Chapter: Modern Pharmacology with Clinical Applications: The Renin–Angiotensin– Aldosterone System and Other Vasoactive Substances

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Natriuretic Peptides

Natriuretic peptides are naturally occurring substances in the body that oppose the activity of the renin– angiotensin system.

Natriuretic Peptides

 

Natriuretic peptides are naturally occurring substances in the body that oppose the activity of the renin– angiotensin system. The natriuretic peptide family con-sists 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 predomi-nates; ANP is synthesized by cardiac myocytes predom-inately in the atria; and CNP is synthesized in the brain, blood vessels, and kidney.

All three peptides exhibit similar biological activi-ties; however, they differ in the potency of individual re-sponses. The target organs of the natriuretic peptides in-clude the kidneys, blood vessels, brain, and adrenal cortex. These peptides exhibit potent diuretic, natri-uretic, and vasodilator effects. Natriuretic peptides pro-mote 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, inhi-bition 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 regu-lation of central control of cardiovascular functions. These biological effects of natriuretic peptides come to-gether to reduce venous return and total peripheral re-sistance, 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 con-gestive heart failure and hypertension. In addition, re-cent 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 recep-tors (subdivided into types A and B) and a receptor thought to serve as a clearance mechanism for the re-moval 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 in-crease in the circulating level of natriuretic peptides such as ANP. Omapatrilat, a vasopeptidase inhibitor, is under study for the treatment of hypertension and con-gestive heart failure.

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