Natriuretic Peptides

Natriuretic peptides are naturally occurring substances in the body that oppose the activity of the renin-angiotensin system. The natriuretic peptide family consists of atrial natriuretic peptide (ANP), brain natri-uretic peptide (BNP), and C-type natriuretic peptide (CNP). All three natriuretic peptides are synthesized from cleavage of a larger precursor polypeptide. In the ventricles and brain, the synthesis of BNP predominates; ANP is synthesized by cardiac myocytes predominately in the atria; and CNP is synthesized in the brain, blood vessels, and kidney.

All three peptides exhibit similar biological activities; however, they differ in the potency of individual responses. The target organs of the natriuretic peptides include the kidneys, blood vessels, brain, and adrenal cortex. These peptides exhibit potent diuretic, natri-uretic, and vasodilator effects. Natriuretic peptides promote endothelial permeability and the movement of water from the intravascular to the extravascular space. In the kidney, natriuretic peptides increase the glomeru-lar filtration rate through vasodilation of the afferent arteriole and constriction of the efferent arteriole, inhibition of the reabsorption of sodium in the proximal and distal tubule, and inhibition of renin synthesis. In the brain, natriuretic peptides are involved in the regulation of central control of cardiovascular functions. These biological effects of natriuretic peptides come together to reduce venous return and total peripheral resistance, thereby improving cardiac performance and reducing blood pressure.

The release of ANP from the heart is regulated acutely by stretch of atrial myocytes and has been used as a marker for cardiovascular diseases, including congestive heart failure and hypertension. In addition, recent results demonstrate an increase in the circulating concentration of ANP following stroke and linkage of the ANP gene to patients who have strokes. Two types of atrial natriuretic receptors have been identified in target tissues, including guanylate cyclase-linked receptors (subdivided into types A and B) and a receptor thought to serve as a clearance mechanism for the removal of circulating ANP. Analogues that act as ANP agonists are being developed for use in hypertension and congestive heart failure.

In addition, a new class of drugs, termed vasopepti-dase inhibitors, inhibit the enzymatic activity of ACE and neutral endopeptidase, the enzyme responsible for the breakdown of natriuretic peptides. The end result is a reduction in the synthesis of angiotensin II and an increase in the circulating level of natriuretic peptides such as ANP. Omapatrilat, a vasopeptidase inhibitor, is under study for the treatment of hypertension and congestive heart failure.

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