Summary
Resistance arteries depolarize and constrict to elevations in intravascular pressure. However, many of the molecular aspects of this phenomenon are not known. We present evidence that large conductance calcium-dependent potassium (KCa) channels, which are activated by intracellular calcium and membrane depolarization, play a fundamental role in regulating the degree of intravascular pressure-induced, myogenic tone. We found that blockers of KCa channels, charybdotoxin (CTX, <100 nM) and TEA+ (<0.5 mM), further depolarized pressurized arteries by as much as 12 mV and decreased diameter by up to 40%. CTX blocked KCa channels in outside-out patches from arterial smooth muscles with half-block constant of 10 nM and external TEA+ caused a flickery block, with a half-block constant of 200 µM. We propose that KCa channels serve as a negative feedback pathway to limit the degree of membrane depolarization and hence vasoconstriction to pressure. In contrast, CTX and TEA+ (<1 mM) were without effect on membrane hyperpolarization and dilation to a wide variety of synthetic (cromakalim, pinacidil, diazoxide, minoxidil sulfate) and endogenous agents [calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide, an endothelial-derived hyperpolarizing factor]. Glibenclamide and low concentrations of external barium that inhibit ATP-sensitive potassium (KATP) channels, however, blocked the hyperpolarizations and dilations to these substances. We have identified KATP channels as well as high-affinity glibenclamide binding sites in arterial smooth muscle. These channels are activated by cromakalim and CGRP, and are blocked by glibenclamide. Further, the existence of KATP channels in arterial smooth muscle suggests the possibility that compromising cellular metabolism through metabolic poisons, hypoxia, or alterations in glucose may open KATP channels and lead to vasodilation. Indeed, other workers have provided evidence that metabolic poisons and hypoxia lead to an increase in glibenclamide-sensitive potassium efflux and vasodilation. We have found that replacement of external glucose by deoxyglucose caused glibenclamide-sensitive coronary artery dilation, membrane hyperpolarization, and activation of KATP channels. We conclude that both KATP and KCa channels serve important functions in the regulation of arterial tone.
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Nelson, M.T., Brayden, J.E. Regulation of arterial tone by calcium-dependent K+ channels and ATP-sensitive K+ channels. Cardiovasc Drug Ther 7 (Suppl 3), 605–610 (1993). https://doi.org/10.1007/BF00877627
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DOI: https://doi.org/10.1007/BF00877627