes full. This type of bowel is referred to as an upper motor neuron bowel reflex. As the person will not be able to sense when the rectum is full, the reflex to empty the rectum can happen at any time unless the bowel is managed properly. The upper motor neurone bowel reflex can be managed to prevent accidental defecation, by causing the defecation reflex to occur at a socially appropriate time. The Flaccid Bowel or Lower Motor Neuron Bowel If the spinal cord injury is below T12, then there may be damage to the defecation reflex, and the anal sphincter muscle may relax, staying open. This type of bowel is referred to as an lower motor neuron bowel or flaccid bowel. The lower motor neurone bowel reflex can be managed to prevent accidental defecation, by emptying the bowel more frequently at a socially appropriate time, by bearing down or the manual removal of stool.

Both types of bowel, reflex and flaccid, can be managed to avoid the accidental opening of the bowel, and to avoid constipation and impaction.

24. Discuss the forces involved in glomerular filtration. The GFR depends on the filtration pressure at the level of the glomerulus, but also on the permeability of the glomerular membrane and the surface area of the glomerular membrane. Obviously, no matter how high the filtration pressure, no fluid will filter if the glomerular filtration membrane is not permeable or has zero surface area.

25. Discuss how GFR is regulated. -the mechanisms adjust blood flow into and out of the glomerulus and alter the glomerular capillary surface are available for filtration. It involves renal autoregulation that maintains a constant GFR despite changes in arterial BP with this there is negative feedback control from the JuxtaGlomerular Apparatus which adjusts local blood pressure and therefore blood volume within each glomerulus. This is termed tubuloglomerular autoregulation. The smooth muscle in the renal arterioles also makes local adjustments to blood pressure which adjust for changes in systemic arterial pressure by maintaining the appropriate pressure gradient between the afferent and efferent arterioles. This is termed myogenic autoregulation. Second is hormonal regulation by Renin-Angiotensin thus Rennin activates angiotensinogen to Angiotensin I and it is later further activated by angiotensin-converting enzyme (ACE) to Angiotensin II. Angiotensin I and Angiotensin II, among other influences, increase systemic blood pressure and blood volume which will tend to increase GFR. Third is by antagonistic interplay of Aldosterone and Atrial Natriuretic Peptide (ANP) wherein Aldosterone, from the adrenal cortex, promotes retention of water and sodium ions and excretion of potassium ions, and, therefore, will tend to increase GFR. Atrial Natriuretic Peptide (ANP) from the atrial walls of the heart promotes retention of potassium ions and excretion of water and sodium ions, and, therefore, will tend to decrease GFR.

26. What establishes a vertical osmotic gradient in the medullary interstitial fluid? Of what importance is this gradient? Interstitial Fluid concentration is 300 mOsm/L at the cortex, and 1200 mOsm/L at the Medulla and the increasing concentrations are called a Vertical Osmotic Gradient. The active transport pump moves NaCl out of the tubule in the ascending Loop of Henle which is impermeable to water and the descending limb is the only part that does not pump Na+ out, and it is permeable to water, increasing concentration inside the tubule The Countercurrent flow of fluid is also necessary for the Vertical Osmotic Gradient

27. Discuss the function and mechanism of action of ADH. The primary function of ADH in the body is to regulate extracellular fluid volume by affecting renal handling of water in which it limits the amount of water being lost in the urine by increasing the amount of water being reabsorbed into the blood, although it is also a vasoconstrictor and pressor agent (hence, the name "vasopressin"). ADH acts on renal collecting ducts via V2 receptors to increase water permeability (cAMP-dependent mechanism), which leads to decreased urine formation (hence, the antidiuretic action of "antidiuretic hormone"). This increases blood volume, cardiac output and arterial pressure.

28. Define plasma clearance. How is this related to the GFR? Plasma clearance is the measure of the filtration capability of the kidney. it has a direct relationship to the GFR of the kidney and factors regulated to maintain body fluid balance is plasma osmolality attributing it to ECF Na concentration and ECF water volume. in order to maintain a normal 300 osmol of the ECF of the blood ADH is secreted acting on the collecting tubules of the kidney depending on how much water is to be secreted to maintain balance.

29. What factors are regulated to maintain the bodys fluid balance? The factors that need to be regulated are: input and output of water, ADH and Aldosterone. Input of water is regulated primarily by changes in the volume ingested (controlled by thirst). An insufficiency of water results in an increased osmolarity in the extracellular fluid. This is sensed by osmoreceptors, which trigger thirst. Output of water is regulated primarily by changes in urine volume (controlled by level of ADH). The body's homeostatic control mechanisms, which maintain a constant internal environment, ensure that a balance between fluid gain and fluid loss is maintained. The hormones ADH (also known as vasopressin) and Aldosterone play a major role in this. If the body is becoming fluid-deficient, there will be an increase in the secretion of these hormones, causing fluid to be retained by the kidneys and urine output to be reduced. Conversely, if fluid levels are excessive, secretion of these hormones is suppressed, resulting in less retention of fluid by the kidneys and a subsequent increase in the volume of urine produced.

