REGULATION OF ARTERIAL TONE BY CALCIUM-DEPENDENT K-SENSITIVE K+ CHANNELS( CHANNELS AND ATP)

Resistance arteries depolarize and constrict to elevations in intravas cular pressure. However, many of the molecular aspects of this phenome non are not known. We present evidence that large conductance calcium- dependent potassium (K(Ca)) channels, which are activated by intracell ular calcium and membrane depolarization, play a fundamental role in r egulating the degree of intravascular pressure-induced, myogenic tone. We found that blockers of K(Ca) channels, charybdotoxin (CTX, <100 nM ) and TEA+ (<0.5 mM), further depolarized pressurized arteries by as m uch as 12 mV and decreased diameter by up to 40%. CTX blocked K(Ca) ch annels in outside-out patches from arterial smooth muscles with half-b lock constant of 10 nM and external TEA+ caused a flickery block, with a half-block constant of 200 muM. We propose that K(Ca) channels serv e as a negative feedback pathway to limit the degree of membrane depol arization and hence vasoconstriction to pressure. In contrast, CTX and TEA+ (<1 mM) were without effect on membrane hyperpolarization and di lation to a wide variety of synthetic (cromakalim, pinacidil, diazoxid e, minoxidil sulfate and endogenous agents [calcitonin gene-related pe ptide (CGRP), vasoactive intestinal peptide, an endothelial-derived hy perpolarizing factor]. Glibenclamide and low concentrations of externa l barium that inhibit ATP-sensitive potassium (K(ATP)) channels, howev er, blocked the hyperpolarizations and dilations to these substances. We have identified K(ATP) channels as well as high-affinity glibenclam ide binding sites in arterial smooth muscle. These channels are activa ted by cromakalim and CGRP, and are blocked by glibenclamide. Further, the existence of K(ATP) channels in arterial smooth muscle suggests t he possibility that compromising cellular metabolism through metabolic poisons, hypoxia, or alterations in glucose may open K(ATP) channels and lead to vasodilation. Indeed, other workers have provided evidence that metabolic poisons and hypoxia lead to an increase in glibenclami de-sensitive potassium efflux and vasodilation. We have found that rep lacement of external glucose by deoxyglucose caused glibenclamide-sens itive coronary artery dilation, membrane hyperpolarization, and activa tion of K(ATP) channels. We conclude that both K(ATP) and K(Ca) channe ls serve important functions in the regulation of arterial tone.