By L. Einar. University of Southern Indiana.

Adrenal Kidney Activation of the sympathetic nervous system occurs in cortex several stressful circumstances (such as hemorrhage) in which the conservation of salt and water by the kidneys is of clear benefit buy cafergot 100 mg amex treatment pain right hand. Estrogens decrease Na excretion 100mg cafergot with amex medial knee pain treatment, probably Angiotensin II Renin by the direct stimulation of tubular Na reabsorption. ANP pro- duces effects that bring blood volume back toward normal, such Glucocorticoids. Chapter 34), increase tubular Na reabsorption and also cause an increase in GFR, which may mask the tubular ef- fect. Osmotic diuretics are solutes that are mones produced by the small intestine in response to salt in- excreted in the urine and increase urinary excretion of Na gestion. Like ANP and urodilatin, they activate guanylyl cy- and K salts and water. Examples are urea, glucose (when clase and produce cGMP as a second messenger, as their the reabsorptive capacity of the tubules for glucose has names suggest. Adrenomedullin is a polypeptide produced been exceeded), and mannitol (a six-carbon sugar alcohol by the adrenal medulla; its physiological significance is still used in the clinic to promote Na excretion or cell shrink- not certain. Osmotic diuretics decrease the reabsorption of Na in the proximal tubule. This response results from the de- stance produced by the adrenal gland. It inhibits Na /K - velopment of a Na concentration gradient (lumen [Na ] ATPase activity and, therefore, inhibits Na transport by the kidney tubules. Bradykinin is produced locally in the plasma Na ]) across the proximal tubular epithelium in the presence of a high concentration of unreabsorbed kidneys and inhibits Na reabsorption. When this occurs, there is sig- Prostaglandins E2 and I2 (prostacyclin) increase Na excretion by the kidneys. These locally produced hor- nificant back-leak of Na into the tubule lumen, down the mones are formed from arachidonic acid, which is liberated concentration gradient. This back-leak results in decreased from phospholipids in cell membranes by the enzyme net Na reabsorption. Further processing is mediated by a cy- most of the filtered Na is normally reabsorbed, osmotic clooxygenase (COX) enzyme that has two isoforms, COX- diuretics, by interfering with this process, can potentially 1 and COX-2. In most tissues, COX-1 is constitutively ex- cause the excretion of large amounts of Na. Osmotic di- pressed, while COX-2 is generally induced by uretics may also increase Na excretion by inhibiting distal inflammation. In the kidney, COX-1 and COX-2 are both Na reabsorption (similar to the proximal inhibition) and constitutively expressed in cortex and medulla. Poorly reabsorbed anions amounts in the renal medulla, where the main role of the result in increased Na excretion. Solutions are electrically neutral; whenever there are more anions in the urine, there prostaglandins is to inhibit Na reabsorption. Because the prostaglandins (PGE2, PGI2) are vasodilators, the inhibi- must also be more cations. If there is increased excretion of phosphate, ketone body acids (as occurs in uncontrolled di- tion of Na reabsorption occurs via direct effects on the 2– tubules and collecting ducts and via hemodynamic effects abetes mellitus), HCO3 , or SO4 , more Na is also ex- (see Chapter 23). To some extent, the Na in the urine can be re- prostaglandins with common nonsteroidal anti-inflamma- placed by other cations, such as K , NH4 , and H. Most of the diuretic drugs used today are Regulated variable specific Na transport inhibitors. For example, the loop di- Extracellular fluid volume uretic drugs (furosemide, bumetanide) inhibit the Na-K- or EABV 2Cl cotransporter in the thick ascending limb, the thiazide diuretics inhibit the Na-Cl cotransporter in the distal con- + Sensor voluted tubule, and amiloride blocks the epithelial Na Renal channel in the collecting ducts (see Chapter 23). Spirono- Na+ Cardiovascular excretion stretch receptors, kidneys lactone promotes Na excretion by competitively inhibit- ing the binding of aldosterone to the mineralocorticoid re- + ceptor. The diuretic drugs are really natriuretic drugs; they produce an increased urine output (diuresis) because water Effector + Kidneys reabsorption is diminished whenever Na reabsorption is decreased.