30. How is the plasma concentration of a hormone normally regulated? The plasma concentration of a hormone is normally regulated by changes in its rate of secretion, and depends on three factors: 1) hormone's rate of secretion into the blood by the endocrine gland

> pulsatility - stimulation causes an increase in the frequency of pulses. 2) Hormone's rate of removal from the blood by metabolic inactivation in the liver and/or excretion in the urine 3) its extent of binding to plasma proteins

31. Discuss the contributions of parathyroid hormone, calcitonin, and vit. D to Ca++ metabolism. Describe the source and control of each of these hormones -Parathyroid hormone: PTH is synthesized and stored in the chief cells of the parathyroid glands. Synthesis is regulated by a feedback mechanism involving the level of blood calcium (and, to a lesser degree, magnesium). The primary function of PTH is to control calcium concentration in the extracellular fluid, which it does by affecting the rate of transfer of calcium into and out of bone, resorption in the kidneys, and absorption from the GI tract. The effect on the kidneys is the most rapid, causing reabsorption of calcium and excretion of phosphorus. The major initial effect on bone is to mobilize calcium from the bone to the extracellular fluid; later, bone formation may be enhanced. PTH does not directly affect calcium absorption from the gut. Its effect is mediated indirectly by regulation of synthesis of the active metabolite of vitamin D.

-Calcitonin: Is a 32-AA polypeptide hormone secreted by the parafollicular cells of the thyroid gland. The concentration of calcium ion in extracellular fluids is the principal stimulus for the secretion of calcitonin by parafollicular cells. The storage of large amounts of preformed hormone in parafollicular cells and rapid release in response to a moderate rise in circulating calcium probably reflect the physiologic role of calcitonin as an emergency hormone to protect against development of hypercalcemia. Calcitonin exerts its effects by interacting with target cells, primarily in the bone and kidney. The actions of PTH and calcitonin are antagonistic on bone resorption but synergistic on decreasing the renal tubular reabsorption of phosphorus.

The hypocalcemic effects of calcitonin are primarily the result of decreased entry of calcium from the bones into plasma, resulting from a temporary inhibition of PTH-stimulated bone resorption. The hypophosphatemia develops from a direct action of calcitonin, which increases the rate of movement of phosphorus out of plasma into soft tissue and bone and inhibits the bone resorption stimulated by PTH and other factors.

-Vitamin D: Major hormone involved in the regulation of Ca++ metabolism next to PTH. Must be metabolically activated first before it can function physiologically. The biologic actions of vit. D depends on hydroxylation in the liver and kidney to form the biologically active form (1, 25-dihydroxyvitamin D [calcitriol]). This conversion in the kidneys is the rate-limiting step in vit. D metabolism and is partly responsible for the delay between vit. D administration and expression of its biologic effects. PTH = active Vit. D circulating phosphorus conc. =active Vit. D

32. What are the biochemical classes of hormones? How do these classes differ from each other in terms of synthesis, storage, circulation, and mechanism of action? Hormones are classied into three biochemical categories: Steroids Proteins/peptides Amines

33. Explain how glucose regulates the secretion of insulin in beta cells

Transport of glucose into beta cells through GLUT-2 transporter proteinsMetabolism of glucose inside the beta cellsProduction of ATP (or NADP+) Then, this closes (the ATP molecule) the K+ channels Depolarization Voltage-gated Ca+ channels open intracellular Ca+ Exocytosis of insulin from secretory granules

The beta cell's primary function is to correlate release of insulin with changes in blood glucose concentration using a glucose transport protein (GLUT2) and a kinase (glucokinase) both of which

have low affinities for glucose. GLUT2 is quite active, but the Km for glucose is around 5 mmol/l. Therefore, transport of glucose into the beta cell is rapid, but only when the blood glucose concentration exceeds post-meal levels. The next component of the glucose sensor is glucokinase, the enzyme that initiates glycolysis. Unlike hexokinase, glucokinase has a low affinity for its substrate. Glucokinase activity increases and decreases parallel to changes in blood glucose levels within the physiological range. Glucokinase activity is, therefore, most sensitive to changes in blood glucose concentration within the physiological range (approximately 4-6 mmol/l). Consequently, both uptake of glucose by the beta cell and initiation of glycolysis closely follow blood glucose levels. We have a system that responds to increases in blood glucose with a rapid uptake and metabolism of glucose, but which is rather sluggish at the glucose levels found between meals. The "glucose sensor pair" GLUT2-GK is also found in the liver and hypothalamus and seems to be the universal glucose sensor. The resting membrane potential of about -60 mV found in beta cells arises from loss of K+ ions to the extracellular space. The distinguishing characteristic of this ion channel in beta cells is that it is bound to a regulatory protein, known as SUR1. This name comes from the fact that this protein is the receptor for sulfonylurea compounds(with hypoglycemic effect). The Kir6.2-SUR1 complex is now known as the KATPchannel. The complete channel consists of a core of four Kir 6.2 subunits surrounded by four SUR1 subunits. The SUR1 complex acts as a regulator of the K+ channel, binding ATP as well as sulfonylurea compounds. Both ATP and tolbutamide have inhibitory actions on the KATP channel and therefore inhibit K+ efflux. This leads to depolarization of the beta cell, Ca++ influx and insulin secretion. Another agent, diazoxide, stimulates the KATP channel and promotes K+ efflux, membrane polarization and inhibition of insulin secretion. *** The classical viewpoint has been that the pancreatic beta cell obtains its energy supply through aerobic glycolysis, using glucose as substrate. However, resting beta cell oxidative phosphorylation may be dependent upon oxidation of fatty acids (discussed later). The rate of fatty acid beta oxidation may limit oxidative phosphorylation. The ATP/ADP ratio is relatively low in beta cells exposed to fasting blood glucose levels. The accelerated glucose uptake found at glucose levels over 5 mmoles/l augments ATP synthesis. In other words, ATP synthesis is dependent upon the rates of glucose uptake and aerobic glycolysis. Variations in ATP levels occur parallel to changes in blood glucose concentration. ATP acts as a second messenger in these cells, informing the KATP channel of variations in blood glucose levels. Stated simply: more glucose, more ATP, increased INHIBITION of K+ transport, depolarization of the beta cell and then, release of insulin. Incidentally, it has been suggested that both PIP2 and ADP levels may be just as important as ATP in regulation of KATP and membrane polarization. * The final element in the signal system for insulin secretion is the voltage-dependent Ca++ (VDCC) channel. This opens when the membrane voltage falls to less than -40 mvolts. The Ca++ that then enters the cell is directly involved in the exocytotic process that releases insulin form the "rapidly released pool" of insulin-containing granules.

