Preservation of mitochondrial function by diazoxide during sustained ischaemia in the rat heart

Abstract

1 A possible mechanism for the action of the K ATP channel opener diazoxide on the improvement of energy metabolism of ischaemic/reperfused hearts was examined. 2 Isolated, perfused rat hearts were subjected to 40 min ischaemia followed by 60 min reperfusion. Diazoxide at concentrations of 3 to 30 mM was present in the perfusion bu er for the last 15 min of pre-ischaemia. 3 Treatment of the perfused heart with diazoxide enhanced the post-ischaemic recovery of ratepressure product, attenuated the post-ischaemic rise in left ventricular end-diastolic pressure, and suppressed the release of creatine kinase and purine nucleosides and bases from the reperfused heart. Treatment of the heart with diazoxide also restored myocardial ATP and creatine phosphate and attenuated the decrease in mitochondrial oxygen consumption rate after reperfusion. This attenuation was maintained at the end of ischaemia as well as at the end of reperfusion. 4 In another set of experiments, myocardial skinned bundles were incubated for 30 min under hypoxic conditions in the presence and absence of diazoxide, and then the mitochondrial oxygen consumption rate was determined. Hypoxia induced a decrease in the mitochondrial oxygen consumption rate of the skinned bundles to approximately 40% of the pre-hypoxic value. In contrast, treatment of the bundles with 30 mM diazoxide preserved the normal mitochondrial oxygen consumption rate during hypoxia. This e ect was abolished concentration-dependently by the combined treatment with either the K ATP channel blocker glibenclamide or 5-hydroxydecanoate. 5 These results suggest that diazoxide is capable of attenuating ischaemia/reperfusion injury of isolated perfused hearts due to preservation of mitochondrial function during ischaemia.

Bioenergetic and volume regulatory effects of mitoKATP channel modulators protect against hypoxia-reoxygenation induced mitochondrial dysfunction

“…1). That is, our findings are consistent with earlier reports on the beneficial effects of a low dose of diazoxide on mammalian mitochondrial coupling (Iwai et al, 2000;Dos Santos et al, 2002). The primary role of the mitoK ATP channel is believed to be mitochondrial volume regulation (Jaburek et al, 1998;Garlid, 2000;Costa et al, 2006).…”

Cardioprotection Techniques: Preconditioning, Postconditioning and Remote Con-ditioning (Basic Science)

“…This proposal has been supported by a number of experimental studies reporting preserved mitochondrial function and maintained levels of high-energy phosphates [66]. The opening of the MitoKATP channel has been demonstrated to increase ATP synthesis [67], preserve mitochondrial energy production [68], decrease ATP hydrolysis [69] and improve energy transfer at reperfusion [69].…”

Diazoxide enhances excitotoxicity-induced neurogenesis and attenuates neurodegeneration in the rat non-neurogenic hippocampus

“…Activation of mitoK ATP channels increases potassium flux into the mitochondrial matrix and avoids excessive mitochondrial contraction that is deleterious for electron transport (Cancherini et al, 2003). Indeed, cells treated with Dzx demonstrate favorable energy profiles with limited damage following stress challenges (Iwai et al, 2000). Furthermore, Dzx has been reported to provide cardioprotection through mitoK ATP activation (Henn et al, 2015).…”