Vascular receptors for atrial natriuretic peptide in hypertension

Atrial natriuretic peptide (ANP) is secreted by the heart in response mainly to atrial distension and circulates in plasma in picomolar concentrations. It binds to receptors in blood vessels which it relaxes, renal glomeruli where it induces increased glomerular filtration rate, renal papilla to produce natriuresis, adrenal glomerulosa celts to inhibit aldosterone secretion, and median eminence and pituitary where it may inhibit vasopressin secretion. In experimental models of hypertension plasma levels of ANP are uniformly elevated, except in spontaneously hypertensive rats, in which plasma ANP may only rise transiently. The action of ANP on smooth muscle cells of the blood vessel wall results in production of cyclic GMP, which appears to be the second messenger producing relaxation of pre-contracted blood vessels. Mechanisms other than cGMP generation have been proposed but remain unproven as mediators of ANP action. Receptors for ANP in blood vessels are of two subtypes: B-receptors (or R₁-receptors), which contain guanylate cyclase in their structure, and C-receptors (or R₂-receptors), which have not been shown to the present to be biologically active. Our studies on vascular ANP receptors are reviewed. In several experimental models of hypertension such as saralasin-insensitive 2-kidney, 1-clip and 1-kidney, 1-clip Goldblatt hypertensive rats and in DOCA-salt hypertensive rats, we have found elevated plasma ANP, as well as decreased binding and ANP-induced vascular relaxation and blood pressure-lowering effects of ANP. Both the B and C ANP receptors appear decreased in density, even after acid washing of membranes to remove any retained circulating ANP. In SHR we have found that plasma ANP was higher than in control WKY rats only transiently at 8 weeks. Binding was significantly lower in 4 and 8 week-old SHR, but cGMP generation and relaxation produced by ANP were increased in the 4 week-old SHR but normal at 8, 12 or 16 weeks. Expression of B-receptors was exaggerated in 4 week-old SHR relative to C receptors in comparison to age-matched WKY and Wistar rats. These results may underly the normalization of blood pressure found in SHR when a small dose of ANP is infused intravenously, in contrast to other models of experimental hypertension which appear to be more resistant to ANP-induced blood pressure lowering effects. In humans with essential hypertension, plasma ANP was increased in patients with moderate to severe uncontrolled high blood pressure, associated with echocardiographic evidence of left ventricular hypertrophy. In these patients, platelet ANP binding was significantly reduced. If these sites resemble vascular ANP sites in their behavior, severely hypertensive patients may be less sensitive to ANP, which may contribute to blood pressure elevation.