*****SHORTER VERSION GLUT2 and glucokinase are activated when blood glucose increase to about 5.5 mmol/l. Aerobic glycolysis will drive the ATP/ADP ratio upwards. The ATP produced inhibits the KATP channel, thus reducing the flow of potassium ions from the beta cell. As a result, the cell becomes increasingly depolarized. Slow depolarization waves are initiated as the membrane potential falls. Action potentials occur at the tops of these waves. Insulin secretion is pulsatile, the hormone being secreted in bursts that occur simultaneously with the action potentials. Calcium causes exocytosis from the "rapidly released pool" and migration of insulin-containing granules from the "reserve pool" to the cell membrane where they are "docked" and energized.

34. Enumerate the effects of insulin in the liver, muscle, and fat cells LIVER: Stimulates GLYCOGENESIS Inhibits GLUCONEOGENESIS Promotes LIPOGENESIS Stimulates PROTEIN SYNTHESIS

MUSCLE: Promotes UPTAKE OF GLUCOSE via GLUT4 Promotes GLYCOGEN SYNTHESIS

Promotes GLYCOLYSIS Promotes PROTEIN SYNTHESIS

FAT CELLS: Promotes UPTAKE OF GLUCOSE via GLUT4 Promotes GLYCOLYSIS Promotes SYNTHESIS OF TGs Inhibits HORMONE-SENSITIVE TG LIPASE Promotes SYNTHESIS OF LIPOPr LIPASE

35. Describe the regulation of thyroid activity by the hypothalamus and anterior pituitary. The secretion of hormones from the thyroid gland is regulated by negative feedback in the hypothalamicpituitarythyroid axis. The hypothalamus secretes TRH, which stimulates the release of TSH from the adenohypophysis of the pituitary. Thyroid-stimulating hormone then stimulates the release of T3 and T4 from the thyroid. In this hormone axis, negative-feedback inhibition is exerted primarily at the level of the pituitary. As the intracellular concentration of T3 in the thyrotroph cells of the pituitary increases, then the responsiveness of these TSH-producing cells to TRH decreases. The mechanism of this decreased responsiveness involves down regulation of TRH receptors. This results in a decrease in the secretion of TSH and, consequently, a decrease in the secretion of T3 and T4. The excess of intracellular T3 that elicits the negative feedback control of secretion comes from two sources: 80% from the deiododination of serum T4 within the thyrotroph cells and 20% from serum T3.

36. Explain how thyroid hormones affect cell activity following interaction with its nuclear receptor. DEIODINATION OF T4 T3 IN PERIPHERAL CELLS THYROID HORMONE-RECEPTOR COMPLEX EFFECTS ON METABOLISM IN DIFFERENT CELLS

Receptors for thyroid hormones are intracellular DNA-binding proteins that function as hormone-responsive transcription factors, very similar conceptually to the receptors for steroid hormones. Thyroid hormones enter cells through membrane transporter proteins. A number of plasma membrane transporters have been identified, some of which require ATP hydrolysis; the relative importance of different carrier systems is not yet clear and may differ among tissues. Once inside the nucleus, the hormone binds its receptor, and the hormone-receptor complex interacts with specific sequences of DNA in the promoters of responsive genes. The effect of the hormone-receptor complex binding to DNA is to modulate gene expression, either by stimulating or inhibiting transcription of specific genes. 37. Describe the hormonal, ovarian, and uterine changes during the entire menstrual cycle. Estrogen secondary sexual characteristics - estradiol - most important; dominant - stimulate bone and muscle growth - maintain secondary sex characteristics - affecting CNS activity - maintain functional accessory reproductive glands and organs - initiate growth and repair of endometrium

