Effects of pinacidil on cerebral and mesenteric arteries--influence of the endothelium

Abstract

The effect of pinacidil on the contractile response to stepwise increases of the extracellular K+ concentration ([K+]o) was investigated in isolated segments of human pial and mesenteric arteries and rabbit basilar and mesenteric arteries. The [K+]o eliciting half maximum contraction (EC50) was lower in human pial (18 mM) and rabbit basilar (27 mM) arteries than in human (33 mM) and rabbit (32 mM) mesenteric arteries, respectively. The alpha-adrenoceptor blocker, prazosin, increased the EC50 value for K+ from 27 to 40 mM and reduced the maximum response in rabbit mesenteric arteries, but had no effect on the K(+)-induced contraction in rabbit basilar arteries, indicating a substantial noradrenergic component of the K+ response in the former arteries. Removal of the endothelium decreased the EC50 value for K+ from 27 to 15 mM in rabbit basilar arteries, whereas the K+ sensitivity was unaffected in rabbit mesenteric arteries. Pinacidil shifted the K+ concentration-response curve to the right in human and rabbit cerebral and mesenteric arteries. In rabbit basilar arteries, but not in mesenteric arteries, the shift was larger in the absence than in the presence of an intact endothelium. When endothelium-denuded rabbit arteries were compared, the inhibitory effect of pinacidil was larger in basilar than in mesenteric arteries. Thus, pinacidil inhibits K(+)-induced contractions in both cerebral and mesenteric arteries, but appears to act preferentially on endothelium-denuded rabbit basilar arteries. Provided that endothelial damage and depolarization-induced vasoconstriction are of pathophysiological importance in cerebrovascular disorders such as stroke and cerebral ischemia secondary to vasospasm after subarachnoid hemorrhage, pinacidil may have a therapeutic potential.