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Electrophysiologic effects of KATPchannel openers (KCOs) are rarely studied for tissue and species specificity, and use-dependent investigations in human tissues are lacking. We therefore investigated in vitro the concentration-dependent effects of the KCO bimakalim [from 10 nMto 10 μM,at 1,000 ms of cycle length (CL) and 37°C] on human (atrium, n = 4, and ventricle, n = 6) and guinea pig (atrium, n = 7, and ventricle, n = 6) transmembrane action potential (AP). The frequency relation (from CL 1,600 to 300 ms, 31°C) of human atrial AP duration 90% (APD90) shortening (10 μMvs. baseline, n = 7) also was determined. A parallel study was performed with the KCO nicorandil (from 10 nMto 1 mM,n = 3) in human atrial APs, at 31°C. Resting membrane potential and maximal upstroke velocity of AP were not modified by bimakalim at maximal concentration, whereas AP amplitude was decreased in both guinea pig preparations (p < 0.05); APD90was shortened in all tissues (p < 0.01). Median effective concentration (EC50) for APD90shortening at 37°C was 0.54 and 2.74 μMin atrial and ventricular human tissue, respectively, and 8.55 and 0.89 μMin atrial and ventricular guinea pig tissue, respectively. In human atrial tissue at 31°C, EC50with bimakalim was 0.39 μM;a much higher value was seen with nicorandil (210 μM). Bimakalim (10 μM)-induced APD90shortening as a function of stimulation rate was greatest at longest CL. Evidence is provided for (a) species (human vs. guinea pig) and tissue (atrium vs. ventricle) differential AP sensitivity to bimakalim; (b) an 500-fold higher efficacy of bimakalim versus nicorandil to shorten human atrial APD90; and (c) normal use-dependence of human atrial APD90shortening with bimakalim at 10 μM.

We investigated whether the adenosine triphosphate (ATP)-sensitive K+(KATP) channel activation by bimakalim, at concentrations devoid of both negative inotropic and action-potential duration (APD) shortening effects, might exhibit myocardial protection after hypoxia and reoxygenation in human atrial myocardium by using 112 preparations. The recovery of contractility of human atrial trabeculae, subjected either to short-duration (5 min) or to long-duration (60 min) and severe (high pacing rate) hypoxia followed by reoxygenation, was assessed by challenging with dobutamine. Treated preparations were exposed to 10 or 100 nMbimakalim, 1 μMglibenclamide, or both before hypoxia. Variations of isometric developed tension (%DT) or APD90were studied. At concentrations <100 nM,bimakalim showed no negative inotropic effects and did not modify significantly APD90, either in normoxia or in hypoxic conditions. In the short-duration hypoxia protocol, preparations treated with bimakalim showed a dobutamine-induced %DT increase significantly higher (p < 0.001) than in controls and similar to that observed in the absence of hypoxia. This bimakalim effect was blocked by glibenclamide. In the long-duration hypoxia protocol, %DT after dobutamine was 50% of that observed 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 human atrial myocardium with pronounced reduction of the positive inotropic action of dobutamine. Pretreatment with bimakalim restores the response expected in the absence of hypoxia, and glibenclamide blocks the effect of bimakalim or further impairs the response to dobutamine when used alone before long-duration hypoxia. Evidence is provided for protective effects of the KATPopener bimakalim on the human myocardial contractile function in conditions of hypoxia/reoxygenation, at concentrations at which negative inotropism and APD90shortening are not contributory.

Considering the Survival With ORal D-sotalol (SWORD) study results, in which mortality was higher in patients treated by the pure class III agent D-sotalol, we tested DL- and D-sotalol (5 and 10 μM) in an in vitro model of "border zone" arrhythmias. Isolated guinea-pig ventricular strips were partly exposed to normoxia ("Normal Zone," NZ) and partly to modified Tyrode's solution ("Ischemic Zone," IZ) for 15 or 30 min ("ischemia"), followed by return to normoxia for 30 min ("reperfusion"). Resting membrane potential, action potential (AP) amplitude, and maximal upstroke velocity of AP were not significantly modified. DL- And D-sotalol, 5 and 10 μM,lengthened AP duration 90% (APD90) in NZ (p < 0.05), whereas these drugs were unable to prevent ischemia-induced APD shortening. By using the accelerated failure time Weibull's model, and a large number of reference experiments to control random variability of analyzed covariates, DL- and D-sotalol increased significantly the incidence of spontaneous arrhythmias during ischemia (χ2= 24.79; p = 0.0367): 83 (5 μMD- and DL-sotalol), 86, and 62% (10 μMD- and DL-sotalol, respectively) versus 32% of controls. During reperfusion, 10 μMDL-sotalol prevented the occurrence of spontaneous arrhythmias (χ2= 46.74; p = 0.0001) similar to what seen with the β-blocking agent propranolol (10 μM). These data, providing evidence for proarrhythmic effects of DL- and D-sotalol on border-zone arrhythmias, concomitant with differential class III actions on NZ versus IZ, might be considered for understanding the SWORD study results.