STIMULANTS General Amphetamines (speed sulph discount 100mg cafergot visa pain management for dogs with arthritis, sulphate proven 100mg cafergot chest pain treatment guidelines, uppers, wake-ups, billy whizz, whizz, whites, base) are synthetic stimulants which as medicines have been formed into a variety of tablets. Their current medical use is very limited and in fact only dexamphetamine sulphate, Dexedrine, is now available for use solely in the treatment of narcolepsy. The only other amphetamine available for medical use is methylphenidate (Ritalin) for the treatment of attention deficit syndrome in children. As a street drug, amphetamine usually comes as a white, grey, yellowish or pinky powder. The purity rate of street powders is less than 10%, the rest being made up of milder stimulants such as caffeine, other drugs such as paracetamol or substances like glucose, dried baby milk, flour or talcum powder. The powder form can be snorted up the nose, mixed in a drink or prepared for injection. During the 1990s, amphetamine was a popular drug among young people attending all-night raves and is probably the next most commonly used illegal drug after cannabis. Recent local surveys have shown between 5% and 18% of 16-year-olds claiming to have used it at least once. This is a crystallised form of meth (or methyl-) amphetamine that can be smoked or injected. It is very strong and can result in intense paranoia and a very unpleasant come-down. After heroin, amphetamine is probably the most commonly injected street drug in the UK. Amphetamines were first discovered in the 1800s but their medical uses were not recognised until the 1930s. Then they were used to counter low blood pressure, for asthmatics and to suppress appetite. Subsequently, amphetamines were prescribed for a whole range of disorders including inability to sleep, epilepsy, migraine, depression and hyperactivity in children. Until 1956 many amphetamine- based drugs could be bought over the counter without a prescription. In the 1970s and 1980s street use of amphetamine increased again and centred on a new generation of young people in the all-night club scene of punk rock and Northern Soul. Illicitly manufactured powdered amphetamine and sniffing replaced tablets stolen from factories as the main form of use. Legal All amphetamines are prescription only drugs under the Medicines Act. Doctors can prescribe them for patients but it is an offence to be in possession of amphetamines without a prescription. Most amphetamines are controlled as class B drugs under the Misuse of Drugs Act. If amphetamines are prepared for injection they become class A drugs and increased penalties apply. They increase breathing and heart rate, lessen appetite and dilate the pupils. Users tend to feel more alert, energetic, confident and cheerful and less bored or tired. With high doses people often experience a rapid flow of ideas and feel they have increased physical and mental powers although this is usually manifest as talking non-stop. Taking a lot, especially over a few days, can produce a temporary panic and paranoia and with high doses the amphetamine psychosis is like a transient episode of schizophrenia. The effects of a single dose last for about 3±4 h and tend to leave the user feeling tired. Users may feel depressed, lethargic, lacking in energy and incredibly hungry without taking the drug. Tolerance also develops with regular use so more is needed to get the same effect. Heavy, regular use often leads to lack of sleep and food and lowers resistance to disease.