Effects of Estrogen: Uterus & external genitalia - increase in size - fat deposition in mons pubis - epithelial change from cuboidal to stratified - more resistant to trauma & infection - proliferation of endometrium - development of endometrial glands Fallopian tubes - increased glandular tissues - increased number and activity of ciliated epithelial cells Breasts - development of stromal tissue - growth of ductile system - deposition of fat Protein deposition - slight increase in total body protein Bones - increase osteoblastic activity - early uniting of epiphysis of long bones - menopause - no estrogen - decrease osteoblastic activity osteoporosis Fat deposition - increased metabolic rate - deposition in thighs and buttocks Hair Distribution - fairly distributed Electrolyte imbalance - water and Na retention - chemical similarity to adrenocortical hormone; significant in pregnancy Progestin - progesterone - for pregnancy and lactation - non-pregnant: secreted by corpus luteum - pregnancy: placenta, after 4 months Follicular phase This phase is also called the proliferative phase because a hormone causes the lining of the uterus to grow, or proliferate, during this time. Through the influence of a rise in follicle stimulating hormone (FSH) during the first days of the cycle, a few ovarian follicles are stimulated.[20] These follicles, which were present at birth[20] and have been developing for the better part of a year in a process known as folliculogenesis, compete with each other for dominance. Under the influence of several hormones, all but one of these follicles will stop growing, while one dominant follicle in the ovary will continue to maturity. The follicle that reaches maturity is called a tertiary, or Graafian, follicle, and it forms the ovum. As they mature, the follicles secrete increasing amounts of estradiol, an estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus, histologically

identified as the proliferative endometrium. The estrogen also stimulates crypts in the cervix to produce fertile cervical mucus, which may be noticed by women practicing fertility awareness. Ovulation During the follicular phase, estradiol suppresses production of luteinizing hormone (LH) from the anterior pituitary gland. When the egg has nearly matured, levels of estradiol reach a threshold above which this effect is reversed and estrogen actually stimulates the production of a large amount LH. This process, known as the LH surge, starts around day 12 of the average cycle and may last 48 hours. The exact mechanism of these opposite responses of LH levels to estradiol is not well understood. In animals, a GnRH surge has been shown to precede the LH surge, suggesting that estrogen's main effect is on the hypothalamus, which controls GnRH secretion. This may be enabled by the presence of two different estrogen receptors in the hypothalamus: estrogen receptor alpha, which is responsible for the negative feedback estradiol-LH loop, and estrogen receptor beta, which is responsible for the positive estradiol-LH relationship. However in humans it has been shown that high levels of estradiol can provoke abrupt increases in LH, even when GnRH levels and pulse frequencies are held constant, suggesting that estrogen acts directly on the pituitary to provoke the LH surge. The release of LH matures the egg and weakens the wall of the follicle in the ovary, causing the fully developed follicle to release its secondary oocyte. The secondary oocyte promptly matures into an ootid and then becomes a mature ovum. The mature ovum has a diameter of about 0.2 mm. After being released from the ovary and into the peritoneal space, the egg is swept into the fallopian tube by the fimbria, which is a fringe of tissue at the end of each fallopian tube. After about a day, an unfertilized egg will disintegrate or dissolve in the fallopian tube. Fertilization by a spermatozoon, when it occurs, usually takes place in the ampulla, the widest section of the fallopian tubes. A fertilized egg immediately begins the process of embryogenesis, or development. The developing embryo takes about three days to reach the uterus and another three days to implant into the endometrium. It has usually reached the blastocyst stage at the time of implantation. In some women, ovulation features a characteristic pain called mittelschmerz (German term meaning middle pain). The sudden change in hormones at the time of ovulation sometimes also causes light mid-cycle blood flow. Luteal phase The luteal phase is also called the secretory phase. An important role is played by the corpus luteum, the solid body formed in an ovary after the egg has been released from the ovary into the fallopian tube. This body continues to grow for some time after ovulation and produces significant amounts of hormones, particularly progesterone. Progesterone plays a vital role in making the endometrium receptive to implantation of the blastocyst and supportive of the early pregnancy; it also has the side effect of raising the woman's basal body temperature.

After ovulation, the pituitary hormones FSH and LH cause the remaining parts of the dominant follicle to transform into the corpus luteum, which produces progesterone. The increased progesterone in the adrenals starts to induce the production of estrogen. The hormones produced by the corpus luteum also suppress production of the FSH and LH that the corpus luteum needs to maintain itself. Consequently, the level of FSH and LH fall quickly over time, and the corpus luteum subsequently atrophies. Falling levels of progesterone trigger menstruation and the beginning of the next cycle. From the time of ovulation until progesterone withdrawal has caused menstruation to begin, the process typically takes about two weeks, with 14 days considered normal. For an individual woman, the follicular phase often varies in length from cycle to cycle; by contrast, the length of her luteal phase will be fairly consistent from cycle to cycle. The loss of the corpus luteum can be prevented by fertilization of the egg; the resulting embryo produces human chorionic gonadotropin (hCG), which is very similar to LH and which can preserve the corpus luteum. Because the hormone is unique to the embryo, most pregnancy tests look for the presence of hCG.

38. Describe the effects of testosterone and dihydrotestosterone on the male body during puberty. Testosterone - produced by Leydig cells in the interstitium of the testis - for growth and division of the testicular germinal cells (first stage in forming sperm) - spermatogenesis - Decrease in GnRH Secretion (negative regulation on the Hypothalamus) - Inhibits LH Secretion (negative regulation on the Pituitary Gland) - Development of Male Accessory Reproductive Organs - Responsible for Male Secondary Sex Characteristics (Distribution of Body Hair, Baldness Voice, Skin, Acne) - Stimulates Protein Anabolism, Bone Growth and Cessation of Bone Growth - Maintains Sex Drive and may enhance aggressive behavior - increases the RBCs Dihydrotestosterone - 5-A-Reductase converts Testosterone to Dihydrotestosterone (DHT) - DHT has approximately three times greater affinity for androgen receptors than testosterone and has 15-30 times greater affinity than adrenal androgens

- During embryogenesis: formation of the male external genitalia, while in the adult DHT acts as the primary androgen in the prostate and in hair follicles 39. Discuss the ionic basis of resting membrane potentials and the action potentials in nerve and skeletal muscle tissues. Phospholipid bilayer prevents non-soluble ions from passing through the lipid component, allowing separation of charges Resting ion channels (leaky channels or non-gated) allows diffusible ions to pass (more leaky K ion channels than Na ion channels) Energy-dependent Na-K Pump (Na-K/ATPase System) contributes to long term Passive fluxes of Ion across the cell membrane decrease concentration of electrical gradients (K efflux) through leaky K channels which determines RMP (resting membrane potential).

