C-type natriuretic peptide-induced vasodilation is dependent on hyperpolarization in human forearm resistance vessels

Animal studies have demonstrated that CNP causes endothelium-independent va sodilation, which is limited by neutral endopeptidase (NEP) activity, Howev er, the vasodilating mechanism of CNP in humans is still unknown. Therefore , we investigated the vasodilator actions of CNP in human forearm resistanc e vessels before and after inhibition of nitric oxide (NO) and then prostac yclin production and after inhibition of Ca2+-dependent potassium channel a ctivation and NEP activity. Three separate studies were performed. In each study, forearm blood flow was recorded by venous occlusion plethysmography in 8 healthy nonsmoking subjects. Brachial artery infusion of CNP (70, 140, 280, and 560 ng per 100 mt forearm volume per minute) caused significant f orearm vasodilation in all studies (forearm blood flow from 3.94 to 8.50 mt per 100 mt forearm volume per minute). Inhibition of the endogenous genera tion of NO by L-N-G-monomethyl arginine (by use of the NO-clamp technique) did not block the maximal vasodilating effects of CNP (forearm blood flow f rom 3.69 to 6.93). In addition, when the cyclooxygenase system was inhibite d by 600 mg of acetylsalicylic acid (aspirin) administered orally 30 minute s before start of measurements, the rise in forearm blood flow remained int act (forearm blood flow from 3.31 to 8.27 mt per 100 mt forearm volume per minute). However, inhibition of Ca2+-dependent potassium channels with tetr aethylammonium chloride (0.1 mg per 100 mt forearm volume per minute) signi ficantly attenuated vasodilation caused by CNP (forearm blood flow from 2.2 8 to 3.06 mt per 100 mt forearm volume per minute), which suggests that CNP opens vascular potassium channels. Vasodilation to all doses of CNP was si gnificantly increased when activity of NEP was blocked with thiorphan (30 n mol/min), which suggests that NEP activity limits vasodilation of CNP. CNP is a dilator of human resistance vessels that mediates its effects through hyperpolarization of the vessel wall independent of the NO and prostaglandi n system. Inhibition of local NEP activity increases CNP bioavailability, T his may be of relevance to cardiovascular disease, given that vascular tone is well balanced between NO and an endothelium-derived hyperpolarizing fac tor, which suggests that in pathological situations, impaired NO activity c an be compensated for by enhanced endothelium-derived hyperpolarizing facto r release to maintain vascular homeostasis.