Selective block of sarcolemmal IK_ATP in human cardiomyocytes using HMR 1098

Purpose: Activation of the myocardial, ATP-dependent potassium current (IK_ATP) during ischemia causes shortening of the action potential duration thereby increasing dispersion of repolarization between ischemic and non-ischemic myocardium and predisposing to reentrant arrhythmias. The IK _ATP inhibitor HMR1098 allows selective block of the sarcolemmal myocardial K_ATP-channel in various animal species. Therefore, we studied the concentration and pH-dependence of HMR1098 in human ventricular myocytes. Methods: Human ventricular cardiomyocytes were isolated enzymatically. IK_ATP was measured with the patch-clamp technique in whole cell configuration at 35°C. Action potentials were recorded using Amphotericine B in perforated patch conditions. In voltage clamp experiments, the K _ATP-channel was activated by application of 1μM rilmakalim, a K_ATP-channel opener. In action potential recordings, 0.1 μM rilmakalim was used. Results: At physiological pH (pH = 7.3) half-maximal block of the rilmakalim-induced current occurred at 0.42 ± 0.008 μM HMR1098 (at 0 mV membrane potential); under acidic conditions as can be expected to be present under ischemic conditions (pH = 6.5), half-maximal block was achieved at markedly lower concentrations (IC₅₀ = 0.24 ± 0.009 μM). In current clamp experiments, block of IK_ATP by HMR1098 was capable of reversing the action potential shortening induced by rilmakalim, and restored the action potential plateau. Conclusions: HMR1098 appears to be useful to prevent IK_ATP-induced shortening of the action potential in human ventricular myocardium. More acidic conditions, as observed in ischemia, increase the sensitivity to HMR1098, indicating a more potent effect in ischemic myocardium. Thus, HMR1098 may be a useful agent to prevent action potential shortening and dispersion of repolarization during ischemia, which may protect against ischemia induced ventricular arrhythmias.