40. Discuss the different stages of synaptic transmission. Stages: Synthesis and storage of neurotransmitters The first step in synaptic transmission is the synthesis and storage of neurotransmitters. There are two broad categories of neurotransmitters. Small-molecule neurotransmitters are synthesized locally within the axon terminal. Some of the precursors necessary for the synthesis of these molecules are taken up by selective transporters on the membrane of the terminal. Others are byproducts of cellular processes that take place within the neuron itself and are thus readily available. The enzymes necessary to catalyze an interaction among these precursors are usually produced in the cell body and transported to the terminal by slow axonal transport. Acetylcholine (ACh), is an example of an excitatory small-molecule neurotransmitter. This important, well-studied neurotransmitter, made up of choline and acetate, is found at various locations throughout the central and peripheral nervous systems and at all neuromuscular junctions. The synthesis of ACh requires the enzyme choline actyltransferase and, like all small-molecule neurotransmitters, takes place within the nerve terminal. Neuropeptides are the second category of neurotransmitters. These messengers differ from small-molecule neurotransmitters in both size and in the way that they are synthesized. Neuropeptides generally range from 3 to 36 amino acids in length, and are thus larger than small-molecule neurotransmitters. Also, neuropeptides must made in the cell body because their synthesis requires peptide bond formation. This process is a great deal more involved than the simple enzymatic reactions involved in making smaller neurotransmitters. The synthesis of a neuropeptide is very much like the synthesis of any secretory protein made by the cell. First, within the cell nucleus, gene transcription takes place, during which a specific peptide-coding sequence of DNA is used as a template to construct a corresponding strand of messenger RNA. The mRNA then travels to a ribosome, where the process of translation begins. During translation, the sequence of nucleotides that make up the mRNA act as a code to string together a corresponding sequence of amino acids that will eventually become the neuropeptide needed at the terminal. Before this molecule can be transported to the terminal for release into the synaptic cleft, it must be processed in the endoplasmic reticulum (ER), packaged in the golgi apparatus, and transported in storage vesicles down the axon to the terminal.

The endogenous opioids, a large family of neuropeptides that act as natural analgesics, provide a good example of how post-translational processing of just one precursor molecule can result in a whole spectrum of different, but related, neurotransmitters. Selective cleaving and splicing of each just three precursor molecules results in the production of the various opioids included in this family of neurotransmitters. Once they are synthesized, neurotransmitters, both small molecules and neuropeptides, are stored in vesicles within the axon terminal until an action potential arrives and they are released. Most small-molecule neurotransmitters are stored in small vesicles that range from 40 to 60 nm in diameter and, in electron micrographs, appear to have clear centers. The vesicles that store neuropeptides are larger, ranging from 90 to 250 nm in diameter. These vesicles appear dark and electron-dense in electron micrographs. Neurotransmitter release at pre-synaptic endings At rest, neurotransmitter-containing vesicles are stored at the terminal of the neuron in one of two places. A small number of vesicles are positioned along the pre-synaptic membrane in places called "active zones." This is where neurotransmitter release occurs. Most vesicles, however, are held close to these zones, yet further from the membrane itself until they are needed. These vesicles are held in place by Ca2+-sensitive vesicle membrane proteins (VAMPs), which bind to actin filaments, microtubules, and various other elements of the cytoskeleton. When an action potential reaches the terminal of a presynaptic neuron, voltage-dependent calcium (Ca2+) channels embedded in the pre-synaptic membrane open and Ca2+ rushes in. This influx of calcium ions triggers a series of events, which ultimately results in the release of the neurotransmitter from a storage vesicle into the synaptic cleft. The first step in this process involves freeing the neurotransmitter-containing vesicles from the bonds that hold them to the cytoskeleton. The vesicles are then free to travel to the active zones, where docking takes place. Docking is the process by which the vesicle and the pre-synaptic membrane line up in a position that will allow them to fuse easily. Fusion then takes place, in which the vesicle membrane and the pre-synaptic membrane connect to form a small opening, a pore, connecting the lumen of the vesicle with the synaptic cleft. This pore grows larger and larger until the vesicle membrane collapses into the pre-synaptic membrane and releases its contents into the synaptic cleft, a process called exocytosis. Following exocytosis, the vesicular membrane, presently a continuous extension of the pre-synaptic membrane, forms a pit and pinches off into the terminal to form a new, vacant vesicle. This vesicle is then either recycled and refilled with more of the neurotransmitter, or sent to the cell body, where it is broken down, processed into a new vesicle, and transported to the terminal where it can then be filled with the neurotransmitter. In cases like Lamberton-Eaton Myasthenic Syndrome, Ca is not allowed by channels to enter in the cell. Activation of post-synaptic receptors by neurotransmitters After release into the synaptic cleft, neurotransmitters interact with receptor proteins on the membrane of the postsynaptic cell, causing ionic channels on the membrane to either open or close. When these channels open, depolarization occurs, res ulting in the initiation of another action potential. There are two types of postsynaptic receptors that recognize neurotransmitters. Ionotropic receptors, also referred to as ligand-gated ion channels, act quickly to depolarize the

