Water excretion

Nontraditional Hormones. Novel hormones identified ia cardiovascular tissue have profound effects on maintenance of blood pressure and blood volume ia mammals. Atrial natriuretic hormone (ANH) is a polypeptide hormone secreted from the atria of the heart. When the cardiac atrium is stretched by increased blood volume, secretion of ANH is stimulated ANH ia turn increases salt and water excretion and reduces blood pressure (6). Endothelin is a polypeptide hormone secreted by endothehal cells throughout the vasculature. Although endothelin is released into the circulation, it acts locally in a paracrine fashion to constrict adjacent vascular smooth muscle and increase blood pressure (7). 

Kidney Function. Prostanoids influence a variety of kidney functions including renal blood flow, secretion of renin, glomerular filtration rate, and salt and water excretion. They do not have a critical role in modulating normal kidney function but play an important role when the kidney is under stress. Eor example, PGE2 and -I2 are renal vasodilators (70,71) and both are released as a result of various vasoconstrictor stimuli. They thus counterbalance the vasoconstrictor effects of the stimulus and prevent renal ischemia. The renal side effects of NSAIDS are primarily observed when normal kidney function is compromised. 

Diuretics have been the mainstay for HF symptom management for many years. 0 Diuretics are used for relief of acute symptoms of congestion and maintenance of euvolemia. These agents interfere with sodium retention by increasing urinary sodium and free water excretion. No prospective data exist on I the effects of diuretics on patient outcomes.14 Therefore, the... 

Most patients with large ascites also retain sodium avidly and may become hyponatremic if there is a decrease in free water excretion. Untreated, this can lead to a decrease in renal function and the hepatorenal syndrome.4,13... 

Angiotensin II receptor antagonists. These agents promote vasodilation (1 TPR), increase sodium and water excretion, and, therefore, decrease plasma volume (1 CO). 

Explain how the control of water excretion regulates plasma osmo-larity... 

Control of water excretion regulation of plasma osmolarity... 

Regulation of the osmolarity of extracellular fluid, including that of the plasma, is necessary in order to avoid osmotically induced changes in intracellular fluid volume. If the extracellular fluid were to become hypertonic (too concentrated), water would be pulled out of the cells if it were to become hypotonic (too dilute), water would enter the cells. The osmolarity of extracellular fluid is maintained at 290 mOsm/1 by way of the physiological regulation of water excretion. As with sodium, water balance in the body is achieved when water intake is equal to water output. Sources of water input include ... 

The potent antidiuretic hormone AVP orchestrates the regulation of free water absorption, body fluid osmolality, cell contraction, blood volume, and blood pressure through stimulation of three G-protein-coupled receptor subtypes Vi-vascular types a and b, V2-renal, and V3-pituitary. Increased AVP secretion is the trademark of several pathophysiological disorders, including heart failure, impaired renal function, liver cirrhosis, and SIADH. As a consequence, these patients experience excess water retention or inadequate free-water excretion, which results in the dilution of sodium concentrations, frequently manifesting as clinical hyponatremia (serum sodium concentration <135mmol/L). This electrolyte imbalance increases mortality rates by 60-fold. Selective antagonism of the AVP V2 receptor promotes water... 

Diuretics effecting salt and water Drugs effecting water excretion ... 

Bolus diuretic administration decreases preload by functional venodilation within 5 to 15 minutes and later (>20 min) via sodium and water excretion, thereby improving pulmonary congestion. However, acute reductions in venous return may severely compromise effective preload in patients with significant diastolic dysfunction or intravascular depletion. 

Hyponatremia predominantly results from an excess of extracellular water relative to sodium because of impaired water excretion. 

Hydrochlorothiazide Antihypertensive Increases sodium and water excretion, decreases blood... 

Atrial natriuretic factor (ANF), produced by cells in the atrium of the heart in response to distension, binds the ANF receptor in vascular smooth muscle and in the kidney. The ANF receptor spans the membrane and has guanylate cyclase activity associated wMi the cytoplasmic domain. It causes relaxation of vascular smooth muscle, resulting in vasodilation, and in the kidney it promotes sodium and water excretion. 

Water. Water resorption in the proximal tubule is a passive process in which water follows the osmotically active particles, particularly the Na" ions. Fine regulation of water excretion (diuresis) takes place in the collecting ducts, where the peptide hormone vasopressin (antidiuretic hormone, ADH) operates. This promotes recovery of water by stimulating the transfer of aquaporins (see p. 220) into the plasma membrane of the tubule cells via V2 receptors. A lack of ADH leads to the disease picture of diabetes insipidus, in which up to 30 L of final urine is produced per day. 

Fluid and electrolytes Promote water excretion Increase glomerular filtration rate inhibit vasopressin release... 

A toxicity that is unique to cyclophosphamide and ifosfamide is cystitis. Dysuria and decreased urinary frequency are the most common symptoms. Rarely, fibrosis and a permanently decreased bladder capacity may ensue. The risk of development of carcinoma of the bladder also is increased. Large intravenous doses have resulted in impairment of renal water excretion, hyponatremia, and increased urine osmolarity and have been associated with hemorrhagic subendocardial necrosis, arrhythmias, and congestive heart failure. Interstitial pulmonary fibrosis may also result from chronic treatment. Other effects of chronic drug treatment include infertility, amenorrhea, and possible mutagenesis and carcinogenesis. 

Mecfianism of Action A guanidine derivative that acts as a potassium-sparing diuretic, antihypertensive, and antihypokalemicby directly interfering with sodium reabsorption in the distai tubule, TherapeuticEffect Increases sodium and water excretion and decreases potassium excretion. 

