Atrial natriuretic peptide and its actions.

ANP release from the cardiac atria is stimulated by blood volume expansion, which stretches the atria. ANP produces effects that bring blood volume back toward normal, such as increased Na+ excretion.

men, inhibiting Na+ reabsorption by inner medullary collecting ducts via cGMP. There is also a brain natriuretic peptide. Guanylin and uroguanylin are polypeptide hormones produced by the small intestine in response to salt ingestion. Like ANP and urodilatin, they activate guanylyl cy-clase and produce cGMP as a second messenger, as their names suggest. Adrenomedullin is a polypeptide produced by the adrenal medulla, its physiological significance is still not certain. Endoxin is an endogenous digitalis-like substance produced by the adrenal gland. It inhibits Na+/K+-ATPase activity and, therefore, inhibits Na+ transport by the kidney tubules. Bradykinin is produced locally in the kidneys and inhibits Na+ reabsorption.

Prostaglandins E2 and I2 (prostacyclin) increase Na+ excretion by the kidneys. These locally produced hormones are formed from arachidonic acid, which is liberated from phospholipids in cell membranes by the enzyme phospholipase A2. Further processing is mediated by a cy-clooxygenase (COX) enzyme that has two isoforms, COX-1 and COX-2. In most tissues, COX-1 is constitutively expressed, while COX-2 is generally induced by inflammation. In the kidney, COX-1 and COX-2 are both constitutively expressed in cortex and medulla. In the cortex, COX-2 may be involved in macula densa-mediated renin release. COX-1 and COX-2 are present in high amounts in the renal medulla, where the main role of the prostaglandins is to inhibit Na+ reabsorption. Because the prostaglandins (PGE2, PGI2) are vasodilators, the inhibition of Na+ reabsorption occurs via direct effects on the tubules and collecting ducts and via hemodynamic effects (see Chapter 23). Inhibition of the formation of prostaglandins with common nonsteroidal anti-inflamma tory drugs (NSAIDs), such as aspirin, may lead to a fall in renal blood flow and to Na+ retention.

Renal Sympathetic Nerves. The stimulation of renal sympathetic nerves reduces renal Na+ excretion in at least three ways:

1) It produces a decline in GFR and renal blood flow, leading to a decreased filtered Na+ load and peritubular capillary hydrostatic pressure, both of which favor diminished Na+ excretion.

2) It has a direct stimulatory effect on Na+ reabsorption by the renal tubules.

3) It causes renin release, which results in increased plasma angiotensin II and aldosterone levels, both of which increase tubular Na+ reabsorption.

Activation of the sympathetic nervous system occurs in several stressful circumstances (such as hemorrhage) in which the conservation of salt and water by the kidneys is of clear benefit.

Estrogens. Estrogens decrease Na+ excretion, probably by the direct stimulation of tubular Na+ reabsorption. Most women tend to retain salt and water during pregnancy, which may be partially related to the high plasma estrogen levels during this time.

Glucocorticoids. Glucocorticoids, such as cortisol (see Chapter 34), increase tubular Na+ reabsorption and also cause an increase in GFR, which may mask the tubular effect. Usually a decrease in Na+ excretion is seen.

Osmotic Diuretics. Osmotic diuretics are solutes that are excreted in the urine and increase urinary excretion of Na+ and K+ salts and water. Examples are urea, glucose (when the reabsorptive capacity of the tubules for glucose has been exceeded), and mannitol (a six-carbon sugar alcohol used in the clinic to promote Na+ excretion or cell shrinkage). Osmotic diuretics decrease the reabsorption of Na+ in the proximal tubule. This response results from the development of a Na+ concentration gradient (lumen [Na+] < plasma Na+]) across the proximal tubular epithelium in the presence of a high concentration of unreabsorbed solute in the tubule lumen. When this occurs, there is significant back-leak of Na+ into the tubule lumen, down the concentration gradient. This back-leak results in decreased net Na+ reabsorption. Because the proximal tubule is where most of the filtered Na+ is normally reabsorbed, osmotic diuretics, by interfering with this process, can potentially cause the excretion of large amounts of Na+. Osmotic diuretics may also increase Na+ excretion by inhibiting distal Na+ reabsorption (similar to the proximal inhibition) and by increasing medullary blood flow.

Poorly Reabsorbed Anions. Poorly reabsorbed anions result in increased Na+ excretion. Solutions are electrically neutral, whenever there are more anions in the urine, there must also be more cations. If there is increased excretion of phosphate, ketone body acids (as occurs in uncontrolled diabetes mellitus), HCO3~, or SO42-, more Na+ is also excreted. To some extent, the Na+ in the urine can be replaced by other cations, such as K+, NH4+, and H+.

Diuretic Drugs. Most of the diuretic drugs used today are specific Na+ transport inhibitors. For example, the loop diuretic drugs (furosemide, bumetanide) inhibit the Na-K-2Cl cotransporter in the thick ascending limb, the thiazide diuretics inhibit the Na-Cl cotransporter in the distal convoluted tubule, and amiloride blocks the epithelial Na+ channel in the collecting ducts (see Chapter 23). Spironolactone promotes Na+ excretion by competitively inhibiting the binding of aldosterone to the mineralocorticoid receptor. The diuretic drugs are really natriuretic drugs,- they produce an increased urine output (diuresis) because water reabsorption is diminished whenever Na+ reabsorption is decreased. Diuretics are commonly prescribed for treating hypertension and edema.

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