Stuart Abramson, MD, MPH

• Clinical Assistant Professor, Tufts University School of
• Medicine, Boston, MA
• Medical Director, Center for
• Dialysis & Hemotherapeutics, Department of Medicine,
• Division of Nephrology, Maine Medical Center,
• Portland, ME
• Extracorporeal Treatment of Poisonings

Since pepsin digests protein symptoms west nile virus glucophage sr 500mg sale, and pepsinogen itself is a protein medicine ball exercises order 500mg glucophage sr amex, pepsin has an autocatalytic effect-as some pepsin is formed treatment for piles buy discount glucophage sr 500mg line, it converts pepsinogen into more pepsin (fig treatment 8th february discount 500mg glucophage sr with visa. The ultimate function of pepsin symptoms 2 purchase line glucophage sr, however medications restless leg syndrome cheap 500mg glucophage sr fast delivery, is to digest dietary proteins to shorter peptide chains, which then pass to the small intestine, where their digestion is completed. Gastric Secretions the gastric glands produce 2 to 3 L of gastric juice per day, composed mainly of water, hydrochloric acid, and pepsin. This enzyme and lingual lipase, which plays a minor role, digest 10% to 15% of the dietary fat in the stomach. This is more acidic than the battery acid of a car and low enough to dissolve tooth enamel or cause a chemical burn on the skin. Intrinsic Factor Parietal cells secrete a glycoprotein called intrinsic factor that is essential to the absorption of vitamin B12 by the small intestine. As we age, the gastric mucosa atrophies and less intrinsic factor is secreted, increasing the risk of anemia. Some people, especially in old age, develop pernicious anemia, the result of an autoimmune disease that destroys gastric mucosa and reduces intrinsic factor secretion. The functions of some of these peptides in digestion will be explained in the following sections, and their roles in appetite regulation are discussed in section 26. The secretion of intrinsic factor is the only indispensable function of the stomach. Digestion can continue following removal of the stomach (gastrectomy), but a person usually must then take Gastric Motility As you begin to swallow, food stimulates mechanoreceptors in the pharynx and they transmit signals to the medulla oblongata. Pepsin catalyzes the production of more pepsin (an autocatalytic effect), as well as partially digesting dietary protein. Soon, the stomach shows a rhythm of peristaltic contractions governed by a basic electrical rhythm set off by enteric pacemaker cells in the muscularis externa. The upper stomach (fundus) does not participate in these, but below the fundus, around midbody, a tight ring of constriction appears about every 20 seconds and progresses downward toward the antrum, becoming stronger as it goes. After food has been in the stomach for 30 minutes or so, these contractions become especially intense. They churn the food, mix it with gastric juice, and promote its physical breakup and chemical digestion. The muscularis is thickest here, and acts as a strong antral pump that breaks up semidigested food into smaller particles and prepares it for the small intestine. A leading wave of antral contraction proceeds to the pyloric valve and closes it tightly. Chyme jets backward through the trailing constriction into the gastric body, where it awaits the next wave of contraction to drive it down again. The repetitive downward propulsion and reverse jetting of chyme break the food into smaller and smaller particles. Food particles are not allowed to pass into the duodenum until they are reduced to 1 to 7 mm in size, and only about 3 mL of chyme is squirted into the duodenum at a time. Allowing only small amounts into the duodenum enables the duodenum to neutralize the stomach acid and digest nutrients little by little. If the duodenum becomes overfilled, it inhibits gastric motility and postpones receiving more chyme; the mechanism for this is discussed later. A typical meal is emptied from the stomach in about 4 hours, but it takes less time if the meal is more liquid, longer if the stomach contents are more acidic, and as long as 6 hours if the meal is high in fat. Vomiting Vomiting is the forceful ejection of stomach and intestinal contents (chyme) from the mouth. It involves multiple muscular actions integrated by the emetic13 center of the medulla oblongata. Vomiting is commonly induced by overstretching of the stomach or duodenum; chemical irritants such as alcohol and bacterial toxins; visceral trauma (especially to the pelvic organs); intense pain; or psychological and sensory stimuli that activate the emetic center (thus, vomiting can be induced by repugnant sights, smells, and thoughts). In retching, thoracic expansion and abdominal contraction create a pressure difference that dilates the esophagus. The lower esophageal sphincter relaxes while the stomach and duodenum contract spasmodically. Chyme enters the esophagus but then drops back into the stomach as the muscles relax; it does not get past the upper esophageal sphincter. Vomiting occurs when abdominal contraction and rising thoracic pressure force the upper esophageal sphincter open, the esophagus and body of the stomach relax, and chyme is driven out of the stomach and mouth by strong abdominal contraction combined with reverse peristalsis of the gastric antrum and duodenum. It may be caused by neurological lesions but is also common in infants after feeding. Aspiration (inhalation) of this acid is very destructive to the respiratory tract. Many have died from aspiration of vomit when they were unconscious or semiconscious. This is the reason that surgical anesthesia, which may induce nausea, must be preceded by fasting until the stomach and small intestine are empty. Vagus nerve fibers from the medulla stimulate the enteric nervous system of the stomach, which, in turn, stimulates secretion by the parietal cells (acid) and G cells (gastrin). The Gastric Phase Digestion and Absorption Salivary and gastric enzymes partially digest protein and lesser amounts of starch and fat in the stomach, but most digestion and nearly all nutrient absorption occur after the chyme passes into the small intestine. The stomach does not absorb any significant amount of nutrients but does absorb aspirin and some lipid-soluble drugs. Alcohol is absorbed mainly by the small intestine, so its intoxicating effect depends partly on how rapidly the stomach is emptied. Protection of the Stomach One might think that the stomach would be its own worst enemy; it is, after all, made of meat. Some people enjoy haggis and tripe, dishes made from animal stomachs, and have no difficulty digesting those. The answer is that the living stomach is protected in three ways from the harsh acidic and enzymatic environment it creates: 1. The epithelial cells are joined by tight junctions that prevent gastric juice from seeping between them and digesting the connective tissue below. The breakdown of these protective mechanisms can result in inflammation and peptic ulcer (see Deeper Insight 25. The gastric phase is a period in which swallowed food and semidigested protein (peptides and amino acids) activate gastric