Regulation of arterial tone by calcium-dependent K+ channels and ATP-sensitive K+ channels.
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 microM. 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Nelson
M T
MT
Department of Pharmacology, University of Vermont, Colchester 05446-2500.
Brayden
J E
JE
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects
D015221:Potassium Channels; D000255:Adenosine Triphosphate; D002118:Calcium