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Hyperosmolality result- decreased by a combination of low arterial blood pressure ing from large organic molecules that do not enter en- (hypotension) and sympathetically mediated vasoconstric- dothelial cells does not cause appreciable increases in NO tion that mucosal tissue damage can result generic 120mg viagra extra dosage erectile dysfunction age at onset. These observations suggest that NaCl entering the en- HEPATIC CIRCULATION dothelial cells is essential to induce NO formation cheap 130mg viagra extra dosage mastercard erectile dysfunction prevalence age. The hepatic circulation perfuses one of the largest organs in The active absorption of amino acids and carbohydrates the body, the liver. The liver is primarily an organ that and the metabolic processing of lipids into chylomicrons maintains the organic chemical composition of the blood by mucosal epithelial cells place a major burden on the mi- plasma. For example, all plasma proteins are produced by crovasculature of the small intestine. There is an extensive the liver, and the liver adds glucose from stored glycogen network of capillaries just below the villus epithelial cells to the blood. The villus capillaries are unusual in and bacteria and detoxifies many man-made or natural or- that portions of the cytoplasm are missing, so that the two ganic chemicals that have entered the body. These areas of fusion, or closed fenestrae, are thought to facilitate the uptake of absorbed materials by The Hepatic Circulation Is Perfused by capillaries. In addition, intestinal capillaries have a higher Venous Blood From Gastrointestinal Organs filtration coefficient than other major organ systems, which and a Separate Arterial Supply probably enhances the uptake of water absorbed by the villi (see Chapter 16). However, large molecules, such as plasma The human liver has a large blood flow, about 1. It is perfused by both the reflection coefficient for the intestinal vasculature is arterial blood through the hepatic artery and venous greater than 0. CHAPTER 17 Special Circulations 283 The venous blood arrives via the hepatic portal vein and accounts for about 67 to 80% of the total liver blood flow (see Table 17. The remaining 20 to 33% of the total flow is through the hepatic artery. The majority of blood flow to the liver is determined by the flow through the stomach and small intestine. About half of the oxygen used by the liver is derived from venous blood, even though the splanchnic organs have removed one third to one half of the available oxygen. The liver has a high metabolic rate and is a large organ; consequently, it has the largest oxygen consumption of all organs in a resting person. The Liver Acinus Is a Complex Microvascular Unit With Mixed Arteriolar and Venular Blood Flow The liver vasculature is arranged into subunits that allow the arterial and portal blood to mix and provide nutrition for the liver cells. The core of each acinus is supplied by a single ter- minal portal venule; sinusoidal capillaries originate from this venule (Fig. A sin- gle liver acinus, the basic subunit of liver struc- ies have fenestrated regions with discrete openings that fa- ture, is supplied by a terminal portal venule and a terminal hepatic cilitate exchange between the plasma and interstitial spaces. The mixture of portal venous and arterial blood occurs The capillaries do not have a basement membrane, which in the sinusoidal capillaries formed from the terminal portal partially contributes to their high permeability. Usually two terminal hepatic venules drain the sinusoidal The terminal hepatic arteriole to each acinus is paired capillaries at the external margins of each acinus. The intermixing of the arterial and portal One might suspect that during digestion, when gas- blood tends to be intermittent because the vascular smooth trointestinal blood flow and, therefore, portal venous blood muscle of the small arteriole alternately constricts and re- flow are increased, the gastrointestinal hormones in portal laxes. This prevents arteriolar pressure from causing a sus- venous blood would influence hepatic vascular resistance. The best evidence is that he- lent to those during digestion, none of the major hormones patic artery and portal venous blood first mix at the level of appears to influence hepatic blood flow. The sinusoidal capillaries are creased hepatic blood flow during digestion would appear drained by the terminal hepatic venules at the outer mar- to be determined primarily by vascular responses of the gins of each acinus; usually at least two hepatic venules drain gastrointestinal vasculatures. The vascular resistances of the hepatic arterial and por- tal venous vasculatures are increased during sympathetic nerve activation, and the buffer mechanism is suppressed.

