Nitric Oxide in the Regulation of Blood Flow: A Historical Overview

Abstract

Nearly 20 years have gone by since we discovered the vascular smooth muscle relaxant properties of nitric oxide (NO). The original observation was made by delivering a gaseous mixture of NO in nitrogen by means of a gas-tight microliter syringe into a tissue bath containing isolated precontracted strips of bovine coronary artery (Gruetter et al. 1979). The pharmacological response was a marked but transient relaxation that was blocked by the prior addition of hemoproteins or methylene blue. Moreover, NO activated soluble guanylate cyclase isolated from bovine coronary artery. The closely similar pharmacological Profile of action of NO and nitroglycerin led us to suspect that nitroglycerin causes vascular smooth muscle relaxation by mechanisms involving NO, perhaps by generating or donating NO. Although the terms “NO donor drugs” or “ nitrovasodilators” were not used in 1979, we were accumulating solid experimental evidence that nitroglycerin, other organic nitrate esters, some organic nitrite esters, and nitroprusside all caused vasodilation by acting as NO donor agents on contact with tissues in aqueous solution. Struck by the extraordinarily high potency of nitroglycerin as a vascular smooth muscle relaxant both in vivo and in vitro, we suspected, as pharmacologists, that tissue receptors for nitroglycerin probably exist, because there must be an endogenous nitroglycerin or similar NO donor or NO itself in mammalian tissues. Of course, we did not appreciate at this time that the vascular endothelium generated and delivered the NO to the underlying smooth muscle cells. In fact, ouroriginal observations on the vasorelaxant properties of NO (Gruetter et al. 1979) were published 1 year before the discovery of endothelium-dependent vasorelaxation and endothelium-derived relaxing factor (Furchgott and Zawadzki 1980).