Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: contribution of nitric oxide and Ca2+-activated K+ channels.
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.


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.
Miura
H
H
Veterans Administration Medical Center, the Department of Internal Medicine, and Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa, USA.
Liu
Y
Y
Gutterman
D D
DD
D000328:Adult; D000368:Aged; D001030:Apamin / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D018999:Charybdotoxin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004594:Electrophysiology; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D011189:Potassium Chloride / Q000493:pharmacokinetics; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014665:Vasodilator Agents; D018999:Charybdotoxin; D009599:Nitroprusside; D001030:Apamin; D009569:Nitric Oxide; D011189:Potassium Chloride; D001920:Bradykinin; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin