Protection of Human Myocardium In Vitro by KATP Activation with Low Concentrations of Bimakalim

Abstract

We investigated whether the adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) 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 nM bimakalim, 1 microM glibenclamide, or both before hypoxia. Variations of isometric developed tension (%DT) or APD90 were 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 K(ATP) opener bimakalim on the human myocardial contractile function in conditions of hypoxia/reoxygenation, at concentrations at which negative inotropism and APD90 shortening are not contributory.

Bimakalim: A Promising KATP Channel Activating Agent

“…The converse is also true: it would not be safe to reduce contractility (for the sake of ATP preservation); APD will be shortened to the extent that arrhythmias will be favored by a mechanism related to reentry due to APD dispersion (43). Our contribution was the demonstration of the concentration-related effects of bimakalim (10 nM-10 mM) on both APD and developed tension (DT) in normoxic human atrial preparations (42) (Fig. 4).…”

“…It is important to interprete these data (43) in relation to the concentration of bimakalim used (1 mM). Further studies are needed to assess whether lower and more clinically relevant concentrations of bimakalim (< l00 nM), which have been shown by our group to have significant cardioprotective properties in superfused hypoxic models (42), are still arrhythmogenic during ischemia. Based on data by Gautier et al (19) and those of other investigators (48,60) the probability to obtain myocardial protection with bimakalim at concentrations < 100 nM (as after 0.25-1 mg per os) is high, whereas the probability of proarrhythmic action is quite low (43).…”

“…KCOs can also induce postischemic arrhythmias and even ventricular fibrillation (60). It is, however, far from being firmly established whether this dichotomy of cytoprotective versus profibrillatory actions of KCOs involves modulation of APD shortening (9,15,26,60), is dose-related (43,48), is mediated through an intracellular site that is independent of any electrophysiologic effects (17,42). In our experiments with human atrial fibers subjected to hypoxia, we found that bimakalim, at 100 nM, had no effect on APD shortening or its kinetics (42).…”

“…Bimakalim is probably the most intensively investigated, potent, and pure activator of adenosine triphosphate sensitive potassium channels (K ATP ), both at plasmalemmal (42,48) and mitochondnal (18) levels. It survived the initial developmental scrutiny with a substantial amount of data, including studies with human tissues (42,48) and even initial clinical studies in volunteers (11,52). Bimakalim is in many respects similar to other potassium channel openers (KCOs) reviewed in other publications (4,27,34,58).…”

Positive Inotropic Effects of Levosimendan are Modulated by KATP Channels in Isolated Human Atrial Trabeculae

“…The methods to obtain human atrial trabeculae working isometrically in vitro have been previously described in detail. [17][18][19] Briefly, a sample of the right atrial appendage (1 cm 2 , 500-1000 mg) was removed and immersed in preoxygenated and modified Tyrode's solution (in mM: NaCl, 120; KCl, 4; CaCl 2 , 2.7; MgCl 2 , 1.1; NaHCO 3 , 25.7; Na H 2 PO 4 , 1.8; and glucose, 11) at 22 ºC. The time between excision and beginning of laboratory processing was 1-5 min.…”