Sodium azide dilates coronary arterioles via activation of inward rectifier K+channels and Na+-K+-ATPase

Abstract

Sodium azide (NaN3), a potent vasodilator, causes severe hypotension on accidental exposure. Although NaN3has been shown to increase coronary blood flow, the direct effect of NaN3on coronary resistance vessels and the mechanism of the NaN3-induced response remain to be established. To address these issues without confounding influences from systemic parameters, subepicardial coronary arterioles were isolated from porcine hearts for in vitro study. Arterioles developed basal tone at 60 cmH2O intraluminal pressure and dilated acutely, in a concentration-dependent manner, to NaN3(0.1 μM to 50 μM). The NaN3response was not altered by the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester or endothelial removal. Neither inhibition of phosphoinositol 3-kinase and tyrosine kinases nor blockade of ATP-sensitive, Ca2+-activated, and voltage-dependent K+channels affected NaN3-induced dilation. However, the vasomotor action of NaN3was significantly attenuated in a similar manner by the inward rectifier K+(KIR) channel inhibitor Ba2+, the Na+-K+ATPase inhibitor ouabain, or the guanylyl cyclase inhibitor 1 H-[1,2,4]oxadiazolo[4,3,- a]quinoxalin-1-one (ODQ). Ba2+, in combination with either ouabain or ODQ, nearly abolished the vasodilatory response. However, there was no additive inhibition by combining ouabain and ODQ. The NaN3-mediated vasodilation was also attenuated by morin, an inhibitor of phosphatidylinositolphosphate (PIP) kinase, which can regulate KIRchannel activity. With the use of whole cell patch-clamp methods, NaN3acutely enhanced Ba2+-sensitive KIRcurrent in isolated coronary arteriolar smooth muscle cells. Collectively, this study demonstrates that NaN3, at clinically toxic concentrations, dilates coronary resistance vessels via activation of both KIRchannels and guanylyl cyclase/Na+-K+-ATPase in the vascular smooth muscle. The KIRchannels appear to be modulated by PIP kinase.