(Circulation. 1999;99:3132-3138.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Human Coronary Arteriolar Dilation to Bradykinin Depends on Membrane Hyperpolarization
Contribution of Nitric Oxide and Ca2+-Activated K+ Channels
From the Veterans Administration Medical Center, the Department of Internal Medicine, and Cardiovascular Center, University of Iowa College of Medicine (H.M.), Iowa City, Iowa, and the VA Medical Center, Cardiovascular Research Center and Department of Internal Medicine, Medical College of Wisconsin (Y.L., D.D.G.), Milwaukee.
Correspondence to David D. Gutterman, MD, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI 53226. E-mail dgutt{at}mcw.edu
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 µm; 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 N
-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.
Key Words: bradykinin • nitric oxide • endothelin • vasodilation • potassium
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