Clotrimazole Is a Potent Vasodilator of the Rat Coronary Microcirculation

Abstract

Clotrimazole (CLT), used in the treatment of patients with sickle cell disease, directly blocks Ca2+-activated K+(K+Ca) channels in red cells and in portal vein smooth muscle cells by a cytochrome P450(cyt P450)-independent mechanism. Therefore, we examined the effects of CLT on vasomotor tone of coronary arterioles. Rat coronary arterioles (80–180 μm in diameter) were studiedin vitroin a pressurized no-flow state with a video microscopy. CLT (0.1 μmol/L) elicited in nonprecontracted vessels a small contraction (<10% baseline diameter,P< 0.05 vs time control), consistent with blockade of a hyperpolarizing K+channel. However, similar contraction was produced by the cyt P450blocker 17-octadecynoic acid (17-ODYA, 100 μmol/L), suggesting possible involvement of arachidonate metabolites of cyt P450. In contrast, microvessels precontracted with the thromboxane A2analog U46619 dilated in response to CLT [>90% relaxation of the U46619-induced precontraction at 100 μmol/L (P< 0.01 vs time control)] and its structural analogs flutrimazole (FLT), UR-4055, UR4057, UR-4058, and UR-4059. This relaxation was cyt P450-independent, since thein vivoCLT metabolite (CLT-carbinol) was equipotent with CLT, and 17-ODYA did not promote relaxation. CLT-induced dilation was not inhibited by the nitric oxide synthase inhibitor NGnitro-l-arginine (100 μmol/L,P> 0.5) or affected by endothelial denudation (P> 0.5). Thus, CLT at concentrations >1 μmol/L is a potent vasodilator of rat coronary arterioles. This dilation is likely mediated through a vascular smooth muscle mechanism independent of cyt P450and is not modulated by nitric oxide or by the endothelium. This effect may arise from CLT's reported ability to inhibit voltage-gated Ca2+channels or to inhibit, in some tissues, Ca2+release from intracellular stores. The CLT- and FLT-induced relaxation may be a property common to this class of drugs and have clinical applicability.