Mechanism of Action A potassium-sparing diuretic that interferes with sodium reabsorption by competitively inhibiting the action of aldosterone in the distal tubule, thus promoting sodium and water excretion and increasing potassium retention. Therapeutic Effect Produces diuresis lowers BP diagnostic aid for primary aldosteronism. 

Drugs effecting water excretion Osmotic ADH agonists ADH antagonists... 

Of historical interest, arsenical antibiotics (8.107) were once used to treat syphilis and mercurial diuretics (8.108) were once used to treat edema and to promote water excretion. Due to their high toxicity, neither is currently used. 

Spironolactone Block cytoplasmic aldosterone receptors in collecting tubules of nephron possible membrane effect Increased salt and water excretion reduces remodeling reduces mortality Chronic heart failure aldosteronism (cirrhosis, adrenal tumor) hypertension Oral duration 24-72 h (slow onset and offset) Toxicity Hyperkalemia, antiandrogen actions... 

Technically, a "diuretic" is an agent that increases urine volume, whereas a "natriuretic" causes an increase in renal sodium excretion. Because natriuretics almost always also increase water excretion, they are usually called diuretics. Osmotic diuretics (see under Agents That Alter Water Excretion) are diuretics that are not directly natriuretic. 

Urea concentration in the medulla plays an important role maintaining the high osmolarity of the medulla and in the concentration of urine. ADH secretion is regulated by serum osmolality and by volume status. A new class of drugs, the vaptans (see under Agents That Alter Water Excretion), are ADH antagonists. 

Agents That Alter Water Excretion OSMOTIC DIURETICS... 

Osmotic diuretics are used to increase water excretion in preference to sodium excretion. This effect can be useful when avid Na + retention limits the response to conventional agents. It can be used to maintain urine volume and to prevent anuria that might otherwise result from presentation of large pigment loads to the kidney (eg, from hemolysis or rhabdomyolysis). Some oliguric patients do not respond to osmotic diuretics. Therefore, a test dose of mannitol (12.5 g intravenously) should be given before starting... 

ANP, BNP, CNP, and DNP are vasoactive agents that alter renal salt and water excretion through effects on vascular tone and cardiac output. Many clinical studies of these agents have been carried out, but there is still no consensus on precisely when they should be used and whether they have beneficial or even deleterious effects on renal function. Work that is in progress may answer these questions. 

Administration of ANP produces prompt and marked increases in sodium excretion and urine flow. Glomerular filtration rate increases, with little or no change in renal blood flow, so that the filtration fraction increases. The ANP-induced natriuresis is due to both the increase in glomerular filtration rate and a decrease in proximal tubular sodium reabsorption. ANP also inhibits the secretion of renin, aldosterone, and vasopressin these changes may also increase sodium and water excretion. Finally, ANP causes vasodilation and decreases arterial blood pressure. Suppression of ANP production or blockade of its action impairs the natriuretic response to volume expansion, and increases blood pressure. 

Urodilatin is synthesized in the distal tubules of the kidneys by alternative processing of the ANP precursor. It elicits potent natriuresis and diuresis, and thus functions as a paracrine regulator of sodium and water excretion. It also relaxes vascular smooth muscle. 

Endothelins exert widespread actions in the body. In particular, they cause dose-dependent vasoconstriction in most vascular beds. Intravenous administration of ET-1 causes a rapid and transient decrease in arterial blood pressure followed by a prolonged increase. The depressor response results from release of prostacyclin and nitric oxide from the vascular endothelium, whereas the pressor response is due to direct contraction of vascular smooth muscle. Endothelins also exert direct positive inotropic and chronotropic actions on the heart and are potent coronary vasoconstrictors. They act on the kidneys to cause vasoconstriction and decrease glomerular filtration rate and sodium and water excretion. In the respiratory system, they cause potent contraction of tracheal and bronchial smooth muscle. 

Aliskiren Inhibits catalytic activity of renin Arteriolar dilation decreased aldosterone secretion increased sodium and water excretion Hypertension... 

Nesiritide Agonist of natriuretic peptide receptors Increased sodium and water excretion t vasodilation Heart failure1... 

Omapatrilat Decreases metabolism of natriuretic peptides and formation of angiotensin II Vasodilation increased sodium and water excretion Hypertension heart failure1... 

Renal system Mild polyuria increased renal blood flow increased glomerular filtration rate Impaired water excretion decreased renal blood flow decreased glomerular filtration rate... 

As well as the increased excretion of bicarbonate, Na+ and K+ excretions are also increased. Because of the solute load, water excretion also increases. This results in hypokalemia and dehydration. 

Studies with [l- 4C]dichloroacetonitrile in rats and mice and 2- C dichloroaccto-nitrile in rats indicated that the substance is rapidly absorbed after oral administration in water. Excretion of radioactivity following dosing with l- C dichloroacctonitrilc is more rapid in mice than in rats. In mice, approximately 84% of the dose was excreted in 24 h (67% in urine, 11% in faeces, 5% as CO ), compared with 67% in rats in six days (44% in urine, 17% in faeces, 6% as CO,). Excretion of 2- < dichloroacctonitrilc radioactivity in rats accounted for about 84% of the dose within 48 h (38% in urine, 12% in faeces, 34% as CO2). The quantitative differences in the route of excretion of the two labels in rats indicate that dichloroacetonitrile is being cleaved in vivo. The 1- relabelled compound behaved like cyanide (lARC, 1991). 

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