(Circulation. 2001;103:119.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Role of Calcium-Sensitive K+ Channels and Nitric Oxide in In Vivo Coronary Vasodilation From Enhanced Perfusion Pulsatility
From the Division of Cardiology, Department of Medicine, and Department of Biomedical Engineering, Johns Hopkins Medical Institutions, Baltimore, Md. The first 2 authors contributed equally to this work.
Correspondence to David A. Kass, MD, Halsted 500, Johns Hopkins University Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail dkass{at}bme.jhu.edu
Background—In vitro studies support K+Ca channel–induced smooth muscle hyperpolarization as underlying acetylcholine-mediated (or bradykinin-mediated) vasodilation that persists despite combined nitric oxide (NO) and PGI2 inhibition. We tested the hypothesis that these channels are activated by enhanced pulsatile perfusion in vivo and contribute substantially to vasodilation from this stimulus.
Methods and Results—The
canine left descending coronary artery was perfused with whole blood at
constant mean pressure, and physiological flow pulsatility was set at
40 or 100 mm Hg by computer servo-pump. Cyclooxygenase was inhibited
by indomethacin. Mean flow increased +18±2%
(P<0.0001) with enhanced
pulsatility. This response declined 
50% by blocking NO synthase
(L-NMMA) or K+Ca
[charybdotoxin (CbTX)+apamin (AP)]. Combining both inhibitors
virtually eliminated the flow rise. Inhibiting either or both pathways
minimally altered basal coronary flow, whereas agonist-stimulated flow
was blocked. Bradykinin-induced dilation declined more with CbTX+AP
than with L-NMMA (-66% versus -46%,
P=0.03) and was fully blocked
by their combination. In contrast, acetylcholine-induced dilation was
more blunted by L-NMMA than by CbTX+AP (-71% versus -44%,
P<0.002) and was not fully
prevented by the combination. Substituting iberiotoxin (IbTX) for CbTX
greatly diminished inhibition of pulse pressure and agonist flow
responses (with or without NOS inhibition). Furthermore, blockade by
IbTX+AP was identical to that by AP alone, supporting a minimal role of
IbTX-sensitive large-conductance
K+Ca
channels.
Conclusions—K+Ca activation and NO comodulate in vivo pulsatility-stimulated coronary flow, supporting an important role of a hyperpolarization pathway in enhanced mechanovascular signaling. Small- and intermediate-conductance K+Ca channels are the dominant species involved in modulating both pulse pressure– and bradykinin-induced in vivo coronary dilation.
Key Words: circulation • ion channels • nitric oxide • bradykinin • endothelium-derived factors
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