Role of calcium-sensitive K+ channels and nitric oxide in in vivo coronaryvasodilation from enhanced perfusion pulsatility

Background-In vitro studies support K-Ca(+) channel-induced smooth muscle h yperpolarization as underlying acetylcholine-mediated (or bradykinin-mediat ed) vasodilation that persists despite combined nitric oxide (NO) and PGI(2 ) inhibition. We tested the hypothesis that these channels are activated by enhanced pulsatile perfusion in vivo and contribute substantially to vasod ilation from this stimulus. Methods and Results-The canine left descending coronary artery was perfused with whole blood at constant mean pressure, and physiological flow pulsati lity 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 enh anced pulsatility. This response declined <approximate to>50% by blocking N O synthase (L-NMMA) or K-Ca(+) [charybdotoxin (CbTX)+apamin (AP)]. Combinin g both inhibitors virtually eliminated the flow rise. Inhibiting either or both pathways minimally altered basal coronary flow, whereas agonist-stimul ated flow was blocked. Bradykinin-induced dilation declined more with CbTXAP than with L-NMMA (-66% versus -46%, P=0.03) and was fully blocked by the ir combination. In contrast, acetylcholine-induced dilation was mon blunted by L-NMMA than by CbTX+AP (-71% versus -44%, P<0.002) and was not fully pr evented by the combination. Substituting iberiotoxin (IbTX) for CbTX greatl y 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-cond uctance K-Ca(+) channels. Conclusions-K-Ca(+) activation and NO comodulate in vivo pulsatility-stimul ated coronary flow, supporting an important role of a hyperpolarization pat hway in enhanced mechanovascular signaling. Small- and intermediate-conduct ance K-Ca(+) channels are the dominant species involved in modulating both pulse pressure- and bradykinin induced in vivo coronary dilation.