Relaxant effect of C-type natriuretic peptide involves endothelium and nitric oxide–cGMP system in rat coronary microvasculature

Objective: Recent evidence suggests a possible role for nitric oxide (NO) in atrial natriuretic peptide-induced blood pressure effects. We tested the hypothesis that C-type natriuretic peptide (CNP)-mediated relaxation of the rat coronary circulation involves NO and activation of soluble guanylyl cyclase. Methods: Rat hearts (n=6 per group) were perfused in vitro at constant flow and the effect of CNP (0.1–3 μmol/l) on coronary perfusion pressure (a measure of vascular tone) and release of guanosine 3′,5′-cyclic monophosphate (cGMP) was determined in absence and presence of the nitric oxide (NO) synthase inhibitor N^G-nitro-l-arginine (l-NNA; 0.2 mmol/l) or the natriuretic peptide receptor antagonist HS-142-1 (50 μg/ml). The involvement of Ca²⁺-gated and ATP-dependent K⁺ channels in CNP-induced relaxation was tested with iberiotoxin (30 nmol/l) and glibenclamide (1 μmol/l), respectively. Rings of rat aorta (n=12) were tested using the organ bath set-up. Results: CNP reduced perfusion pressure from 134±2 mmHg (baseline) to 71±1 mmHg (−48%) and this effect was significantly attenuated by l-NNA (−37%) or HS-142-1 (−19%). In presence of glibenclamide, CNP reduced perfusion pressure to 92±2 mmHg (−32%), in presence of iberiotoxin to 93±1 mmHg (−30% and in their combined presence to 102±2 mmHg (−23%) (P<0.05 vs. corresponding control). Basal release of cGMP was increased up to 4-fold by CNP and this increase was reduced (−50%) in presence of l-NNA or HS-142-1 (−68%). By contrast, relaxation of rat aortic rings mounted in organ baths was insensitive to inhibition by l-NNA. Conclusion: Relaxation of the coronary resistance vessels of the rat by CNP is partly mediated by the NO–cGMP pathway. These novel data support the existence of an endogenous link between soluble and particulate guanylyl cyclases in the control of natriuretic peptide-mediated coronary resistance vessel function.