Related Experiment Video
Updated: Aug 24, 2026
Contractions of Human-iPSC-derived Cardiomyocyte Syncytia Measured with a Ca-sensitive Fluorescent Dye in Temperature-controlled 384-well Plates
Published on: October 18, 2018
Selective block of sarcolemmal IKATP in human cardiomyocytes using HMR 1098
Stefan Kääb1, Ludwig Zwermann, Andreas Barth
1LMU München, Klinikum der Universität-Grosshadern, Department of Medicine I, 81366 Munich, Germany. Stefan.Kaab@med.uni-muenchen.de
Insights
The ATP-dependent potassium current (IK(ATP)) inhibitor HMR1098 effectively blocks myocardial K(ATP)-channels in human ventricular cells. Its potency increases in acidic conditions, suggesting a protective role against ischemia-induced arrhythmias.
Area of Science:
- Cardiology
- Electrophysiology
- Pharmacology
Background:
- Myocardial ATP-dependent potassium current (IK(ATP)) activation during ischemia shortens action potential duration.
- This shortening increases repolarization dispersion, predisposing to reentrant arrhythmias.
- HMR1098 selectively blocks sarcolemmal myocardial K(ATP)-channels.
Purpose of the Study:
- To investigate the concentration and pH-dependence of HMR1098 in human ventricular myocytes.
- To assess HMR1098's effect on action potential duration and plateau.
Main Methods:
- Human ventricular cardiomyocytes isolated enzymatically.
- IK(ATP) measured using patch-clamp technique (whole cell configuration at 35°C).
- Action potentials recorded in perforated patch conditions; K(ATP)-channels activated by rilmakalim.
Main Results:
- At physiological pH (7.3), IC(50) for HMR1098 was 0.42 µM.
- Under acidic conditions (pH 6.5), IC(50) decreased to 0.24 µM, indicating increased sensitivity.
- HMR1098 reversed action potential shortening and restored the plateau.
Conclusions:
- HMR1098 effectively prevents IK(ATP)-induced action potential shortening in human ventricular myocardium.
- Increased sensitivity to HMR1098 under acidic (ischemic) conditions suggests enhanced efficacy.
- HMR1098 may protect against ischemia-induced ventricular arrhythmias by preventing action potential shortening and repolarization dispersion.
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 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.
Results:
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.
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.
