Ru₃₆₀, a specific mitochondrial calcium uptake inhibitor, improves cardiac post‐ischaemic functional recovery in rats in vivo

Abstract

Background and purpose: The mitochondrial permeability transition pore (mPTP), an energy-dissipating channel activated by calcium, contributes to reperfusion damage by depolarizing the mitochondrial inner membrane potential. As mitochondrial Ca 2 þ overload is a main inductor of mPTP opening, we examined the effect of Ru 360 , a selective inhibitor of the mitochondrial calcium uptake system against myocardial damage induced by reperfusion in a rat model. Experimental approach: Myocardial reperfusion injury was induced by a 5-min occlusion of the left anterior descending coronary artery, followed by a 5-min reperfusion in anaesthetized open-chest rats. We measured reperfusion-induced arrhythmias and functions indicative of unimpaired mitochondrial integrity to evaluate the effect of Ru 360 treatment. Key results: Reperfusion elicited a high incidence of arrhythmias, haemodynamic dysfunction and loss of mitochondrial integrity. A bolus intravenous injection of Ru 360 (15-50 nmol kg À1 ), given 30-min before ischaemia, significantly improved the above mentioned variables in the ischaemic/reperfused myocardium. Calcium uptake in isolated mitochondria from Ru 360 -treated ventricles was partially diminished, suggesting an interaction of this compound with the calcium uniporter. Conclusions and implications:We showed that Ru 360 treatment abolishes the incidence of arrhythmias and haemodynamic dysfunction elicited by reperfusion in a whole rat model. Ru 360 administration partially inhibits calcium uptake, preventing mitochondria from depolarization by the opening of the mPTP. We conclude that myocardial damage could be a consequence of failure of the mitochondrial network to maintain the membrane potential at reperfusion. Hence, it is plausible that Ru 360 could be used in reperfusion therapy to prevent the occurrence of arrhythmia.

The role of the mitochondrial calcium uniporter in cerebral ischemia/reperfusion injury in rats involves regulation of mitochondrial energy metabolism

“…By contrast, treatment with spermine, an activator of the uniporter, led to converse results. MCU was demonstrated to have a regulatory effect in focal cerebral I/R injury, consistent with previous studies (21)(22)(23). In addition, the mechanism by which MCU regulates cerebral I/R injury was hypothesized to be associated with improved mitochondrial energy metabolism due to MCU inhibition.…”

“…A previous study reported that ΔΨ m decrease was an initiator and was also a consequence of MPTP opening (51). As as an inhibitor of MCU, Ru360 may normalize mitochondrial membrane depolarization by preventing the opening of the MPTP during I/R (22). The results of the present study revealed changes in ΔΨ m , specifically, membrane depolarization during I/R, normalization by RR and accelerated collapse following spermine treatment, that are indicative of the regulatory functions of MCU on ΔΨ m during I/R.…”

KATPChannels in the Cardiovascular System

“…Even if ATP levels are not substantially changed, K ATP channel openers can improve the free energy of ATP hydrolysis, as demonstrated with 31 P-NMR measurements in hypoxic guinea pig hearts (173). It is possible that K ATP channel openers may preserve mitochondrial function during ischemia, similar to the preservation of mitochondrial integrity that is observed with L-type Ca 2ϩ channel blockers (464, 591) and with blockers of the mitochondrial permeability transition pore (180), or by inhibiting Ca 2ϩ uptake into mitochondria (224,254). This putative protective effect may be direct, due to effects of the KCOs on mitochondrial K ATP channels (263) or on the mitochondrial F 1 F 0 -ATPase (11).…”

Mitochondrial calcium overload is a key determinant in heart failure

“…Both increased and reduced mitochondrial Ca 2+ levels have been implicated in mitochondrial dysfunction and increased reactive oxygen species (ROS) production in heart failure (HF) (6,7,(9)(10)(11)(12)(13)(14)(15)(16)(17). Albeit Ca 2+ is required for activation of key enzymes (i.e., pyruvate dehydrogenase phosphatase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase) in the tricarboxylic acid (also known as Krebs) cycle (18, 19), excessive mitochondrial Ca 2+ uptake has been associated with cellular dysfunction (14,20).…”