activity. About one-half of acid secretion and two-thirds of total gastric secretion occur during this phase. Ingested food stimulates gastric activity in two ways: by stretching the stomach and by raising the pH of its contents. Stretch activates two reflexes: a short reflex mediated through the myenteric plexus and a long reflex mediated through the vagus nerves and brainstem. Histamine is a paracrine secretion from enteroendocrine cells in the gastric glands. All three of these signals stimulate parietal cells to secrete hydrochloric acid and intrinsic factor. As dietary protein is digested, it breaks down into smaller peptides and amino acids, which directly stimulate the G cells to secrete even more gastrin-a positive feedback loop that accelerates protein digestion (fig. But as digestion continues and these peptides are emptied from the stomach, the pH drops lower and lower. The Intestinal Phase the intestinal phase begins when chyme starts arriving in the duodenum; it enables the duodenum to control the rate of gastric emptying so the duodenum has time to process the chyme and is not overwhelmed by a sudden overload. Stretching of the duodenum accentuates vagovagal reflexes that stimulate the stomach, and peptides and amino acids in the chyme stimulate G cells of the duodenum to secrete intestinal gastrin, which further stimulates the stomach. Soon, however, the acid and semidigested fats in the duodenum trigger the enterogastric reflex-the duodenum sends inhibitory signals to the stomach by way of the enteric nervous system, and sends signals to the medulla that (1) inhibit the vagal nuclei, thus reducing vagal stimulation of the stomach; and (2) stimulate sympathetic neurons, which send inhibitory signals to the stomach. Regulation of Gastric Function the nervous and endocrine systems collaborate to increase gastric secretion and motility when food is eaten and to suppress them as the stomach empties. Gastric activity is divided into three stages called the cephalic, gastric, and intestinal phases, based on whether the stomach is being controlled by the brain, by itself, or by the small intestine, respectively (fig. The Cephalic Phase the cephalic phase is the stage in which the stomach responds to the mere sight, smell, taste, or thought of food, even before food enters the stomach. These sensory and mental inputs converge on the hypothalamus, which relays signals to the medulla oblongata. Peptic ulcers occur even more commonly in the duodenum and occasionally in the esophagus. If untreated, they can perforate the organ and cause fatal hemorrhaging or peritonitis. There is no evidence to support the popular belief that peptic ulcers result from psychological stress. Hypersecretion of acid and pepsin is sometimes involved, but even normal secretion can cause ulceration if the mucosal defense is compromised by other causes. Most ulcers involve an acid-resistant bacterium, Helicobacter pylori, that invades the mucosa of the stomach and duodenum and opens the way to chemical damage to the tissue. At one time, the most widely prescribed drug in the United States was cimetidine (Tagamet), which was designed to treat peptic ulcers by reducing acid secretion. Histamine stimulates acid secretion by binding to sites on the parietal cells called H2 receptors; cimetidine, an H2 blocker, prevents this binding. Lately, however, ulcers have been treated more successfully with antibiotics against Helicobacter combined with bismuth suspensions such as Pepto-Bismol. This is a much shorter and less expensive course of treatment and permanently cures about 90% of peptic ulcers, as compared with a cure rate of only 20% to 30% for H2 blockers. Here the yellowish floor of the ulcer is partially obscured by black blood clots, and fresh blood is visible around the margin of the ulcer. The effect of this is that gastrin secretion declines and the pyloric sphincter contracts tightly to limit the admission of more chyme into the duodenum. This gives the duodenum time to work on the chyme it has already received before being loaded with more. Name four types of epithelial cells of the gastric and pyloric glands and state what each one secretes. Explain how the gastric glands produce hydrochloric acid and why this produces an alkaline tide. What positive feedback cycle can you identify in the formation and action of pepsin Key 2 Gastric phase Food stretches the stomach and activates myenteric and vagovagal reflexes. Sympathetic nerve fibers suppress gastric activity, while vagal (parasympathetic) stimulation of the stomach is now inhibited. The posterior aspect of the liver has a deep sulcus that accommodates the inferior vena cava. Microscopic Anatomy the interior of the liver is filled with innumerable tiny cylinders called hepatic lobules, about 2 mm long by 1 mm in diameter. A lobule consists of a central vein passing down its core, surrounded by radiating plates of cuboidal cells called hepatocytes (fig. The pages of the book would fan out around the spine somewhat like the plates of hepatocytes fan out from the central vein of a liver lobule. These are lined by a fenestrated endothelium that separates the hepatocytes from the blood cells, but allows blood plasma into the space between the hepatocytes and endothelium. Blood filtering through the sinusoids comes directly from the stomach and intestines. After a meal, the hepatocytes absorb glucose, amino acids, iron, vitamins, and other nutrients from it for metabolism or storage. At the same time, they secrete albumin, lipoproteins, clotting factors, angiotensinogen, and other products into the blood. Between meals, they break down stored glycogen and release glucose into the circulation. The sinusoids also contain phagocytic cells called hepatic macrophages, which remove bacteria and debris from the blood. The liver secretes bile into narrow channels, the bile canaliculi, between the back-to-back layers of hepatocytes within each plate. Bile passes from there into small bile ductules between the lobules, and these converge to ultimately form right and left hepatic ducts. A short distance farther on, this is joined by the cystic duct coming from the gallbladder (fig. Their union forms the bile duct, which descends through the lesser omentum toward the duodenum. Near the duodenum, the bile duct joins the duct of the pancreas and forms an expanded chamber called the hepatopancreatic ampulla. The ampulla terminates at a fold of tissue, the major duodenal papilla, on the duodenal wall. This papilla contains a muscular hepatopancreatic sphincter, which regulates the passage of bile and pancreatic juice into the duodenum. Between meals, this sphincter is closed and prevents the release of bile into the intestine. In cross sections, the stroma is especially visible in the triangular areas where three or more lobules meet. Here there is often a hepatic triad consisting of a bile ductule and two blood vessels-branches of the hepatic artery proper and the hepatic portal vein. The small intestine receives not only chyme from the stomach but also secretions from the liver and pancreas, which enter the digestive tract near the junction of the stomach and small intestine.

