PROTECTIVE EFFECTS OF RANOLAZINE AND PROPRANOLOL, ALONE OR COMBINED, ON THE STRUCTURAL AND FUNCTIONAL ALTERATIONS OF CARDIOMYOCYTE MITOCHONDRIA IN A PIG MODEL OF ISCHEMIA/REPERFUSION
Bernard Bui-Xuan , Leila Dehina and Quadiri Timour
Laboratoire de Pharmacologie Médicale, EA 4612 - Neurocardiologie. Physiopathologie des
Troubles du Rythme Cardiaque, Université Claude Bernard, 8 avenue Rockefeller, 69373 Lyon cedex
08, France
Abstract:
Introduction: Preventing the consequences of ischemia/reperfusion (I/R)-induced lesions in the clinic requires the administration of pharmacological agents prior to restoring coronary vascularization. The aim of this study was to evaluate the effects of ranolazine and propranolol in these circonstances.
Methods: Thirty domestic pigs were randomly assigned to 5 groups of 6 animals including (i) sham animals; (ii) untreated animals with 45-min ischemia and 1-min reperfusion; animals administered intravenously with (iii) ranolazine, or (iv) propranolol, or (v) both combined, prior to 45-min ischemia and 1-min reperfusion. Hemodynamic and electrophysiologic parameters were measured during ischemia and after 1 minute of reperfusion. Structural and functional parameters of mitochondria were analyzed in tissue samples taken from ischemic area at the end experiment.
Results: I/R induced expected effects namely accelerated HR, decreased dMAP and LV dP/dt max, and altered mitochondrial structural and functional parameters including decreased oxygen consumption, increased reactive oxygen species production, and reduced calcium retention capacity resulting in the opening of mitochondrial permeability transition pores. Ranolazine and propranolol administered either alone or combined prior to I/R significantly decreased all of these deleterious consequences.
Conclusion. Effects of ranolazine and propranolol are seemingly due to the prevention of calcium overload and resulting lesions in mitochondria.