Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post‐ischaemic functional recovery in rats in vivo
G de J García‐Rivas, K Carvajal… - British journal of …, 2006 - Wiley Online Library
G de J García‐Rivas, K Carvajal, F Correa, C Zazueta
British journal of pharmacology, 2006•Wiley Online LibraryBackground 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 Ca2+ overload is a main
inductor of mPTP opening, we examined the effect of Ru360, 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 …
dissipating channel activated by calcium, contributes to reperfusion damage by depolarizing
the mitochondrial inner membrane potential. As mitochondrial Ca2+ overload is a main
inductor of mPTP opening, we examined the effect of Ru360, 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 …
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 Ca2+ overload is a main inductor of mPTP opening, we examined the effect of Ru360, 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 Ru360 treatment.
Key results
Reperfusion elicited a high incidence of arrhythmias, haemodynamic dysfunction and loss of mitochondrial integrity. A bolus intravenous injection of Ru360 (15‐50 nmol kg−1), given 30‐min before ischaemia, significantly improved the above mentioned variables in the ischaemic/reperfused myocardium. Calcium uptake in isolated mitochondria from Ru360‐treated ventricles was partially diminished, suggesting an interaction of this compound with the calcium uniporter.
Conclusions and implications
We showed that Ru360 treatment abolishes the incidence of arrhythmias and haemodynamic dysfunction elicited by reperfusion in a whole rat model. Ru360 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 Ru360 could be used in reperfusion therapy to prevent the occurrence of arrhythmia.
British Journal of Pharmacology (2006) 149, 829–837. doi:10.1038/sj.bjp.0706932
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