It receives the following tributaries keratin treatment glucophage sr 500 mg online, then empties into the superior vena cava at the level of vertebra T4 symptoms zoloft dose too high buy cheap glucophage sr 500mg on line. The right ascending lumbar vein drains the right abdominal wall medications information discount glucophage sr 500 mg visa, then penetrates the diaphragm and enters the thoracic cavity symptoms zoloft dosage too high best glucophage sr 500mg. The azygos vein begins where the ascending lumbar vein meets the right subcostal vein beneath rib 12 treatment 6th february glucophage sr 500mg cheap. The first (superior) one empties into the right brachiocephalic vein; intercostals 2 and 3 join to form a right superior intercostal vein before emptying into the azygos; and intercostals 4 through 11 each enter the azygos vein separately lanza ultimate treatment order discount glucophage sr on-line. The right esophageal, mediastinal, pericardial, and bronchial veins (not illustrated) drain their respective organs into the azygos vein. It begins where the left ascending lumbar vein, having just penetrated the diaphragm, joins the subcostal vein below rib 12. The hemiazygos then receives the lower three posterior intercostal veins, esophageal veins, and mediastinal veins. At the level of vertebra T9, it crosses to the right and empties into the azygos vein. It receives drainage from posterior intercostal veins 4 through 8 and sometimes the left bronchial veins. It crosses to the right at the level of vertebra T8 and empties into the azygos vein. The left posterior intercostal veins 1 to 3 are the only ones on this side that do not ultimately drain into the azygos vein. The second and third unite to form the left superior intercostal vein, which empties into the left brachiocephalic vein. This system provides venous drainage from the wall and viscera of the thorax, but the visceral tributaries are not illustrated. Middle Inferior After passing through the aortic hiatus, the aorta descends through the abdominal cavity and ends at the level of vertebra L4, where it branches into right and left common iliac arteries. Major Branches of the Abdominal Aorta the abdominal aorta gives off arteries in the order listed here (fig. Those indicated in the plural are paired right and left, and those indicated in the singular are solitary median arteries. Each issues two or three small superior suprarenal arteries to the ipsilateral adrenal (suprarenal) gland. The middle suprarenal arteries arise laterally from the aorta, usually at the same level as the superior mesenteric artery; they supply the adrenal glands. The renal arteries supply the kidneys and issue a small inferior suprarenal artery to each adrenal gland. The ovarian arteries of the female and testicular arteries of the male (collectively called the gonadal arteries) are long, slender arteries that arise from the midabdominal aorta and descend along the posterior body wall to the female pelvic cavity or male scrotum, and supply the gonads. The gonads begin their embryonic development near the kidneys, and the gonadal arteries are then quite short. As the gonads descend to the pelvic cavity, these arteries grow and acquire their peculiar length and course. They supply the posterior abdominal wall (muscles, joints, and skin) and the spinal cord and other tissues in the vertebral canal. The median sacral artery, a tiny median artery at the inferior end of the aorta, supplies the sacrum and coccyx. Branches of the Celiac Trunk the celiac circulation to the upper abdominal viscera is perhaps the most complex route off the abdominal aorta. Because it has numerous anastomoses, the bloodstream does not follow a simple linear path but divides and rejoins itself at several points (fig. As you study the following description, locate these branches in the figure and identify the points of anastomosis. The short, stubby celiac trunk, barely more than 1 cm long, is a median branch of the aorta just below the diaphragm. It immediately gives rise to three branches-the common hepatic, left gastric, and splenic arteries. The common hepatic artery passes to the right and issues two main branches-the gastroduodenal artery and the hepatic artery proper. The gastroduodenal artery gives off the right gastro-omental (gastroepiploic21) artery to the stomach. It gives off the right gastric artery, then branches into right and left hepatic arteries. The right hepatic artery issues a cystic artery to the gallbladder, then the two hepatic arteries enter the liver from below. The left gastric artery supplies the stomach and lower esophagus, arcs around the lesser curvature (superomedial margin) of the stomach, and anastomoses with the right gastric artery (fig. Thus, the right and left gastric arteries approach from opposite directions and supply this margin of the stomach. The left gastric also has branches to the lower esophagus, and the right gastric also supplies the duodenum. The splenic artery supplies blood to the spleen, but gives off the following branches on the way there: a. The left gastro-omental (gastroepiploic) artery arcs around the greater curvature (inferolateral margin) of the stomach and anastomoses with the right gastro-omental artery. These two arteries stand off about 1 cm from the stomach itself and travel through the superior margin of the greater omentum, a fatty membrane suspended from the greater curvature (see figs. Mesenteric Circulation the mesentery is a translucent sheet that suspends the intestines and other abdominal viscera from the posterior body wall (see figs. It contains numerous arteries, veins, and lymphatic vessels that supply and drain the intestines. The arterial supply arises from the superior and inferior mesenteric arteries; numerous anastomoses between these ensure adequate collateral circulation to the intestines even if one route is temporarily obstructed. It arises medially from the upper abdominal aorta and gives off the following branches: 1. The inferior pancreaticoduodenal artery, already mentioned, branches to pass around the anterior and posterior sides of the pancreas and anastomose with the two branches of the superior pancreaticoduodenal artery. Twelve to 15 jejunal and ileal arteries form a fanlike array that supplies nearly all of the small intestine (portions called the jejunum and ileum). The inferior mesenteric artery arises from the lower abdominal aorta and serves the distal part of the large intestine (fig. Arteries of the Pelvic Region the two common iliac arteries arise by branching of the aorta, descend for another 5 cm, and then, at the level of the sacroiliac joint, each divides into an