Close association between the reduction in myocardial energy metabolism and infarct size: Dose-response assessment of cyclosporine

被引:35
作者
Niemann, CU
Saeed, M
Akbari, H
Jacobsen, W
Benet, LZ
Christians, U
Serkova, N
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Anesthesiol, Denver, CO 80262 USA
[2] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA
[4] Univ Bremen, Dept Biol Chem, Bremen, Germany
关键词
D O I
10.1124/jpet.102.036848
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 H-1 and P-31 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 Krebs' 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.
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页码:1123 / 1128
页数:6
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