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The field of gene therapy is in its channel protein or a membrane protein that regulates infancy buy generic cafergot 100mg on line groin pain treatment exercises, and although there have been no “cures” for chloride channels buy cafergot 100mg visa unifour pain treatment center nc. The gene was identified in 1989 and en- cystic fibrosis, much has been learned about the prob- codes a protein of 1,480 amino acids, the cystic fibrosis lems presented by the inefficient and short-lived transfer transmembrane conductance regulator (CFTR). The next phase of gene therapy will fo- dence indicates that CFTR contains both a chloride channel cus on improving the technology for gene delivery. Although it functions as an ion therapy may become a reality for many lung diseases channel, it has structural similarities to adenosine triphos- during this century. Sodium ions are that directly use metabolic energy to transport ions against transported out of the cell and potassium ions are brought a gradient of concentration or electrical potential are in. It is known as a P-type ATPase because the protein is known as ion pumps. The direct use of metabolic energy to phosphorylated during the transport cycle (Fig. The carry out transport defines a primary active transport pump counterbalances the tendency of sodium ions to en- mechanism. The source of metabolic energy is ATP syn- ter the cell passively and the tendency of potassium ions to thesized by mitochondria, and the different ion pumps hy- leave passively. It maintains a high intracellular potassium drolyze ATP to ADP and use the energy stored in the third concentration necessary for protein synthesis. Because of this abil- a role in the resting membrane potential by maintaining ion ity to hydrolyze ATP, ion pumps also are called ATPases. The sodium-potassium pump can be inhibited ei- The most abundant ion pump in higher organisms is the ther by metabolic poisons that stop the synthesis and sup- sodium-potassium pump or Na /K -ATPase. It is found ply of ATP or by specific pump blockers, such as the car- in the plasma membrane of practically every eukaryotic cell diac glycoside digitalis. The sodium- plasma membrane, in the membrane of the endoplasmic potassium pump is an integral membrane protein consisting reticulum, and, in muscle cells, in the sarcoplasmic reticu- 28 PART I CELLULAR PHYSIOLOGY lum membrane. They pump Mitochondria have F-type ATPases located in the inner calcium ions from the cytosol of the cell either into the ex- mitochondrial membrane. This type of proton pump nor- tracellular space or into the lumen of these organelles. Instead of using the energy organelles store calcium and, as a result, help maintain a stored in ATP molecules to pump protons, its principal low cytosolic concentration of this ion (see Chapter 1). It is present in the luminal membrane of the parietal the respiratory chain. By pumping protons into the lumen of the stomach in exchange Secondary Active Transport. The net effect of ion for potassium ions, this pump maintains the low pH in the pumps is maintenance of the various environments needed stomach that is necessary for proper digestion (see Chapter for the proper functioning of organelles, cells, and organs. It is also found in the colon and in the collecting ducts Metabolic energy is expended by the pumps to create and of the kidney. Its role in the kidney is to secrete H ions into maintain the differences in ion concentrations. They ion releases potential energy when it moves down an elec- pump protons from the cytosol into these organelles, keep- trochemical gradient, just as a body releases energy when ing the inside of the organelles more acidic (at a lower pH) falling to a lower level. Cells have developed several carrier mechanisms to ATPases because they were first discovered in intracellular transport one solute against its concentration gradient by vacuolar structures, have now been detected in plasma using the energy stored in the favorable gradient of an- membranes. In mammals, most of these mechanisms use plasma membrane of kidney cells is characterized as a V- sodium as the driver solute and use the energy of the type ATPase. By secreting protons, it plays an important sodium gradient to carry out the “uphill” transport of an- role in acidifying the tubular urine. A solute is moved against its con- expose the binding sites to the cytosol, where Na readily dissoci- centration gradient by coupling it to Na moving down a favor- ates because of the low intracellular Na concentration. Binding of extracellular Na to the carrier protein lease of Na decreases the affinity of the carrier for solute and may increase the affinity of binding sites for solute, so that solute forces the release of the solute inside the cell, where solute con- also can bind to the carrier, even though its extracellular concen- centration is already high. CHAPTER 2 The Plasma Membrane, Membrane Transport, and the Resting Membrane Potential 29 dient is maintained by the action of the sodium-potassium in the human intestine has been cloned and sequenced. It is pump, the function of these transport systems also de- called sodium-dependent glucose transporter (SGLT). Although they do not protein contains 664 amino acids, and the polypeptide directly use metabolic energy for transport, these systems chain is thought to contain 14 membrane-spanning seg- ultimately depend on the proper supply of metabolic en- ments (Fig.