external and internal iliac artery. Shortly after its origin, the internal iliac divides into anterior and posterior trunks. The superior vesical22 artery supplies the urinary bladder and distal end of the ureter. It arises indirectly from the anterior trunk by way of a short umbilical artery, a remnant of the artery that supplies the fetal umbilical cord. In men, the inferior vesical artery supplies the bladder, ureter, prostate gland, and seminal vesicle. In women, the corresponding vessel is the vaginal artery, which supplies the vagina and part of the bladder and rectum. The obturator artery exits the pelvic cavity through the obturator foramen and supplies the adductor muscles of the medial thigh. In women, the uterine artery is the main blood supply to the uterus and supplies some blood to the vagina. It passes up the uterine margin, then turns laterally at the uterine tube and anastomoses with the ovarian artery, thus supplying blood to the ovary as well (see part I. The lateral sacral arteries lead to tissues of the sacral canal, skin, and muscles posterior to the sacrum. The superior gluteal artery supplies the skin and muscles of the gluteal region and the muscle and bone tissues of the pelvic wall. It forms by the union of the right and left common iliac veins at the level of vertebra L5 and drains many of the abdominal viscera as it ascends the posterior body wall. The internal iliac veins drain the gluteal muscles; the medial aspect of the thigh, the urinary bladder, rectum, prostate, and ductus deferens of the male; and the uterus and vagina of the female. They unite with the external iliac veins, which drain the lower limb and are described in table 20. The ovarian veins of the female and testicular veins of the male (collectively called the gonadal veins) drain the gonads. The left renal vein also receives blood from the left gonadal and left suprarenal veins. Why do the veins that drain the ovaries and testes terminate so far away from the gonads Colon Ileum Rectum (a) Tributaries of the hepatic portal system Inferior vena cava Hepatic v. Veins of the Abdominal Wall A pair of ascending lumbar veins receives blood from the common iliac veins below and from the aforementioned lumbar veins of the posterior body wall (see fig. The ascending lumbar veins give off anastomoses with the inferior vena cava beside them as they ascend to the diaphragm. The left ascending lumbar vein passes through the diaphragm via the aortic hiatus and continues as the hemiazygos vein above. The right ascending lumbar vein passes through the diaphragm to the right of the vertebral column and continues as the azygos vein. The Hepatic Portal System the hepatic portal system receives all of the blood draining from the abdominal digestive tract, as well as from the pancreas, gallbladder, and spleen (fig. It is called a portal system because it connects capillaries of the intestines and other digestive organs to modified capillaries (hepatic sinusoids) of the liver; thus, the blood passes through two capillary beds in series before it returns to the heart. The hepatic portal system gives the liver first claim to these nutrients before the blood is distributed to the rest of the body. It also allows the blood to be cleansed of bacteria and toxins picked up from the intestines, an important function of the liver. The inferior mesenteric vein receives blood from the rectum and distal part of the colon. It converges in a fanlike array in the mesentery and empties into the splenic vein. The superior mesenteric vein receives blood from the entire small intestine, ascending colon, transverse colon, and stomach. It, too, exhibits a fanlike arrangement in the mesentery and then joins the splenic vein to form the hepatic portal vein. The splenic vein drains the spleen and travels across the abdominal cavity toward the liver. Along the way, it picks up pancreatic veins from the pancreas, then the inferior mesenteric vein, then ends where it meets the superior mesenteric vein. The hepatic portal vein is the continuation beyond the convergence of the splenic and superior mesenteric veins. It travels about 8 cm upward and to the right, receives the cystic vein from the gallbladder, then enters the inferior surface of the liver. In the liver, it ultimately leads to the innumerable microscopic hepatic sinusoids. The left and right gastric veins form an arc along the lesser curvature of the stomach and empty into the hepatic portal vein. In the intestinal forms of the disease, parasitic worms called blood flukes live in the small veins of mesenteries and the intestinal wall. Some of their eggs wash up the mesenteric veins into the hepatic portal circulation and lodge in venules of the liver. Here, they cause severe inflammation that results in a knot or granuloma of fibrous scar tissue around each egg. As these granulomas accumulate and the liver becomes more and more fibrous, they obstruct blood flow and cause portal hypertension, a backup of pressure into the hepatic portal system. Normally weighing 150 g, the spleen can grow to 1,000 g or more and extend even into the pelvic cavity. Increased capillary blood pressure causes the spleen, liver, and mesenteries to "weep" serous fluid into the peritoneal cavity. Portal hypertension and ascites can also occur in many other obstructive liver diseases such as alcoholic cirrhosis. The abdomen is distended with accumulated serous fluid that has filtered from the liver, spleen, and intestinal blood vessels. Concisely contrast the destinations of the external and internal carotid arteries. Briefly state the organs or parts of organs that are supplied with blood by (a) the cerebral arterial circle, (b) the celiac trunk, (c) the superior mesenteric artery, and (d) the internal iliac artery. If you were dissecting a cadaver, where would you look for the internal and external jugular veins Trace the path of a blood cell from the left lumbar body wall to the superior vena cava, naming the vessels through which it would travel. The principal vessels of the appendicular region are detailed in the next four tables. Although the appendicular arteries are usually deep and well protected, the veins occur in both deep and superficial groups; you may be able to see several of the superficial ones in your forearms and hands. Deep veins run parallel to the arteries and often have similar names (femoral artery and femoral vein, for example). In several cases, the deep veins occur in pairs flanking the corresponding artery (such as the two radial veins traveling alongside the radial artery). These blood vessels will be described in an order corresponding to the direction of blood flow.

