Protection of human myocardium in vitro by K-ATP activation with low concentrations of bimakalim

We investigated whether the adenosine triphosphate (ATP)-sensitive K+ (K-AT P) channel activation by bimakalim, at concentrations devoid of both negati ve inotropic and action-potential duration (APD shortening effects, might e xhibit myocardial protection after hypoxia and reoxygenation in human atria l myocardium by using 112 preparations. The recovery of contractility of hu man atrial trabeculae, subjected either to short-duration (5 min) or to lon g-duration (60 min) and severe thigh pacing rate) hypoxia followed by reoxy genation, was assessed by challenging with dobutamine. Treated preparations were exposed to 10 or 100 nM bimakalim, 1 mu M glibenclamide, or both befo re hypoxia. Variations of isometric developed tension (%DT) or APD(90) were studied. At concentrations <100 nM, bimakalim showed no negative inotropic effects and did not modify significantly APD(90), either in normoxia or in hypoxic conditions. In the short-duration hypoxia protocol. preparations t reated with bimakalim showed a dobutamine-induced %DT increase significantl y higher (p < 0.001) than in controls and similar to that observed in the a bsence of hypoxia. This bimakalim effect was blocked by glibenclamide. In t he long-duration hypoxia protocol, %DT after dobutamine was 50% of that obs erved in normoxic Preparations. Preparations treated with bimakalim showed after dobutamine %DT more than twofold above controls (p < 0.001), whereas in the glibenclamide group, recovery of DT with dobutamine remained 50% of what observed in normoxia (p < 0.001). In conclusion, exposure to hypoxia ( either short- or long-lasting) and reoxygenation affects contractility of h uman atrial myocardium with pronounced reduction of the positive inotropic action of dobutamine. Pretreatment with bimakalim restores the response exp ected in the absence of hypoxia, and glibenclamide blocks the effect of bim akalim or further impairs thr response to dobutamine when used alone before long-duration hypoxia. Evidence is provided for protective effects of the K-ATP opener bimakalim on the human myocardial contractile function in cond itions of hypoxia/reoxygenation, at concentrations at which negative inotro pism and APD(90) shortening are not contributory.