Direct, pleiotropic protective effect of cyclosporin A against simulated ischemia-induced injury in isolated cardiomyocytes

• Published in: European journal of pharmacology 2005-03, Vol.511 (2), p.109-120
• Main Authors: Bès, Sandrine, Vandroux, David, Tissier, Cindy, Devillard, Lisa, Brochot, Amandine, Tatou, Etienne, Duvillard, Laurence, Rochette, Luc, Athias, Pierre
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Biological and medical sciences; Cell contraction; Cell Hypoxia; Cell Survival - drug effects; Cells, Cultured; Cyclosporin A; Cyclosporine - pharmacology; Dose-Response Relationship, Drug; Electrophysiology; Heat shock protein; HSP70 Heat-Shock Proteins - genetics; Immunosuppressive Agents - pharmacology; Ischemia–reperfusion; L-Lactate Dehydrogenase - secretion; Medical sciences; Mitochondria; Mitochondria - drug effects; Mitochondria - physiology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; Neonatal rat cardiomyocyte; Oxygen - pharmacology; Pharmacology. Drug treatments; Protein release; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Time Factors; Transcription, Genetic - drug effects; Troponin I - secretion
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2005.02.016

Cyclosporin A is an immunosuppressor that prolongs graft survival but its use is limited by cardiotoxicity. The effects of cyclosporin A on several functional and biological characteristics were thus evaluated in rat cardiomyocytes in normal conditions and in a substrate-free, hypoxia–reoxygenation model of ischemia–reperfusion. Cyclosporin A (100 and 1000 ng/ml) did not induce cardiocytotoxicity in basal conditions. Simulated ischemia gradually decreased and then blocked the spontaneous electromechanical activity. Cyclosporin A at 100 and 1000 ng/ml permitted the maintenance of electromechanical functions that were abolished in control cells. Cyclosporin A also improved the post-“ischemic” functional recovery. Cyclosporin A reduced the “ischemia”-induced lactate dehydrogenase and troponine I releases and the successive rises in heat shock protein mRNA observed after “ischemia” and reoxygenation. Moreover, cyclosporin A improved the resumption of the mitochondrial function. To conclude, cyclosporin A displayed a direct, pleiotropic protection of isolated cardiomyocytes against physiological, metabolic, structural and stress signaling changes induced by ischemia–reperfusion mimicked in vitro.