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Proinsulin has a connecting (C) peptide symptoms 5 weeks pregnant cramps glucophage sr 500 mg with amex, 31 amino acids long acute treatment order glucophage sr uk, that is removed to leave insulin medications to avoid during pregnancy generic glucophage sr 500 mg mastercard. The cells release thyroglobulin by exocytosis from their apical surfaces into the lumen symptoms 3 days before period purchase 500mg glucophage sr otc. Where the Tg folds back on itself and two tyrosines meet gas treatment purchase 500mg glucophage sr with visa, or where one tyrosine meets another on an adjacent Tg medicine mound texas order glucophage sr with a mastercard, the tyrosines link to each other through their side groups. One tyrosine then breaks away from its Tg, but for the time being, the hormone remains anchored to Tg through its other tyrosine. Tg is stored in the follicles until the thyroid gland receives a signal to release it. It is not stored in the endocrine cells, but in the extracellular spaces enclosed by the thyroid follicles. In the blood, it binds to various transport proteins that carry it to its target cells. Hormone Transport To get from an endocrine cell to a target cell, a hormone must travel in the blood, which is mostly water. Most of the monoamines and peptides are hydrophilic, so mixing with the blood plasma is no problem for them. To travel in the watery bloodstream, they must bind to hydrophilic transport proteins-albumins and globulins synthesized by the liver. A hormone attached to a transport protein is called a bound hormone, and one that is not attached is an unbound (free) hormone. Transport proteins not only carry the hydrophobic hormones, but also prolong their half-lives. They protect hormones from being broken down by enzymes in the blood plasma and liver and from being filtered out of the blood by the kidneys. Free hormone may be broken down or removed from the blood in a few minutes, whereas bound hormone may circulate for hours to weeks. Steroid hormones bind to globulins such as transcortin, the transport protein for cortisol. However, 85% of it remains unbound, and correspondingly, it has a half-life of only 20 minutes. Nerve fibers supply some endocrine glands and elicit the release of their hormones. For example, the sympathetic nervous system stimulates the adrenal medulla to secrete epinephrine and norepinephrine in situations of stress. In childbirth, nerve signals originate from stretch receptors in the uterus, travel up the spinal cord and brainstem to the hypothalamus, and stimulate the release of oxytocin (see fig. Hormones from the hypothalamus regulate secretion by the anterior pituitary gland, and pituitary hormones stimulate other endocrine glands to release thyroid hormone, sex hormones, and cortisol. For example, rising blood glucose concentration stimulates the release of insulin, low blood osmolarity stimulates the secretion of aldosterone, and a low blood calcium level stimulates the secretion of parathyroid hormone. Peptide hormones such as growth hormone and oxytocin, and catecholamines such as epinephrine and dopamine, are stored in secretory vesicles of the endocrine cell until needed and released by exocytosis when the cell receives a stimulus to do so. Steroid hormones such as estrogen and cortisol, however, are not stored in vesicles or released by exocytosis. They do not accumulate in the endocrine cell, but are released as fast as they are synthesized by diffusion through the cell surface. But this does not mean they are secreted at a constant rate, hour by hour and day by day. Thyroid hormone Hormone Receptors and Mode of Action Hormones stimulate only those cells that have receptors for them- their target cells. The receptors are proteins or glycoproteins located on the plasma membrane, in the cytoplasm, or in the nucleus. They act like switches to turn certain metabolic pathways on or off when the hormones bind to them. Receptor defects lie at the heart of several endocrine diseases (see Deeper Insight 17. Unlike enzymes, receptors do not chemically change their ligands, but they do exhibit enzymelike specificity and saturation. Saturation is the condition in which all the receptor molecules are occupied by hormone molecules. For example, a defect or deficiency of insulin receptors causes type 2 diabetes mellitus. Androgen insensitivity syndrome is due to an androgen receptor defect or deficiency; it causes genetic males to develop feminine genitalia and other features (see Deeper Insight 27. For this reason, estrogen replacement therapy should not be used for women with estrogen-dependent cancer. Being hydrophobic, they diffuse easily through the phospholipid regions of the plasma membrane. In either case, the receptor associates with the target gene in the nucleus, controlling its transcription. For a good example of this, see the permissive effect of estrogen on progesterone action on the uterus under "Hormone Interactions" later in this section. Within the target-cell cytoplasm, an enzyme removes one iodine and converts it to the active form, T3. This T3, as well as a smaller amount of T3 produced directly by the thyroid and absorbed from the blood, enters the nucleus and binds to receptors in the chromatin. T3 also activates the transcription of genes for a norepinephrine receptor and part of the muscle protein myosin, thus enhancing the responsiveness of cells such as cardiac muscle to sympathetic stimulation and increasing the strength of the heartbeat. Steroid and thyroid hormones typically require several hours to days to show an effect. This lag is due to the time required for genetic transcription, translation, and accumulation of enough protein product to have a significant effect on target-cell metabolism. Peptides and Catecholamines Peptides and catecholamines are hydrophilic and cannot penetrate a target cell, so they must stimulate its physiology indirectly. They bind to cell-surface receptors, which are linked to second-messenger systems on the other side of the plasma membrane (fig. Two other second-messenger systems begin with one of the phospholipids in the plasma membrane. It can open Ca2+ channels in the plasma membrane, letting Ca2+ into the cell from the extracellular fluid, or it can open channels in the endoplasmic reticulum, causing it to release a flood of Ca2+ into the cytosol. It binds to certain calcium-dependent cytoplasmic enzymes that alter cell metabolism. It binds to membrane channels and changes their permeability to other solutes, in some cases altering the membrane potential (voltage) of the cell. This initial burst of calcium then opens channels in the plasma membrane that admit still more calcium into the cell from the extracellular fluid. Calcium binds to calmodulin, and stimulates the labor contractions (see contraction of smooth