Aldosterone, produced by the adrenal cortex, acts at epithelial cells in the distal tubule of the nephron to increase the reabsorption of sodium and is therefore con sidered an important hormone in the regulation of electrolyte balance. Aldosterone exerts its effects at the nephron through mineralocorticoid receptors, which translocate to the nucleus upon aldosterone binding and exert genomic effects leading to increased sodium reabsorption. In addition to the epithelial effects of al-dosterone at mineralocorticoid receptors, nonepithelial cells, including cardiac muscle and vascular smooth muscle cells and cells in the brain, can respond to al-dosterone and result in left ventricular hypertrophy, cardiac and vascular fibrosis, and stimulation of sympathetic nervous system activity.
Spironolactone (Aldactone), an antagonist of the al-dosterone mineralocorticoid receptor, is used to treat primary aldosteronism, essential hypertension, and congestive heart failure (see Chapter 21). In the treatment of hypertension resulting from adrenal adenoma (primary al-dosteronism) and in patients with essential hypertension, spironolactone lowers blood pressure primarily through blockade of epithelial mineralocorticoid receptors in the kidney, reductions in sodium and water reabsorption, and diuresis. The use of spironolactone in the treatment of essential hypertension is typically restricted to patients who do not respond appropriately to other agents and is often used in combination drug therapy. In large-scale clinical trials in patients with severe heart failure, administration of spironolactone markedly reduced morbidity and mortality without reducing blood pressure. Spironolactone is used to treat patients with moderate to severe heart failure who exhibit symptoms and ventricular dysfunction despite treatment with an ACE inhibitor or a diuretic.
Adverse effects of spironolactone therapy include hyperkalemia, gastrointestinal problems, gynecomastia (breast enlargement in males), and impotence. Gyneco-mastia and impotence arising from spironolactone treatment are results of significant blockade of the androgen and mineralocorticoid receptors. Novel selective mineralocorticoid receptor antagonists, such as eplere-none, are in clinical trials.
The kallikrein-kinin system is an enzymatic pathway giving rise to two predominant vasoactive peptides, kallidin and bradykinin. Kallikrein, the enzyme responsible for the formation of these peptides, exists in plasma and tissues. However, circulating levels of the end products, kallidin and bradykinin, are quite low because the kallikrein enzymes are present largely in inactive forms. In addition, the short half-life of these pep-tides (15 seconds) also contributes to low plasma levels. In general, the kinins produce relaxation of vascular smooth muscle and vasodilation. Bradykinin causes vascular smooth muscle relaxation by stimulating the endothelium to release prostacyclin and nitric oxide. Blood flow to the brain, heart, viscera, skeletal muscle, and glands is increased. In nonvascular smooth muscle, bradykinin will produce a contractile response.
Other actions of kinins include activation of clotting factors simultaneously with the production of brady-kinin. In the kidney, bradykinin production results in an increase in renal papillary blood flow, with a secondary inhibition of sodium reabsorption in the distal tubule. In the peripheral nervous system, bradykinin is important for the initiation of pain signals. It is also associated with the edema, erythema, and fever of inflammation.
Bradykinin exerts its physiological effects via two receptors, the B1 and B2 receptors, with most of its physiological effects being mediated by the B2 receptor. The precise function of the B1 receptor is unclear; however, some of the chronic inflammatory responses to bradykinin may be mediated through actions at this receptor.
Bradykinin antagonists of the B2 receptor are currently in development and may find utility in the treatment of pain associated with burns and such chronic inflammatory disorders as arthritis, asthma, and chronic pain.
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