Myocardial toxicity of cyclosporin A: inhibition of calcium ATPase and nitric oxide synthase activities and attenuation by fructose-1,6-diphosphate in vitro.

Use of cyclosporin A (CsA) in transplantation medicine has been shown to cause a number of toxic cellular side effects, which has prompted a search for formulations that afford protection from these undesirable sequelae. Previously we demonstrated that fructose-1,6-diphosphate (FDP) can reverse a variety of toxic cellular effects that arise upon use of various chemical agents. The present studies were undertaken to study the effects of CsA on rat myocardial Ca2+, calmodulin (Cam)-dependent enzymes such as Ca2+ ATPase and nitric oxide synthase (NOS) and the role of FDP in attenuating these changes in vitro. Rat ventricular sarcoplasmic Ca2+ ATPase was studied by measuring the inorganic phosphorous liberated on ATP hydrolysis and rat heart 100,000 g fraction NOS activity by monitoring the formation of [3H]-citrulline in the presence of 10-1000 microM CsA and 1000 microM CsA + 1000 microns FDP in vitro. CsA in all concentrations significantly (P < 0.001) inhibited both Ca2+ ATPase and NOS activities of rat myocardium and FDP at 1000 microM concentration completely reversed the 1000 microM CsA-inhibited Ca2+ ATPase and cNOS activities of rat myocardium. These data indicate that CsA may inhibit Ca2+ ATPase and NOS activities in the rat myocardium through interference with its Ca2+/Cam-mediated events and thus may cause myocardial toxicity. FDP may reverse these changes.