neuron and pass on the action potential (or hyperpolarize the neuron and inhibit additional action potentials). These receptors are made up of five individual protein subunits embedded in the cell membrane, and arranged to form a single pore that spans this membrane. When a neurotransmitter associates with the extracellular recognition site, the membrane-spanning subunits of the receptor quickly open to form a pore through which the necessary ions can pass. Depolarization usually occurs a millisecond or two after the action potential has been received and lasts only up to ten milliseconds. Alpha-bungarotoxin from Cobra snakes and other tropical snakes prevents binding of Ach to nicotinic Ach receptors. Inactivation of neurotransmitters After a neurotransmitter molecule has been recognized by a post-synaptic receptor, it is released back into the synaptic cleft. Once in the synapse, it must be quickly removed or chemically inactivated in order to prevent constant stimulation of the post-synaptic cell and an excessive firing of action potentials. Some neurotransmitters are removed from the synaptic cleft by special transporter proteins on the pre-synaptic membrane. These transporter proteins carry the neurotransmitter back into the pre-synaptic cell, where it is either re-packaged into a vesicle and stored until it is once again needed to transmit a chemical message, or broken down by enzymes. As example: Organophosphate insecticide and nerve gas are irreversible acetylcholinesterase inhibitors.

41. Discuss the ionic basis of excitatory post-synaptic potentials. What neurotransmitters produce EPSPs? Opening of sodium channels to allow large numbers of positive electrical charges to flow to the interior of the postsynaptic cell. This raises the intracellular membrane potential in the positive direction up toward the threshold level for excitation. Depressed conduction through chloride or potassium channels or both. This decreases the diffusion of negatively charged K ions to the outside. Various changes in the internal metabolism of the postsynaptic neuron to excite cell activity or, in some instances, to increase the number of excitatory membrane receptors or decrease the number of inhibitory membrane receptors. The neurotransmitters that produce EPSPs are Ach, dopamine, epinephrine, norepinephrine, serotonin, melatonin, histamine, glutamate and aspartate.

42. Discuss the ionic basis of inhibitory post-synaptic potentials. Name neurotransmitters which produce IPSPs. The inhibitory synapses open mainly chloride channels, allowing easy passage of chloride ions. The Nerst potential for chloride ions to be about -70mv. This potential is more negative than -60mv normally present inside the resting neuronal membrane. Therefore, opening the chloride ions to move

from the ECF to the interior, which will make the interior membrane potential more negative than normal, approaching -70mv level. Opening potassium channels will allow positively charged potassium ions to move to the exterior, and this will also make the interior membrane potential more negative than usual. Thus, both Cl influx and K efflux increase the degree of intracellular negativity, which is called hyperpolarization. This inhibits the neurons because the membrane potential is even more negative than the normal intracellular potential. The neurotransmitters that produce IPSPs are GABA, glycine and taurine.

43. Discuss the excitation-contraction coupling in muscle physiology. How does the action potential from the sarcolemma (plasma membrane) travel to the interior of the muscle cell to trigger muscle contraction? - Excitationcontraction (EC) coupling is an action potential arrives to depolarize the cell membrane. By mechanisms specific to the muscle type, this depolarization results in an increase in cytosolic calcium that is called a calcium transient. This increase in calcium activates calcium-sensitive contractile proteins that then use ATP to cause cell shortening. In skeletal muscle the method of excitation contraction coupling relies on the ryanodine receptor being activated by a domain spanning the space between the T tubules and the sarcoplasmic reticulum to produce the calcium transient responsible for allowing contraction. 1. The alpha motor neuron produces an action potential that propagates down its axon to the neuromuscular junction. 2. The action potential is sensed by a voltage-dependent calcium channel which causes an influx of Ca2+ ions. This influx results in exocytosis of synaptic vesicles containing acetylcholine. 3. Acetylcholine diffuses across the synapse and binds to nicotinic acetylcholine receptors on the myocyte, opening them. An influx of Na+ and an efflux of K+ results, depolarizing the cell and generating an end-plate potential. 4. The end-plate potential propagates throughout the myocyte's sarcolemma and into the Ttubule system. 5. The T-tubule system contains voltage-dependent calcium channels known as dihydropyridine receptors (DHP) which are activated by the end-plate potential. 6. Rather than releasing calcium from the T-tubules, activated dihydropyridine receptors transmit the voltage-mediated signal through a mechanical linkage to the ryanodine receptorsin the sarcoplasmic reticulum. This process involves a conformational change which allosterically activates type 1 ryanodine receptors. 7. Activated ryanodine receptors then open their channels. 8. Opening of the ryanodine receptors allows a flow of Ca2+ from the sarcoplasmic reticulum into the cytoplasm. In this release, Ca2+ unbinds from the calcium-binding protein called calsequestrin.

