Close Association Between the Reduction in Myocardial Energy Metabolism and Infarct Size: Dose-Response Assessment of Cyclosporine

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Abstract
Cyclosporine protects the heart against ischemia/reperfusion injury, but its effect on cardiac metabolism is largely unknown. We assessed cyclosporine-induced metabolic changes in the rat heart prior to occlusion using magnetic resonance spectroscopy (MRS) and correlated effects with infarct size in a coronary occlusion/reperfusion model. The two study groups were cyclosporine and cyclosporine + coronary occlusion (n = 20/group). Rats were pretreated with cyclosporine (5, 10, 15, and 25 mg/kg/day) or the vehicle by oral gavage for 3 days (n = 4/dose). On day 4, hearts of rats in the cyclosporine group were excised, and extracted cell metabolites were measured using 1H and 31P MRS. The second group was subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion. Infarct size and area at risk were measured using a double staining method. In the cyclosporine group, cyclosporine reduced cardiac energy metabolism (ATP:r = −0.89, P < 0.001) via depression of oxidative phosphorylation and the Krebs9 cycle in a dose-dependent manner. The decrease of ATP levels was positively correlated with changes of NAD+ (r = 0.89), glutamate (r = 0.95), glutamine (r = 0.84), and glucose concentrations (r = 0.92, all P < 0.002). It was inversely correlated with lactate (r = −0.93,P < 0.001). In the coronary occlusion group, cyclosporine dose dependently reduced the ratio [area of infarct/area of the left ventricle] (r = −0.86,P < 0.01), with 15 mg/kg/day being the most effective cyclosporine dose. The reduction in infarct size correlated with the reduction in oxidative phosphorylation (ATP:r = 0.97; NAD+: r = 0.82, P < 0.01). The reduction in cardiac energy metabolism before occlusion may be the cause of myocardial preservation during ischemia/reperfusion.