Pharmacological activation of plasma-membrane K ATP channels reduces reoxygenation-induced Ca 2+ overload in cardiac myocytes via modulation of the diastolic membrane potential

István Baczkó, Wayne R. Giles, Peter E. Light

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Abstract

1. The opening of cardiac plasma-membrane ATP-sensitive K + channels (pmK ATP) can protect the heart against ischaemia/reperfusion injury. We recently demonstrated that the resting membrane potential (E m) of ventricular myocytes strongly modulates reoxygenation-induced Ca 2+ overload. This led to the hypothesis that activation of pmK ATP can influence the extent of chemically induced hypoxia (CIH)/reoxygenation Ca 2+ overload via hyperpolarization of the diastolic membrane potential of ventricular myocytes. 2. The membrane potential (E m) of isolated rat myocytes was determined using the perforated patch-clamp technique and DiBac 4(3) imaging. Intracellular Ca 2+ ([Ca 2+] i) was monitored using FURA-2 imaging. 3. CIH/reoxygenation caused a significant depolarization of E m and a substantial increase in [Ca 2+] i. The K ATP opener pinacidil (100 μM) and the pmK ATP opener P-1075 (100 μM) hyperpolarized the E m of normoxic myocytes. Pinacidil (100 μM) and P-1075 (10 and 100 μM), applied during reoxygenation, hyperpolarized E m and prevented reoxygenation-induced increases in [Ca 2+] i. 4. Myocyte hypercontracture and death increased in parallel with an E m depolarization of 10-15 mV and increases in [Ca 2+] i. Under these conditions, the selective pmK ATP channel inhibitor HMR 1098 further depolarized myocyte membrane potential and increased hypercontracture. 5. In conclusion, activation of pmK ATP channels can prevent CIH/reoxygenation-induced Ca 2+ overload via a mechanism that is dependent on hyperpolarization of diastolic membrane potential. Hyperpolarization toward normal resting membrane potential favours the Ca 2+ extrusion mode of Na +/Ca 2+ exchange.

Original languageEnglish
Pages (from-to)1059-1067
Number of pages9
JournalBritish Journal of Pharmacology
Volume141
Issue number6
DOIs
Publication statusPublished - Mar 1 2004

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Keywords

  • ATP-sensitive potassium channels
  • Calcium overload
  • Heart
  • Membrane potential
  • Sodium/calcium exchange

ASJC Scopus subject areas

  • Pharmacology

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