Abstract
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. Human ventricular cardiomyocytes were isolated enzymatically. IK(ATP) was measured with the patch-clamp technique in whole cell configuration at 35 degrees 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 1 microM rilmakalim, a K(ATP)-channel opener. In action potential recordings, 0.1 microM rilmakalim was used. At physiological pH (pH = 7.3) half-maximal block of the rilmakalim-induced current occurred at 0.42 +/- 0.008 microM 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 (IC(50) = 0.24 +/- 0.009 microM). 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. 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.
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