9. Ca2+ released from the sarcoplasmic reticulum binds to Troponin C by the actin filaments, which subsequently causes the troponin complex to pull tropomyosin away from the myosin binding sites on nearby actin filaments. Myosin cross-bridge binding sites on the actin filaments are now uncovered. 10. By hydrolyzing ATP, myosin forms cross bridges with the actin filaments. Activation of this crossbridge cycling may induce a shortening of the sarcomeres and the muscle as a whole, but not if the tension is insufficient to overcome the load imparted on the muscle. 11. Provided a force is applied that exceeds the load, a concentric contraction initiates. During this contraction, actin's interaction with myosin results in its movement toward the center of the sarcomere, or M-line, through a series of calcium-induced power strokes. 12. A sarcomere will remain contracted in this tightly bound state of rigor mortis unless sufficient ATP is present to bind with myosin, as a myosin head that is not bound to actin is bound to ATP. 13. Simultaneously, the sarco/endoplasmic reticulum Ca2+-ATPase actively pumps Ca2+ back into the sarcoplasmic reticulum where Ca2+ rebinds to calsequestrin. 14. With Ca2+ no longer bound to troponin C, the troponin complex slips position from the open state to its blocking position. As a consequence of this change, tropomyosin slips into a position that covers the binding sites on actin. 15. Since cross-bridge cycling is ceasing then any load on the muscle causes the inactive sarcomeres to lengthen.

44. Discuss the sliding filament mechanism of muscle contraction. The process of a muscle contracting can be divided into 5 sections:

1. A nervous impulse arrives at the neuromuscular junction, which causes a release of a chemical called Acetylcholine. The presence of Acetylcholine causes the depolarisation of the motor end plate which travels throughout the muscle by the transverse tubules, causing Calcium (Ca+) to be released from the sarcoplasmic reticulum. 2. In the presence of high concentrations of Ca+, the Ca+ binds to Troponin, changing its shape and so moving Tropomyosin from the active site of the Actin. The Myosin filaments can now attach to the Actin, forming a cross-bridge. 3. The breakdown of ATP releases energy which enables the Myosin to pull the Actin filaments inwards and so shortening the muscle. This occurs along the entire length of every myofibril in the muscle cell. 4. The Myosin detaches from the Actin and the cross-bridge is broken when an ATP molecule binds to the Myosin head. When the ATP is then broken down the Myosin head can again attach to an Actin binding site further along the Actin filament and repeat the 'power stroke'. This repeated pulling of the Actin over the myosin is often known as the ratchet mechanism.

5. This process of muscular contraction can last for as long as there is adequate ATP and Ca+ stores. Once the impulse stops the Ca+ is pumped back to the Sarcoplasmic Reticulum and the Actin returns to its resting position causing the muscle to lengthen and relax. It is important to realise that a single power stroke results in only a shortening of approximately 1% of the entire muscle. Therefore to achieve an overall shortening of up to 35% the whole process must be repeated many times. It is thought that whilst half of the cross-bridges are active in pulling the Actin over the Myosin, the other half are looking for their next binding site.

45. Discuss the role of the autonomic nervous system. The autonomic nervous system (ANS) controls the bodys internal environment. It is important in the process of homeostasis. It also helps control the heart rate, blood pressure, digestion, respiration, blood pH and other bodily functions. These controls are done automatically below the conscious level. The ANS has two divisions that differ in anatomy and function.

a. Sympathetic nervous system Promotes a "fight or flight" response, corresponds with arousal and energy generation, and inhibits digestion.

Diverts blood flow away from the gastro-intestinal (GI) tract and skin via vasoconstriction.

Blood flow to skeletal muscles and the lungs is enhanced (by as much as 1200% in the case of skeletal muscles). Dilates bronchioles of the lung, which allows for greater alveolar oxygen exchange. Increases heart rate and the contractility of cardiac cells (myocytes), thereby providing a mechanism for the enhanced blood flow to skeletal muscles. Dilates pupils and relaxes the ciliary muscle to the lens, allowing more light to enter the eye and far vision. Provides vasodilation for the coronary vessels of the heart. Constricts all the intestinal sphincters and the urinary sphincter. Inhibits peristalsis. Stimulates orgasm. b. Parasympathetic nervous system

Promotes a "rest and digest" response, promotes calming of the nerves return to regular function, and enhances digestion.

Dilates blood vessels leading to the GI tract, increasing blood flow. This is important following the consumption of food, due to the greater metabolic demands placed on the body by the gut. The parasympathetic nervous system can also constrict the bronchiolar diameter when the need for oxygen has diminished. Dedicated cardiac branches of the Vagus and thoracic Spinal Accessory nerves impart Parasympathetic control of the Heart or Myocardium. During accommodation, the parasympathetic nervous system causes constriction of the pupil and contraction of the ciliary muscle to the lens, allowing for closer vision. The parasympathetic nervous system stimulates salivary gland secretion, and accelerates peristalsis, so, in keeping with the rest and digest functions, appropriate PNS activity mediates digestion of food and indirectly, the absorption of nutrients. Is also involved in erection of genitals, via the pelvic splanchnic nerves 24. Stimulates sexual arousal.

Summary Actions of the ANS Sympathetic Eye Heart Bronchioles Iris dilates Increased heart rate Bronchodilatation Parasympathetic Iris constricts Decreased heart rate Bronchoconstriction

Bladder

Sphincter constricts Detrusor muscle relaxes

Sphincter relaxes

Detrusor muscle contracts

Intestine

Secretions decrease Motility decreases

Secretions increase Motility increases Sphincter constricts Muscle wall relaxes

Rectum

Sphincter relaxes Muscle wall contracts

46. Discuss the role of ANS in temperature regulation, citing the afferent limbs, central structures involved, and efferent limb of the thermoregulatory reflexes involved.

