Further attenuation of endothelium-dependent relaxation imparted by natriuretic peptide receptor antagonism

Nitric oxide (NO) is an important endothelium-derived relaxing factor that functions via activation of soluble guanylyl cyclase and cGMP generation in vascular smooth muscle. Recently, studies have described the synthesis and secretion of C-type natriuretic peptide (CNP) from endothelial cells. This peptide also mediates relaxation via cGMP but through activation of partic ulate guanylyl cyclase. We tested the hypothesis that endothelium-dependent relaxations to acetylcholine or bradykinin in isolated canine coronary art eries involve both releases of NO and CNP. Rings of canine coronary arterie s were incubated with either inhibitors of NO production (N-G-monomethyl-La rginine, L-NMMA) or the natriuretic peptide receptor antagonist HS-142-1. C NP caused concentration-dependent relaxations of rings with and without end othelium. These relaxations were attenuated by HS-142-1. Relaxations to ace tylcholine and bradykinin were attenuated by L-NMMA alone but not attenuate d by HS-142-1 alone. Coinhibition with L-NMMA and HS-142-1 significantly in hibited acetylcholine- and bradykinin-induced relaxation to a magnitude gre ater than either inhibitor alone. In summary, st novel interaction between the NO and the natriuretic peptide system is demonstrated by increased atte nuation of endothelium-dependent relaxations to acetylcholine and bradykini n when both NO synthase and natriuretic peptide receptors are inhibited. Th ese investigations support the concept of release of multiple endothelium-d erived factors in response to acetylcholine- and bradykinin-receptor stimul ation in endothelial cells, which may include CNP, as well as NO.