Article date: March 2004
By: István Baczkó, Wayne R Giles, Peter E Light in Volume 141, Issue 6, pages 1059-1067
The opening of cardiac plasma‐membrane ATP‐sensitive K+ channels (pmKATP) can protect the heart against ischaemia/reperfusion injury. We recently demonstrated that the resting membrane potential (Em) of ventricular myocytes strongly modulates reoxygenation‐induced Ca2+ overload. This led to the hypothesis that activation of pmKATP can influence the extent of chemically induced hypoxia (CIH)/reoxygenation Ca2+ overload via hyperpolarization of the diastolic membrane potential of ventricular myocytes.
The membrane potential (Em) of isolated rat myocytes was determined using the perforated patch‐clamp technique and DiBac4(3) imaging. Intracellular Ca2+ ([Ca2+]i) was monitored using FURA‐2 imaging.
CIH/reoxygenation caused a significant depolarization of Em and a substantial increase in [Ca2+]i. The KATP opener pinacidil (100 μM) and the pmKATP opener P‐1075 (100 μM) hyperpolarized the Em of normoxic myocytes. Pinacidil (100 μM) and P‐1075 (10 and 100 μM), applied during reoxygenation, hyperpolarized Em and prevented reoxygenation‐induced increases in [Ca2+]i.
Myocyte hypercontracture and death increased in parallel with an Em depolarization of 10–15 mV and increases in [Ca2+]i. Under these conditions, the selective pmKATP channel inhibitor HMR 1098 further depolarized myocyte membrane potential and increased hypercontracture.
In conclusion, activation of pmKATP channels can prevent CIH/reoxygenation‐induced Ca2+ overload via a mechanism that is dependent on hyperpolarization of diastolic membrane potential. Hyperpolarization toward normal resting membrane potential favours the Ca2+ extrusion mode of Na+/Ca2+ exchange.
The opening of cardiac plasma‐membrane ATP‐sensitive K+ channels (pmKATP) can protect the heart against ischaemia/reperfusion injury. We recently demonstrated that the resting membrane potential (Em) of ventricular myocytes strongly modulates reoxygenation‐induced Ca2+ overload. This led to the hypothesis that activation of pmKATP can influence the extent of chemically induced hypoxia (CIH)/reoxygenation Ca2+ overload via hyperpolarization of the diastolic membrane potential of ventricular myocytes.
The membrane potential (Em) of isolated rat myocytes was determined using the perforated patch‐clamp technique and DiBac4(3) imaging. Intracellular Ca2+ ([Ca2+]i) was monitored using FURA‐2 imaging.
CIH/reoxygenation caused a significant depolarization of Em and a substantial increase in [Ca2+]i. The KATP opener pinacidil (100 μM) and the pmKATP opener P‐1075 (100 μM) hyperpolarized the Em of normoxic myocytes. Pinacidil (100 μM) and P‐1075 (10 and 100 μM), applied during reoxygenation, hyperpolarized Em and prevented reoxygenation‐induced increases in [Ca2+]i.
Myocyte hypercontracture and death increased in parallel with an Em depolarization of 10–15 mV and increases in [Ca2+]i. Under these conditions, the selective pmKATP channel inhibitor HMR 1098 further depolarized myocyte membrane potential and increased hypercontracture.
In conclusion, activation of pmKATP channels can prevent CIH/reoxygenation‐induced Ca2+ overload via a mechanism that is dependent on hyperpolarization of diastolic membrane potential. Hyperpolarization toward normal resting membrane potential favours the Ca2+ extrusion mode of Na+/Ca2+ exchange.
British Journal of Pharmacology (2004) 141, 1059–1067. doi:10.1038/sj.bjp.0705702
DOI: 10.1038/sj.bjp.0705702
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