The body increases and lowers its core temperature using a temperature control system that works like a thermostat. Increased body temperature activates mechanisms promoting heat loss, and lowered body temperature activates mechanisms enabling the accumulation or production of heat. Such a system is called a feedback control system, because it uses as input the total or partial output of the system, meaning that the consequences of the process dictate how it will go on further. A feedback system has three components: sensors that register the change, a control center that receives the signals of the sensors, and an effector mechanism, meaning a pathway for the commands of the control center when it responds to the information received from the sensors. In thermoregulation, the control center is located in the hypothalamus, a tiny cluster of brain cells located in the brain just above the pituitary gland. It also contains the key temperature sensors. Other sensors, located all over the body, record whether the body temperature is too high or too low. Central integration of thermoregulation is controlled primarily in the preoptic and anterior hypothalamus, where a set-point is established by a balance between the activities of the thermosensitive neurons. When body temperature is below the set-point, autonomic reflexes generate heat by shivering and reduce convective heat loss by cutaneous vasoconstriction and piloerection. When body temperature exceeds the set-point, sudomotor activity stimulates sweating to increase evaporative heat loss and precludes cutaneous vasoconstriction and piloerection. There are three main effector mechanisms involved in thermoregulation. The first is the vaso-motor system, which consists of the nerves that act on vascular smooth muscle to control blood vessel diameter; the second is provided by metabolic effectors, which are substances produced by the body to increase its activity. The third main effector mechanism is

provided by the sweat glands. The vasomotor system is responsible for two physiological responses called vasodilation and vasoconstriction. The first increases blood flow in the tissues and the second decreases it. 47. MOLECULAR BASIS FOR THE EXCITATORY AND INHIBITORY ACTIONS: A. NOREPINEPHRINE Adrenergic alpha 1 receptor= contractile effects on smooth muscle 1. CARDIAC MUSCLE Adrenergic beta 1 receptor = mediates stimulatory effects of NE and Epinephrine on heart; ex. Increased Heart rate 2. GASTRO-INTESTINAL SMOOTH MUSCLE Adrenergic beta 2 receptor = relaxant effects 3. BROWN FAT Adrenergic beta 3 receptor = stimulates release of free fatty acids from adipose tissue. B. ACETYLCHOLINE 1. CARDIAC MUSCLE Cholinergic Muscarinic 2 = inhibitory 2. GASTRO-INTESTINAL SMOOTH MUSCLE Cholinergic Muscarinic 3 smooth muscles; ex. Increased motility. = relaxing sphincters; ex. Allow passage of food = increasing glandular secretions of the GIT 48a. Discuss the stretch reflex. Draw the neural circuit = contracting

When a muscle is stretched, primary sensory fibers (Group Ia afferent neurons) of the muscle spindle respond to both changes in muscle length and velocity and transmit this activity to the spinal cord in the form of changes in the rate of action potentials. Likewise, secondary sensory fibers (Group II afferent neurons) respond to muscle length changes (but with a smaller velocity-sensitive component) and transmit this signal to the spinal cord. The Ia afferent signals are transmitted monosynaptically to many alpha motor neurons of the receptor-bearing muscle. The reflexly-evoked activity in the alpha motoneurons is then transmitted via their efferent axons to the extrafusal fibers of the muscle, which generate force and thereby resist the stretch. The Ia afferent signal is also transmitted polysynaptically through interneurons (Renshaw cells) which inhibit alpha motoneurons of antagonist muscles, causing them to relax.

Striking the patellar tendon with a tendon hammer just below the patella stretches the muscle spindle in the quadriceps femoris muscle. This produces a signal which travels back to the spinal cord and synapses (without interneurons) at the level of L4 in the spinal cord, completely independent of higher centres. From there, an alpha-motor neuron conducts an efferent impulse back to the quadriceps femoris muscle, triggering contraction. This contraction, coordinated with the relaxation of the antagonistic flexor hamstring muscle causes the leg to kick. This reflex is a reflex of proprioception which helps maintain posture and balance, allowing to keep one's balance with little effort or conscious thought.

48b. Discuss the inverse stretch reflex. Draw the neural circuit

In a Golgi tendon reflex, skeletal muscle contraction causes the agonist muscle to simultaneously lengthen and relax. This reflex is also called the inverse myotatic reflex, because it is the inverse of the stretch reflex. Though muscle tension is increasing during the contraction, alpha motor neurons in the spinal cord supplying the muscle are inhibited. However, antagonistic muscles are activated. A tendon reflex operates as follows: 1. As the tension applied to a tendon increases, the Golgi tendon organ (sensory receptor) is stimulated (depolarized to threshold). 2. Nerve impulses (action potentials) arise and propagate into the spinal cord along a sensory neuron. 3. Within the spinal cord (integrating center), the sensory neuron activates an inhibitory interneuron that makes a synapse with a motor neuron. 4. The inhibitory neurotransmitter inhibits (hyperpolarizes) the motor neuron, which then generates fewer nerve impulses. 5. The muscle relaxes and relieves excess tension.

The inverse stretch reflex acts as a kind of safety mechanism. As an increasing load is applied to a muscle the tension in the muscle increases. When an extreme load threatens to damage the muscle because of excessive tension, the Golgi tendon organs will be maximally activated. This will result in complete inhibition of the appropriate alpha motor neurons, leading to complete relaxation of the muscle.