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This makes sense from a physiological perspective The thyroid hormones exert negative-feedback effects because the thyroid hormones are important in regulating on both the hypothalamus and the pituitary purchase 130 mg viagra extra dosage amex erectile dysfunction medication options. Brief exposure of thalamic TRH-secreting neurons buy viagra extra dosage 130mg amex erectile dysfunction drugs history, thyroid hormones reduce experimental animals to a cold environment stimulates the TRH mRNA and TRH prohormone to decrease TRH re- secretion of TSH, presumably a result of enhanced TRH se- 590 PART IX ENDOCRINE PHYSIOLOGY cretion. Newborn humans behave much the same way, in Human GHRH is a peptide composed of a single chain that they respond to brief cold exposure with an increase in of 44 amino acid residues. This response to cold does not occur in GHRH consisting of 40 amino acid residues is also present adult humans. GHRH is synthesized in the cell bodies of neu- The hypothalamic-pituitary-thyroid axis, like the hypo- rons in the arcuate nuclei and ventromedial nuclei of the thalamic-pituitary-adrenal axis, follows a diurnal circadian hypothalamus. Peak TSH secretion occurs in the early illary networks giving rise to the portal vessels. Physi- neurons receive a stimulus for GHRH secretion, they dis- cal and emotional stress can alter TSH secretion but the ef- charge GHRH from their axon terminals into the hy- fects of stress on the hypothalamic-pituitary-thyroid axis pophyseal portal circulation. These receptors are coupled to adenylyl cyclase by a stimulatory G protein, G. The inter-s action of GHRH with its receptors activates adenylyl cy- GH Regulates Growth During Childhood clase, increasing the concentration of cyclic AMP (cAMP) and Remains Important Throughout Life in the somatotroph. The rise in cAMP activates protein ki- As its name implies, growth hormone (GH) promotes the nase A (PKA), which, in turn, phosphorylates proteins that growth of the human body. It does not appear to stimu- stimulate GH secretion and GH gene expression. GHRH 2 late fetal growth, nor is it an important growth factor dur- binding to its receptor also increases intracellular Ca , ing the first few months after birth. In addition, some evidence sential for the normal rate of body growth during suggests that GHRH may stimulate PLC, causing the hy- childhood and adolescence. Growth hormone (also called somatotropin) is se- creted by the anterior pituitary throughout life and re- Somatotroph mains physiologically important even after growth has stopped. In addition to its growth-promoting action, GH has effects on many aspects of carbohydrate, lipid, and protein metabolism. For example, GH is thought to be one of the physiological factors that counteract and, thus, modulate some of the actions of insulin on the liver and peripheral tissues. Human GH GH mRNA is a globular 22 kDa protein consisting of a single chain of Gi cAMP PKA P proteins 191 amino acid residues with two intrachain disulfide bridges. Human GH has considerable structural similarity AC to human PRL and placental lactogen. ATP Growth hormone is produced in somatotrophs of the an- Gs terior pituitary. It is synthesized in the rough ER as a larger prohormone consisting of an N-terminal signal peptide and Ca2 GH GHRH the 191-amino acid hormone. The signal peptide is then cleaved from the prohormone, and the hormone traverses Secretory the Golgi apparatus and is packaged in secretory granules. As a result, the normal rate of GH production depends on GH these hormones. For example, a thyroid hormone deficient individual is also GH-deficient. This important action of The actions of GHRH and somatostatin on FIGURE 32. GHRH binds to membrane receptors that are coupled to adenylyl cyclase (AC) by stimula- Regulation of GH Secretion by GHRH and Somatostatin. Cyclic AMP (cAMP) rises in the cell and ac- The secretion of GH is regulated by two opposing hypo- tivates protein kinase A (PKA), which then phosphorylates pro- teins (P proteins) involved in stimulating GH secretion and the thalamic releasing hormones. Ca is also involved in the ac- tion and somatostatin inhibits GH secretion by inhibiting tion of GHRH on GH secretion.

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Carbohydrate Bound to antigen cheap viagra extra dosage 130mg with amex erectile dysfunction cause of divorce, IgG can activate serum complement 200mg viagra extra dosage with mastercard erectile dysfunction medication prices, which releases several inflammatory and bactericidal medi- ators. At the surface of bacteria, exposed Fc portions of IgG Heavy chain molecules facilitate the phagocytosis of bacteria by blood 450 amino acids phagocytes, a process called opsonization. Each heavy chain and light chain pos- of the fundamental Y-shaped antibody unit. In most IgA sesses a constant region (where the amino acid sequence of indi- molecules, two antibody units are held together by a secre- vidual molecules is similar) and a variable region, where tory piece (J chain), a protein synthesized by epithelial alterations in the amino acid sequence convey to the antibody its individual antigen specificity. In this conformation, IgA is actively secreted into saliva, tears, colostrum, and mucus. IgM is the first antibody secreted chains (two heavy chains and two light chains) held together after an initial immune challenge and provides resistance as a Y-shaped molecule by one or more disulfide bridges. Each polypeptide chain possesses both a conserved constant Its size and large number of antigen-binding sites provide region and a variable region, where considerable amino acid the molecule with an excellent capacity for agglutination, sequence heterogeneity is found even within a single anti- the ability to clump particulate antigens, such as bacteria body class. Clumped antigens are efficiently and widely diverse antigen-binding ability of antibody molecules, quickly removed by fixed phagocytic cells of the mono- for it is the variable region that actually