Endothelial NO/cGMP system contributes to natriuretic peptide-mediated coronary and peripheral vasodilation

We tested the hypothesis that the endothelial nitric oxide (NO)-soluble gua nylyl cyclase system is involved in atrial natriuretic Peptide (ANP) and C- type natriuretic peptide (CNP) mediated regulation of coronary and peripher al vascular resistance. Rat hearts were perfused via the aorta at constant flow and the effect of ANP and CNP on coronary perfusion pressure and relea se of cGMP was determined in the absence and presence of the nitric oxide s ynthase inhibitor N-G-nitro-L-arginine (L-NNA; 0.2 mmol/L) and the specific inhibitor of soluble guanylyl cyclase ODQ (20 mu mol/L), respectively (n = 6). ANP (10-300 nmol/L) reduced perfusion pressure from 133 +/- 2 to 53 +/ - 2 mm Hg (-60%, control) in the presence of L-NNA from 132 +/- 1 to 71 +/- 1 mm Hg (-46%) and in the presence of ODQ from 133 +/- 1 to 85 +/- 2 (-36% ) (n = 6; P < 0.05). Disruption of the coronary endothelium by perfusion of hearts with collagenase reduced the relaxant effect of ANP to a similar ex tent as L-NNA. Basal release of cGMP was increased up to sixfold by ANP and this increase was reduced by L-NNA and ODQ (n = 6; P < 0.05). The coronary relaxant effect of CNP (0.1-3 mu mol/L) was similarly attenuated by L-NNA and ODQ (II = 6). In conscious mice, a low dose of L-NNA (30 nmol) consiste ntly reduced the blood pressure lowering effect of ANP (30 nmol) by similar to 40% (n = 7), whereas the hypotensive effect of nitroprusside (0.15 mu m ol) was not affected (n = 5). We conclude that the coronary dilatory and hy potensive action of natriuretic peptides involves the endothelium and is pa rtly mediated by soluble guanylyl cyclase. The data may explain previous ob servations in humans with congestive heart failure showing impaired vascula r ANP responses. (C) 2001 Academic Press.