Pinacidil prevents membrane depolarisation and intracellular Ca2+ loading in single cardiomyocytes exposed to severe metabolic stress.

Abstract

Recently, it has been proposed that, besides sarcolemmal K(ATP) channels, the activation of mitochondrial K(ATP) channels may also contribute to the cardioprotective action of potassium channel openers. In this respect, use of drugs that target both mitochondrial and sarcolemmal K(ATP) channels, such as pinacidil, may be a promising therapeutic strategy against metabolic injury of the heart. Therefore, the main objective of the present study was to determine whether pinacidil could maintain the value of resting membrane potential and intracellular Ca2+ homeostasis in cardiac cells exposed to metabolic stress. Experiments were performed on isolated ventricular cardiomyocytes. The membrane potential was monitored during experiments using whole cell patch clamp electrophysiology and the intracellular Ca2+ concentration was measured by a digital epifluorescence imaging. Chemical hypoxia-reoxygenation was induced by application and removal of the mitochondrial poison 2,4 dinitrophenol (DNP). Under hypoxia-reoxygenation, membrane depolarisation and intracellular Ca2+ loading was induced by Ca2+ influx during hypoxia and release of Ca2+ from intracellular stores during reoxygenation. The K(ATP) channel activator, pinacidil, prevented intracellular Ca2+ loading and membrane depolarisation, irrespective of whether the channel opener was applied throughout the duration of hypoxia-reoxygenation or transiently during the hypoxic or reoxygenation stage. Thus, the present study provides evidence that pinacidil, a non-selective K(ATP) channel opener, can handle membrane potential and intracellular Ca2+ homeostasis in cardiomyocytes under hypoxia-reoxygenation irrespective of the stage of the metabolic insult. This provides further evidence, at the single cell level, that targeting K(ATP) channels may be a valuable approach to protect the myocardium against metabolic challenge.

• Authors: S Jovanovic, A Jovanovic
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 7 Issue 6 Pg. 639-43 (Jun 2001) ISSN: 1107-3756 [Print] Greece
• PMID: 11351278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dinitrophenols
• Potassium Channels
• Uncoupling Agents
• Pinacidil
• Oxygen
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cell Membrane (metabolism)
• Dinitrophenols (pharmacology)
• Guinea Pigs
• Hypoxia
• Kinetics
• Membrane Potentials
• Microscopy, Fluorescence
• Myocardium (cytology, metabolism)
• Oxygen (metabolism)
• Patch-Clamp Techniques
• Pinacidil (pharmacology)
• Potassium Channels (metabolism, physiology)
• Stress, Physiological
• Uncoupling Agents (pharmacology)