Protective effect of gap junction uncouplers given during hypoxia against reoxygenation injury in isolated rat hearts

Abstract

Rodríguez-Sinovas, Antonio, David García-Dorado, Marisol Ruiz-Meana, and Jordi Soler-Soler. Protective effect of gap junction uncouplers given during hypoxia against reoxygenation injury in isolated rat hearts.

δ-Opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC-ε-mediated phosphorylation of connexin 43

“…In our recent studies (20,23), both ischemic PC and an opener of the mitochondrial ATP-sensitive K ϩ (mK ATP ) channel, which is involved in the PC mechanism, significantly reduced gap junction permeability to a chemical tracer in the ischemic rabbit myocardium. Inhibition of gap junction communication by pharmacological gap junction blockers infused during ischemia or upon reperfusion has been shown to reduce infarct size in pig, rabbit, and rat hearts, as does ischemic PC (8,20,28). These findings support the notion that PC-induced suppression of gap junction permeability contributes to myocardial protection from ischemia-reperfusion injury.…”

“…However, the extent of protection by PC is generally less in isolated cell preparations than in whole hearts (1,19,22,35). Furthermore, there is also evidence to suggest that a part of myocardial protection by PC in whole hearts is achieved by chemical uncoupling of cardiomyocytes during ischemia-reperfusion, resulting in suppressed extension of injury within the area at risk (8,20,23,28). In our recent studies (20, 23), both ischemic PC and an opener of the mitochondrial ATP-sensitive K ϩ (mK ATP ) channel, which is involved in the PC mechanism, significantly reduced gap junction permeability to a chemical tracer in the ischemic rabbit myocardium.…”

Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

“…The protective effect of Gap 27 on the infarct size (Przyklenk et al, 2005) is comparable in magnitude to the effects reported by (Hawat et al, 2010) with Gap 26 (Table 1), Gap 26 is a peptide that corresponds to a sequence on the first extracellular loop of Cx43 and that has been demonstrated to interact with the extracellular loops (Liu et al, 2006). The sometimes variable outcome of work with gap junction inhibitors may be related to actions of these substances on hemichannels, as well as on gap junction channels (Garcia-Dorado et al, 1997;2002;Rodriguez-Sinovas et al, 2006;Miura et al, 2010). Gap 26 and Gap 27 peptides, for example, inhibit more rapidly hemichannel function in comparison to their uncoupling effects on gap junctions (Decrock et al, 2009a).…”

Roles of Cx43-associated protein kinases in suppression of gap junction-mediated chemical coupling by ischemic preconditioning

“…Intracellular Na ϩ overload, which occurs during ischemia and primes the cardiomyocyte for Ca 2ϩ overload at the time of reperfusion, has been shown to propagate via gap junctions to adjacent cardiomyocytes (28). Administration of gap junction inhibitors before ischemia or at the time of reperfusion significantly limits infarct size (7,19,20,26). Furthermore, involvement of gap junction modulation in PC has been suggested by the findings that both PC and PC mimetics suppress gap junction permeability during ischemia.…”

“…The contribution of PC-induced gap junction blockade to myocardial protection is difficult to assess since there is no selective and direct opener of closed gap junctions. However, there are several lines of circumstantial evidence suggesting that chemical uncoupling of the gap junction during ischemiareperfusion is a part of the mechanism of infarct size limitation afforded by PC: infarct size-limiting effects of structurally different gap junction blockers (7,19,20,26), suppression of gap junction permeability by PC mimetics (20,21), and partial loss of protection afforded by a ␦-opioid receptor agonist when suppression of gap junction permeability was abrogated (20). In addition to myocardial necrosis, arrhythmias during ischemia-reperfusion are suppressed by PC (6,24,25), which is possibly associated with alteration in electrical coupling of cardiomyocytes (6,13,24).…”