muscle in section 11. The general point of all this is that hydrophilic hormones such as those listed in the blue box at the left side of figure 17. Amplification of the process at each step allows for a very small hormonal stimulus to cause a very large metabolic effect. Yet by merely "knocking on the door" (binding to a surface receptor), they can initiate a flurry of metabolic activity within. Ultimately these pathways lead to metabolic pathways being switched on or off within the cell. Rather than using a second-messenger system, it binds to a plasma membrane enzyme, tyrosine kinase, which directly phosphorylates cytoplasmic proteins. These are modest numbers as chemical reactions go, and yet even at this low estimate, each glucagon molecule would trigger the production of 1 billion molecules of reaction product. Whatever the actual numbers may be, you can see how signal amplification enables a very small stimulus to produce a very large effect. Their circulating concentrations are very low compared with other blood substances-on the order of nanograms per deciliter. Because of signal amplification, target cells do not need a great number of hormone receptors. Modulation of Target-Cell Sensitivity Target cells can adjust their sensitivity to a hormone by changing the number of receptors for it. In up-regulation, a cell increases the number of hormone receptors and becomes more sensitive to the hormone (fig. In late pregnancy, for example, the uterus produces oxytocin receptors, preparing itself for the surge of oxytocin that will occur during childbirth. Down-regulation is the process in which a cell reduces its receptor population and thus becomes less sensitive to a hormone (fig. This sometimes happens in response to long-term exposure to a high hormone concentration. For example, adipocytes down-regulate when exposed to high concentrations of insulin, and cells of the testis down-regulate in response to high concentrations of luteinizing hormone. Hormone therapy often involves long-term use of abnormally high pharmacological doses of hormone, which may have Signal Amplification Hormones are extraordinarily potent chemicals. Through a mechanism called signal amplification (or a cascade effect), one hormone molecule triggers the synthesis of not just one enzyme molecule but an enormous number (fig. For example, when estrogen from the ovaries enters the cells of the uterine mucosa, it binds to its nuclear receptors and activates the gene for a protein that functions as the progesterone receptor. Progesterone comes later in the menstrual cycle, binds to these receptors, and stimulates transcription of the gene for a glycogen-synthesizing enzyme. The uterine cells then synthesize and accumulate glycogen for the nourishment of an embryo in the event of pregnancy. Progesterone has no effect on the uterine lining unless estrogen has been there earlier and prepared the way by inducing the synthesis of progesterone receptors. During pregnancy, estrogen from the placenta inhibits the mammary glands from responding to prolactin; thus milk is not secreted until the placenta is shed at birth. Two ways in which adverse side effects can arise are: (1) Excess hormone may bind to receptor sites for other related hormones and mimic their effects; and (2) a target cell may convert one hormone into another, such as testosterone to estrogen. Thus, long-term high doses of testosterone can, paradoxically, have feminizing effects. Hormonal signals, like nervous signals, must be turned off when they have served their purpose. Most hormones are taken up and degraded by the liver and kidneys and then excreted in the bile or urine. As noted earlier, hormones that bind to transport proteins are removed from the blood much more slowly than hormones that do not employ transport proteins. Growth hormone, for example, uses no transport protein and has a half-life of only 6 to 20 minutes. Thyroxine, by contrast, is protected by transport proteins and maintains a physiologically effective level in the blood for up to 2 weeks after its secretion ceases. Why do corticosteroids and thyroid hormones require transport proteins to travel in the bloodstream Hormone Interactions No hormone travels in the bloodstream alone, and no cell is exposed to only one hormone. Cells ignore the majority of them because they have no receptors for them, but most cells are sensitive to more than one. Synergistic effects, in which two or more hormones act together to produce an effect that is greater than the sum of their separate effects. When they act together, however, the testes produce some 300,000 sperm per minute. Glycogenesis is the synthesis of glycogen; glycogenolysis is its hydrolysis (breakdown to glucose); and gluconeogenesis is the synthesis of glucose from noncarbohydrates, especially fats and proteins. The response typically involves elevated levels of epinephrine and cortisol; some physiologists now define stress as any situation that raises the cortisol level. It affects us all from time to time, and we react to it in ways that are mediated mainly by the endocrine and sympathetic nervous systems. Physical causes of stress (stressors) include injury, surgery, hemorrhage, infection, intense exercise, temperature extremes, pain, and malnutrition. Whatever the cause, the body reacts to stress in a fairly consistent way called the stress response or general adaptation the initial response to stress is an alarm reaction mediated mainly by norepinephrine from the sympathetic nervous system and epinephrine from the adrenal medulla. One of their effects, the consumption of stored glycogen, is particularly important in the transition to the next stage of the stress response. Angiotensin helps to raise the blood pressure, and aldosterone promotes sodium and water conservation, which helps to offset possible losses by sweating and bleeding. If a stressful situation is not resolved before the glycogen is gone, the body enters the stage of resistance, in which the first priority is to provide alternative fuels for metabolism. Cortisol promotes the breakdown of fat and protein into glycerol, fatty acids, and amino acids, providing the liver with raw material for gluconeogenesis. Like epinephrine, cortisol inhibits glucose uptake by most organs and thus has a glucose-sparing effect. It also inhibits protein synthesis, leaving the free amino acids available for gluconeogenesis. Excessive cortisol secretion (or medical use of hydrocortisone) can, however, have some adverse effects. Cortisol suppresses the secretion of sex hormones such as estrogen, testosterone, and luteinizing hormone, causing disturbances of fertility and sexual function. It inhibits the synthesis of protective leukotrienes and prostaglandins (discussed shortly), suppresses antibody production, and kills immature T and B cells- two important families of immune cells.

