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1 Hospitals Vall d'Hebron, Laboratorio de Cardiologia Experimental, 08035 Barcelona, Spain
* To whom correspondence should be addressed. E-mail: dgdorado{at}vhebron.net.
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, 18
-glycyrrhetinic acid and palmitoleic acid on intracellular calcium concentration during simulated hypoxia (NaCN 2 mM) in isolated cardiomyocytes. Then, we analyzed their effects on developed and diastolic tension and electrical impedance in forty-seven 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 18-glycyrrhetinic acid nor palmitoleic acid, attenuated the increase in cytosolic [Ca2+] 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.
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