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Purpose: Activation of the myocardial, ATP-dependent potassium current (IKATP) 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 IKATPinhibitor HMR1098 allows selective block of the sarcolemmal myocardial KATP-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. IKATPwas 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 KATP-channel was activated by application of 1μM rilmakalim, a KATP-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 IKATPby 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 IKATP-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.