Hirschsprung disease is usually evident even in the newborn medications adhd buy glucophage sr no prescription, which fails to have its first expected bowel movement medications for migraines best buy for glucophage sr. It affects four times as many infant boys as girls medicine 8 capital rocka order glucophage sr 500mg on-line, and although its incidence in the general population is about 1 in 5 medicine cups glucophage sr 500 mg lowest price,000 live births medicine games order glucophage sr 500mg, it occurs in about 1 out of 10 infants with Down syndrome symptoms after miscarriage purchase glucophage sr australia. In Central and South America, biting insects called kissing bugs transmit parasites called trypanosomes to humans. These parasites, similar to the ones that cause African sleeping sickness, cause Chagas13 disease. Among other effects, they destroy the autonomic ganglia of the enteric nervous system, leading to a massively enlarged and often gangrenous colon. All cardiac muscle, smooth muscle, and gland cells with cholinergic innervation have muscarinic receptors. Nicotinic receptors work by opening ligandgated ion channels and producing an excitatory postsynaptic potential in the target cell. This neurotransmitter is secreted by nearly all sympathetic postganglionic fibers (table 15. Nerve fibers that secrete it are called adrenergic fibers, and the receptors for it are called adrenergic receptors. These contrasting effects result from the different actions of two subclasses of -adrenergic receptors-1 and 2. These are named for another botanical toxin helpful to their discovery- nicotine. Yet when it binds to the -adrenergic receptors of cardiac muscle, it has an excitatory effect. Such contrasting effects-increased pulmonary airflow and a stronger, faster heartbeat-are obviously appropriate to a state of exercise. Here again there are two receptor subclasses, 1 and 2, which mediate different effects. Many naturally occurring drugs bind selectively to one or another class or subclass of receptor. Atropine binds only to muscarinic receptors and curare only to nicotinic receptors, for example. The autonomic effects on glandular secretion are often the indirect results of action on blood vessels. Many glandular secretions begin as a filtrate of the blood, which is then modified by the gland cells. Increasing the blood flow through a gland (such as a salivary or sweat gland) tends to increase secretion, and reducing the blood flow reduces secretion. Sympathetic fibers may also secrete enkephalin, substance P, neuropeptide Y, somatostatin, neurotensin, or gonadotropin-releasing hormone. Among other functions, this mechanism is crucial to penile erection (see Deeper Insight 27. How can the sympathetic nervous system stimulate platelets, considering that platelets are drifting cell fragments in the bloodstream with no nerve fibers leading to them In some cases, these effects are exerted through dual innervation of the same effector cells, as in the heart, where nerve fibers of both divisions terminate on the same muscle cells. In other cases, antagonistic effects arise because each division innervates different effector cells with opposite effects on organ function. In the iris of the eye, for example, sympathetic fibers innervate pupillary dilator cells and parasympathetic fibers innervate constrictor cells (fig. Cooperative effects are seen when the two divisions act on different effectors to produce a unified overall effect. The parasympathetic division stimulates serous cells of the salivary glands to secrete a watery, enzyme-rich secretion, while the sympathetic division stimulates mucous cells of the same glands to secrete mucus. In such cases, the two divisions may have either antagonistic or cooperative effects on the same organ. Shows antagonistic effects of the sympathetic (yellow) and parasympathetic (blue) divisions on the iris. If a person is in a state of fear, would you expect the pupils to be dilated or constricted For example, the parasympathetic division forms an extensive plexus in the wall of the digestive tract and exerts much more influence over it than the sympathetic division does. In the ventricles of the heart, by contrast, there is much less parasympathetic than sympathetic innervation. The adrenal medulla, piloerector muscles, sweat glands, and many blood vessels receive only sympathetic fibers. The most significant example of control without dual innervation is regulation of blood pressure and routes of blood flow. The sympathetic fibers to a blood vessel have a baseline sympathetic tone, which keeps the vessels in a state of partial constriction called vasomotor tone (fig. An increase in firing rate constricts a vessel by increasing smooth muscle contraction. A drop in firing frequency dilates a vessel by allowing the smooth muscle to relax. The blood pressure in the vessel, pushing outward on its wall, then dilates the vessel. Sympathetic control of vasomotor tone can shift blood flow from one organ to another according to the changing needs of the body. In times of emergency, stress, or exercise, the skeletal muscles and heart receive a high priority and the sympathetic division dilates the arteries that supply them. Processes such as digestion, nutrient absorption, and urine formation can wait; thus the sympathetic division constricts arteries to the gastrointestinal tract and kidneys. It also reduces blood flow through the skin, which may help to minimize bleeding in the event that the stressproducing situation leads to injury. Furthermore, since there is not enough blood in the body to supply all the organ systems equally, it is necessary to temporarily divert blood away from some organs in order to supply an adequate amount to the muscular system. How can the sympathetic division cause smooth muscle to relax in some organs but contract in others What are the two ways in which the sympathetic and parasympathetic systems can affect each other when they both innervate the same target organ How can the sympathetic nervous system have contrasting effects in a target organ without dual innervation Smooth muscle relaxation allows blood pressure within the vessel to push the vessel wall outward. Black lines crossing each nerve fiber represent action potentials, with a high firing frequency in part (a) and a lower frequency in part (b). In this section we