AIMS: The possible contribution of the cardiac mitochondrial permeability transition pore (PTP) towards the cardioprotective effects of Na(+)-H(+) exchanger-1 (NHE-1) inhibition was studied in hearts subjected to ischaemia/reperfusion (IR). METHODS AND RESULTS: Langendorff-perfused rat hearts were subjected to 40 min of global ischaemia and 60 min of reperfusion in the presence or absence of the NHE-1 specific inhibitor AVE-4890 (AVE, 5 microM). Mitochondrial PTP opening was determined in the intact heart using 2-deoxy-[(3)H]-glucose entrapment and in isolated mitochondria by monitoring the decrease of the calcium-induced light scattering. Mitochondrial respiration was measured with a Clark-type oxygen electrode whereas release of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) and levels of cleaved poly-(ADP-ribose) polymerase (PARP) were analysed by western blotting. IR induced mitochondrial PTP opening, which was inhibited by 28% (P < 0.05) with AVE treatment. Mitochondria isolated from AVE-treated hearts demonstrated significantly less calcium-induced swelling and higher substrate oxidation at complex I and II as well as cytochrome c oxidase and citrate synthase activity. AVE treatment also suppressed IR-induced release of AIF and EndoG from mitochondria, prevented the IR-induced rise in cleaved PARP levels, and was associated with significantly enhanced postischaemic recovery of left ventricular developed pressure and a significant decrease in lactate dehydrogenase release. AVE did not affect PTP opening directly in isolated mitochondria. CONCLUSION: The beneficial effect of NHE-1 inhibition in hearts subjected to IR is associated with attenuation of mitochondrial PTP opening and apoptosis and the resultant mitochondrial dysfunction. The effect of AVE on PTP opening most likely is indirect, as pore opening was not affected by direct administration of AVE to mitochondrial suspensions.
AIMS: The possible contribution of the cardiac mitochondrial permeability transition pore (PTP) towards the cardioprotective effects of Na(+)-H(+) exchanger-1 (NHE-1) inhibition was studied in hearts subjected to ischaemia/reperfusion (IR). METHODS AND RESULTS: Langendorff-perfused rat hearts were subjected to 40 min of global ischaemia and 60 min of reperfusion in the presence or absence of the NHE-1 specific inhibitor AVE-4890 (AVE, 5 microM). Mitochondrial PTP opening was determined in the intact heart using 2-deoxy-[(3)H]-glucose entrapment and in isolated mitochondria by monitoring the decrease of the calcium-induced light scattering. Mitochondrial respiration was measured with a Clark-type oxygen electrode whereas release of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) and levels of cleaved poly-(ADP-ribose) polymerase (PARP) were analysed by western blotting. IR induced mitochondrial PTP opening, which was inhibited by 28% (P < 0.05) with AVE treatment. Mitochondria isolated from AVE-treated hearts demonstrated significantly less calcium-induced swelling and higher substrate oxidation at complex I and II as well as cytochrome c oxidase and citrate synthase activity. AVE treatment also suppressed IR-induced release of AIF and EndoG from mitochondria, prevented the IR-induced rise in cleaved PARP levels, and was associated with significantly enhanced postischaemic recovery of left ventricular developed pressure and a significant decrease in lactate dehydrogenase release. AVE did not affect PTP opening directly in isolated mitochondria. CONCLUSION: The beneficial effect of NHE-1 inhibition in hearts subjected to IR is associated with attenuation of mitochondrial PTP opening and apoptosis and the resultant mitochondrial dysfunction. The effect of AVE on PTP opening most likely is indirect, as pore opening was not affected by direct administration of AVE to mitochondrial suspensions.
Authors: Mohammed Aldakkak; David F Stowe; James S Heisner; Marisha Spence; Amadou K S Camara Journal: J Cardiovasc Pharmacol Date: 2008-09 Impact factor: 3.105
Authors: Erinne R Dabkowski; Kelly A O'Connell; Wenhong Xu; Rogerio F Ribeiro; Peter A Hecker; Kadambari Chandra Shekar; Caroline Daneault; Christine Des Rosiers; William C Stanley Journal: Cardiovasc Drugs Ther Date: 2013-12 Impact factor: 3.727