TY - JOUR
T1 - Selective block of sarcolemmal IKATP in human cardiomyocytes using HMR 1098
AU - Kääb, Stefan
AU - Zwermann, Ludwig
AU - Barth, Andreas
AU - Hinterseer, Martin
AU - Englert, Heinrich C.
AU - Gögelein, Heinz
AU - Näbauer, Michael
N1 - Funding Information:
This study was supported by a research grant from Aventis Pharma, Germany and by BMBF Grant no. 01GS0109.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003
Y1 - 2003
N2 - 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 IK ATP inhibitor 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. IKATP 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 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 IKATP 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 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.
AB - 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 IK ATP inhibitor 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. IKATP 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 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 IKATP 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 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.
KW - ATP-dependent potassium current
KW - Arrhythmia
KW - Human cardiomyocytes
KW - Patch clamp
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U2 - 10.1023/B:CARD.0000015858.34009.0c
DO - 10.1023/B:CARD.0000015858.34009.0c
M3 - Article
C2 - 15107598
AN - SCOPUS:17744411400
VL - 17
SP - 435
EP - 441
JO - Cardiovascular Drugs and Therapy
JF - Cardiovascular Drugs and Therapy
SN - 0920-3206
IS - 5-6
ER -