briefly consider how it is influenced by various levels of the central nervous system. Anger raises the blood pressure, fear makes the heart race, thoughts of good food make the stomach rumble, sexual thoughts or images increase blood flow to the genitals, and anxiety inhibits sexual function. The limbic system, an ancient part of the cerebral cortex, is involved in many emotional responses and has extensive connections with the hypothalamus, a site of several nuclei of autonomic control. Thus, the limbic system provides a pathway connecting sensory and mental experiences with the autonomic nervous system. This small but vital region in the floor of the brain contains many nuclei for primitive functions, including hunger, thirst, thermoregulation, emotions, and sexuality. Artificial stimulation of different regions of the hypothalamus can activate the fight-or-flight response typical of the sympathetic nervous system or have the calming effects typical of the parasympathetic. Output from the hypothalamus travels largely to nuclei in more caudal regions of the brainstem, and from there to the cranial nerves and the sympathetic neurons in the spinal cord. Many of these nuclei belong to the reticular formation, which extends from the medulla to the hypothalamus. Autonomic output from these nuclei travels by way of the spinal cord and the oculomotor, facial, glossopharyngeal, and vagus nerves. Finally, the spinal cord integrates such autonomic reflexes as micturition (urination), defecation, erection, and ejaculation (details are in sections 23. Fortunately, the brain is able to inhibit defecation and urination consciously, but when injuries sever the spinal cord from the brain, the autonomic spinal reflexes alone control the elimination of urine and feces. What system in the brain connects our conscious thoughts and feelings with the autonomic control centers of the hypothalamus Intermittent attacks of paleness, cyanosis, and pain in the fingers and toes, caused when cold or emotional stress triggers excessive vasoconstriction in the digits; most common in young women. Raynaud disease You can find other autonomic nervous system disorders described in the following places: the mass reflex reaction in Deeper Insight 13. A few examples will illustrate the clinical relevance of neurotransmitter and receptor functions. A number of drugs work by stimulating adrenergic and cholinergic neurons or receptors. Sympatholytics15 are drugs that suppress sympathetic action by inhibiting norepinephrine release or by binding to adrenergic receptors without stimulating them. This interferes with the effects of epinephrine and norepinephrine on the heart and blood vessels. Pilocarpine, for example, relieves glaucoma (excessive pressure in the eyeball) by dilating a vessel that drains fluid from the eye. It is sometimes used to dilate the pupils for eye examinations and to dry the mucous membranes of the respiratory tract before inhalation anesthesia. The drugs we have mentioned so far act on the peripheral nervous system and its effectors. Strychnine, for example, blocks the inhibitory action of glycine on spinal motor neurons. The neurons then overstimulate the muscles, causing spastic paralysis and sometimes death by suffocation. Sigmund Freud predicted that psychiatry would eventually draw upon biology and chemistry to deal with emotional problems once treated only by counseling and psychoanalysis. A branch of neuropharmacology called psychopharmacology has fulfilled his prediction. This field dates to the 1950s when chlorpromazine, an antihistamine, was incidentally found to relieve the symptoms of schizophrenia. The management of clinical depression is one example of how contemporary psychopharmacology has supplemented counseling approaches. Some forms of depression result from deficiencies of the monoamine neurotransmitters. Thus, they yield to drugs that prolong the effects of the monoamines already present at the synapses. One of the earliest-known antidepressants was imipramine, which blocks the synaptic reuptake of serotonin and norepinephrine. However, it produces undesirable side effects such as dry mouth and irregular cardiac rhythms. It is also used to treat fear of rejection, excess sensitivity to criticism, lack of self-esteem, and inability to experience pleasure, all of which were long handled only through counseling, group therapy, or psychoanalysis. Our growing understanding of neurochemistry also gives us more insight into the action of addictive drugs of abuse such as amphetamines and cocaine. Amphetamines ("speed") chemically resemble norepinephrine and dopamine, two neurotransmitters associated with elevated mood. But when dopamine is not reabsorbed by the neurons, it diffuses out of the synaptic cleft and is degraded elsewhere. Cocaine thus depletes the neurons of dopamine faster than they can synthesize it, so that finally there is no longer an adequate supply to maintain normal mood. The postsynaptic neurons make new dopamine receptors as if "searching" for the neurotransmitter-all of which leads ultimately to anxiety, depression, and the inability to experience pleasure without the drug. Caffeine is similar enough to block the action of adenosine by binding to its receptors. Why the autonomic effect on a target cell depends on both the neurotransmitter released and the type of receptor on the target cell 2. Neurotransmitter stability and how it relates to the duration of sympathetic versus parasympathetic effects 6. Autonomic control of certain organs by dual innervation, and examples of antagonistic and cooperative effects on an organ 8. Why this system is called autonomic; how it differs from the somatic motor system 3. Why it cannot be said that at any given moment, either the sympathetic or the parasympathetic division is active; the meaning of autonomic tone 5. How autonomic efferent pathways differ from somatic efferent pathways; the meanings of preganglionic and postganglionic fibers 5. Origin of the sympathetic preganglionic fibers and the routes they take to the sympathetic chain ganglia 2. Anatomy of the sympathetic chain; the number of ganglia at its various levels; and the body regions supplied by nerve fibers issuing from each group of ganglia 3. The gray and white communicating rami that connect the sympathetic ganglia to the spinal nerves; the reason they are named 10.