Some studies suggest that 5-HT1B receptors are responsible but evidence for this is inconsistent buy 100mg cafergot with visa pain and spine treatment center dworkin. Another possibility is that it is in fact the metabolite of d-fenfluramine generic 100mg cafergot otc a better life pain treatment center golden valley az, norfenfluramine, which increases satiety through its potent activation of 5-HT2C receptors. Although this remains unconfirmed, 5-HT2C knock-out mutant mice are less sensitive to the effects of this drug on satiety than are their wild-type counterparts. A final, important distinction between sibutramine and d-fenfluramine is that the actions of the former, but not the latter, rest on its modification of both 5-HT and noradrenergic transmission. Thus, the reduction in food intake by sibutramine is partially blocked by a1-orb1-adrenoceptor antagonists as well as 5-HT2A/2C or 5-HT2B/2C antagonists. In fact, there appears to be a synergistic interaction between these two transmitter systems. This is illustrated by a study of the effects of the selective serotonin 208 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION reuptake inhibitor, fluoxetine, and the selective noradrenaline uptake inhibitor, nisoxetine on food intake and BAT thermogenesis. Using doses of these drugs that were ineffective on either measure when given alone, they did increase both satiety (Jackson et al. NPY, leptin, orexins, corticosteroids and other monoamines) and it will take a great deal of research to unravel all these networks. However, the progress that has been made so far underlines the crucial role played by 5-HT in this process and reinforces the view that drugs targeting specific 5-HT receptors could turn out to be effective anti-obesity agents that lack the adverse effects of 5-HT releasing agents. REFERENCES Adell, A, Casanovas, JM and Artigas, F (1997) Comparative study in the rat of the actions of different types of stress in the release of 5-HT in the raphe nuclei and forebrain areas. Barnes, NM and Sharp, T (1999) A review of central 5-HT receptors and their function. Blakely, RD, Ramamoorthy, S, Schroeter, S, Qian, Y, Apparsundaram, S, Galli, A and DeFelice, LJ (1998) Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins. Blundell, JE (1977) Is there a role for serotonin (5-hydroxytryptamine) in feeding? Curzon, G, Gibson, EL and Oluyomi, AO (1997) Appetite suppression by commonly used drugs depends on 5-HT receptors but not on 5-HT availability. Heal, DJ, Cheetham, SC, Prow, MR, Martin, KF and Buckett, WR (1998) A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying drugs. Jackson, HC, Needham, AM, Hutchins, LJ, Mazurkiewicz, SE and Heal, DJ (1997) Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat. Jacobs, BL and Azmitia, EC (1992) Structure and function of the brain serotonin system. Jacobs, BL and Fornal, CA (1999) Activity of serotonergic neurons in behaving animals. Krebs-Thomson, K, Paulus, MP and Geyer, MA (1998) Effects of hallucinogens on locomotor and investigatory activity and patterns: influence of 5-HT2A and 5-HT2C receptors. Leibowitz, SF, Alexander, JT (1998) Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Lowry, CA, Odda, JE, Lightman, SL and Ingram, CD (2000) Corticotropin-releasing factor (CRF) increases the in vitro firing rates of serotonergic neurones in the rat dorsal raphe nucleus: evidence for selective activation of a topographically organised mesolimbocortical system. Massot, O, Rousselle, JC, Grimaldi, B, Cloez-Tayarani, I, Fillion, MP, Plantefol, M, Bonnin, A, Prudhomme, N and Fillion, G (1998) Molecular, cellular and physiological characteristics of 5-HYDROXYTRYPTAMINE 209 5-HT-moduline, a novel endogenous modulator of 5-HT1B receptor subtype. McQueen, JK, Wilson, H, Sumner, BEH and Fink, G (1999) Serotonin transporter (SERT) mRNA and binding site densities in male rat brain affected by sex steroids. Petty, F, Kramer, G, Wilson, L and Jordan, S (1994) In vivo serotonin release and learned helplessness. Petty, F, Jordan, S, Kramer, GL, Zukas, PK and Wu, J (1997) Benzodiazepine prevention of swim-stress induced sensitization of cortical biogenic amines: an in vivo microdialysis study. Povlock, SL and Amara, SG (1997) The structure and function of norepinephrine, dopamine and serotonin transporters. Ramamoorthy, S and Blakely, RD (1999) Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants.

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