Nitric oxide inhibition of endothelin-1 release in the vasculature: in vivo relevance of in vitro findings.

Abstract

A key function of endothelial derived nitric oxide (NO) is to limit the constrictor capacity of endothelin (ET)-1.1,2 Thus, an imbalance between NO and ET-1 can result in ET-1–dependent increased vascular tone.1 Indeed, the importance of sustained, NO inhibition of the ET-1 drive to increase tone is exemplified in vivo by the rapid, ET-1–mediated arterial pressure elevation after acute NO synthase (NOS) inhibition.2 Moreover, the ET-1 pressor effect after NOS inhibition is independent of other pressor systems and, thus, reflects the relative importance of NO suppression of this ET-1 drive.2 Two, nonmutually exclusive mechanisms thought to underlie the ET-1 dependency of the increased vascular tone responsible for the NOS inhibitor-induced pressure elevation are (1) NO inhibition of constriction to endogenously released ET-1.1,2 This mechanism is essentially supported by demonstrations that NOS inhibitor enhanced the constrictor effects of exogenous ET-1 in several in vivo and ex vivo preparations.3–14 Thus, an assumption underlying these observations is that the constrictor actions of exogenous and endogenous ET-1 are similarly affected by NO; (2) NO inhibition of ET-1 release.1,2 Although the detailed mechanism underlying the NO inhibition of acute ET-1 release has not been clearly established, possibilities include decreased conversion of the immediate precursor to ET-1, big ET-1, to ET-115 and inhibition of pathways involved in the exocytosis of Weibel–Palade bodies,16 endothelial granules that store ET-1.17 However, it should be noted that in vivo findings that actually demonstrate the fundamental phenomenon of NO inhibition of ET-1 release are generally lacking.2 Thus, studies purported to demonstrate NO inhibition of ET-1 release have relied largely on isolated vessels and cultured endothelium, as described herein. This review assessed these in vitro findings, with a specific focus toward elucidating the …