Protective effect of gap junction uncouplers given during hypoxia against reoxygenation injury in isolated rat hearts
- 1 February 2006
- journal article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 290 (2), H648-H656
- https://doi.org/10.1152/ajpheart.00439.2005
Abstract
It has been shown that cell-to-cell chemical coupling may persist during severe myocardial hypoxia or ischemia. We aimed to analyze the effects of different, chemically unrelated gap junction uncouplers on the progression of ischemic injury in hypoxic myocardium. First, we analyzed the effects of heptanol, 18α-glycyrrhetinic acid, and palmitoleic acid on intracellular Ca2+ concentration during simulated hypoxia (2 mM NaCN) in isolated cardiomyocytes. Next, we analyzed their effects on developed and diastolic tension and electrical impedance in 47 isolated rat hearts submitted to 40 min of hypoxia and reoxygenation. All treatments were applied only during the hypoxic period. Cell injury was determined by lactate dehydrogenase (LDH) release. Heptanol, but not 18α-glycyrrhetinic acid nor palmitoleic acid, attenuated the increase in cytosolic Ca2+ concentration induced by simulated ischemia in cardiomyocytes and delayed rigor development (rigor onset at 7.31 ± 0.71 min in controls vs. 14.76 ± 1.44 in heptanol-treated hearts, P < 0.001) and the onset of the marked changes in electrical impedance (tissue resistivity: 4.02 ± 0.29 vs. 7.75 ± 1.84 min, P = 0.016) in hypoxic rat hearts. LDH release from hypoxic hearts was minimal and was not significantly modified by drugs. However, all gap junction uncouplers, given during hypoxia, attenuated LDH release during subsequent reoxygenation. Dose-response analysis showed that increasing heptanol concentration beyond the level associated with maximal effects on cell coupling resulted in further protection against hypoxic injury. In conclusion, gap junction uncoupling during hypoxia has a protective effect on cell death occurring upon subsequent reoxygenation, and heptanol has, in addition, a marked protective effect independent of its uncoupling actions.Keywords
This publication has 25 references indexed in Scilit:
- Junctional and nonjunctional effects of heptanol and glycyrrhetinic acid derivates in rat mesenteric small arteriesBritish Journal of Pharmacology, 2004
- Gap junction-mediated spread of cell injury and death during myocardial ischemia–reperfusionCardiovascular Research, 2004
- Protective role of gap junctions in preconditioning against myocardial infarctionAmerican Journal of Physiology-Heart and Circulatory Physiology, 2004
- Mechanisms of Delayed Electrical Uncoupling Induced by Ischemic PreconditioningCirculation Research, 2003
- In Vivo and In Situ Ischemic Tissue Characterization Using Electrical Impedance SpectroscopyaAnnals of the New York Academy of Sciences, 1999
- Increased dispersion of ventricular repolarization and ventricular tachyarrhythmias in the globally ischaemic rabbit heartEuropean Heart Journal, 1993
- Increased dispersion of ventricular repolarization and ventricular tachyarrhythmias in the globally ischaemic rabbit heartEuropean Heart Journal, 1993
- Modulation of voltage-dependent Ca channel current by arachidonic acid and other long-chain fatty acids in rabbit intestinal smooth muscle.The Journal of general physiology, 1992
- Block of sodium current by heptanol in voltage-clamped canine cardiac Purkinje cells.Circulation Research, 1991
- Effect of oxygen withdrawal on active and passive electrical properties of arterially perfused rabbit ventricular muscle.Circulation Research, 1989