combines with the cyte-macrophage system. These The amino terminal portions of the variable regions, the cells are heavily granulated. The granules contain histamine, antigen-binding sites, are known as the Fab regions. Each leukotrienes, and other biologically active agents that in- antibody unit possesses two identical antigen-binding sites, crease vascular permeability, dilate blood vessels (and, one at each end of the “Y. The granules are released when IgE, consisting of Fc and Fab regions of antibody molecules can bound to mast cells at the Fc region, binds its specific anti- TABLE 11. The ensuing allergic responses range from hay fever, openings in blood vessels. The aggregates form a physical hives, and bronchial asthma (induced by local or inhaled al- barrier that begins to limit blood loss soon after the open- lergens) to systemic anaphylaxis, a potentially fatal response ing occurs. Second, phospholipids on the platelet plasma triggered when antigen is given systemically. Platelet activation results in the sequential responses of ad- HEMOSTASIS herence, aggregation, and secretion. Adherence is initiated when one or more substances, released from cells or activated Circulating in a high-pressure, closed system that communi- in plasma at the site of a hemorrhage, bind to receptors in the cates with all tissues and cells in the body, blood exchanges platelet plasma membrane. Receptor binding results, via sec- oxygen, nutrients, and wastes and provides necessary compo- ond messengers, in adherence (to other platelets and the in- nents for host defense. This communication takes place largely ner, endothelial surface of blood vessels) and secretion. Endothelial cells also rapidly de- fragile capillaries may result from minor tissue injury associ- ploy cellular adherence antigens known as integrins on the ated with normal physical activity or from massive tissue outer surface of their plasma membranes during wound trauma as a result of serious injury or infection, and may healing. These adherence antigens are deployed to the cell quickly lead to death. Any opening in the vascular network membrane by cellular processes set in motion by factors may lead to massive bruising or blood loss if left unrepaired. In turn, activated endothelial cells injury, components of the hemostatic system are activated. They may be activated on exposure to for- forming a bridge between cell surface receptors and colla- eign surfaces during bleeding, or by torn tissue at the site of gen in the subendothelial matrix.

Likewise order 130 mg viagra extra dosage visa erectile dysfunction quiz, removal of dealers from the street appears to simply allow others to move in to supply the constant demand cheap viagra extra dosage 150 mg otc erectile dysfunction young adults. The idea is to gradually reduce the dose of methadone until the person is able to come off drugs without suffering withdrawal symptoms. The problem is that many users seem to quickly go back on heroin so that some doctors prescribe methadone on a maintenance basis, not reducing the dosage until the person feels ready to give up, a process that can be lengthy. One school of thought would claim that this approach simply keeps people dependent on a different drug. The opposite view is that methadone keeps people away from the dangerous street market in heroin, with the associated risks of crime and overdose. Unfortunately, many users obtain methadone legally and then sell it to buy street heroin. Recent years have also seen the development of needle exchange schemes whereby users of injectable heroin can receive clean equipment rather than sharing needles to minimise the threat of hepatitis and HIV. These schemes seem to be very effective although it has been claimed that they encourage injecting. Another issue is heroin- related crime, especially theft, burglary and forgery, as a dependent user will need about £50 a day to pay for the drug. The cost to the community is unknown but some police forces have estimated that up to one-third of crime relates to drug use. Legal Heroin and other opiates are controlled under the Misuse of Drugs Act making it illegal to possess them or to supply them to other people without a prescription. Effects Heroin and other opiates are drugs that depress the nervous system. The desired effect on the street is not the analgesia that is the reason for their medical use but the feeling of warmth, reduction in anxiety and detachment. The effects of both smoked and obviously injected heroin are rapid and then last several hours but this varies with how much is taken and the route of application. Mental anguish is removed and hence the use of the drug as a means of escape from social and other pressures becomes clearer. Although initial use can result in a feeling of nausea and even actual vomiting these 504 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION unpleasant reactions are subject to tolerance. With high doses of heroin a marked sedation takes over and people can fall asleep. Excessive doses can lead to severe sedation and vomiting Ð the combination can be lethal. This is further compounded by the fact that opioids can depress the respiratory centre and with non-medical use the most common form of death is from respiratory failure. With regular use tolerance develops as does psychological and physical dependence. The withdrawal syndrome leads to unpleasant flu-like symptoms which may include aches, tremor, sweating, chills and muscular spasms. These fade after about a week but can be a major deterrent to giving up the drug. While many people do successfully give up long-term heroin use, coming off and staying off heroin can be very difficult. Fatal overdoses can happen, especially when users take their initial dose after a break during which tolerance has faded, or when opiate use is combined with use of other drugs such as alcohol, tranquillisers or other opiates. Many regular heroin users will use other opiates or depressant drugs when they cannot get hold of heroin.

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