Faculty Collaboration Database

Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: contribution of nitric oxide and Ca2+-activated K+ channels. Circulation 1999 Jun 22;99(24):3132-8

Date

06/22/1999

Pubmed ID

10377076

DOI

10.1161/01.cir.99.24.3132

Scopus ID

2-s2.0-0033594946 (requires institutional sign-in at Scopus site)   177 Citations

Abstract

BACKGROUND: K+ channel activation in vascular smooth muscle cells (VSMCs) plays a key role in regulating vascular tone. It has been proposed that endothelium-derived hyperpolarizing factor (EDHF) contributes to microvascular dilation more than nitric oxide (NO) does. Whether hyperpolarization is important for coronary arteriolar dilation in humans is not known. Bradykinin (BK), an endogenous vasoactive substance, is released from ischemic myocardium and regulates coronary resistance. Therefore, we tested the effects of inhibiting NO synthase, cyclooxygenase, and K+ channels on the changes in diameter and membrane potential (Em) in response to BK in isolated human coronary microvessels.

METHODS AND RESULTS: Arterioles (97+/-4 micrometers; n=120) dissected from human right atrial appendages (n=78) were cannulated at a distending pressure of 60 mm Hg and zero flow. Changes in vessel diameter (video microscopy) and VSMC Em (glass microelectrodes) were measured simultaneously. In vessels constricted and depolarized (Em; -50+/-3 to -28+/-2 mV) with endothelin-1 (ET), dilation to BK was associated with greater membrane hyperpolarization (-48+/-3 mV at 10(-6) mol/L) than dilation to sodium nitroprusside (SNP) (-34+/-2 mV at 10(-4) mol/L) for similar degrees of dilation. Treatment with Nomega-nitro-L-arginine methyl ester (L-NAME; 10(-4) mol/L), an NO synthase inhibitor, partially decreased dilation to BK (maximum dilation 61+/-10% versus control 92+/-4%; P<0.05). Charybdotoxin (CTX; 10(-8) mol/L), a large-conductance Ca2+-activated K+ channel blocker, or apamin (10(-7) mol/L), a small-conductance Ca2+-activated K+ channel blocker, inhibited both dilation (CTX 22+/-6% and apamin 45+/-10% versus control 69+/-6%; P<0.05) and membrane hyperpolarization (CTX -31+/-2 mV and apamin -37+/-2 mV versus control -44+/-2 mV; P<0.05) to BK, whereas glibenclamide (10(-6) mol/L), an ATP-sensitive K+ channel blocker, was without effect.

CONCLUSIONS: Vasodilation of human coronary arterioles to BK is largely dependent on membrane hyperpolarization by Ca2+-activated K+ channel activation, with apparently less of a role for endothelium-derived NO. This suggests a role for K+ channel activation in regulating human coronary arteriolar tone.

Author List

Miura H, Liu Y, Gutterman DD

Author

David Gutterman MD Emeritus Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Apamin
Bradykinin
Calcium
Charybdotoxin
Coronary Vessels
Cyclooxygenase Inhibitors
Electrophysiology
Endothelin-1
Endothelium, Vascular
Enzyme Inhibitors
Female
Humans
In Vitro Techniques
Indomethacin
Male
Membrane Potentials
Middle Aged
Muscle, Smooth, Vascular
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitroprusside
Potassium Channel Blockers
Potassium Channels
Potassium Chloride
Vasodilation
Vasodilator Agents