A novel cardioprotective agent, JTV-519, is abolished by nitric oxide synthase inhibitor on myocardial metabolism in ischemia-reperfused rabbit hearts

We investigated the effect of a novel cardioprotective agent, JTV-519, with or without a nitric oxide synthase inhibitor, L-NAME, on the myocardial metabolism and contraction during ischemia and reperfusion by means of phosphorus 31-nuclear magnetic resonance (P-31-NMR) in Langendorff rabbit hearts, After 20 min normothermic global ischemia, postischemic reperfusion was carried out for 30 min. JTV-519 was administered from 40 min prior to the global ischemia. Twenty-one hearts were divided into three experimental groups consisting of 7 hearts each: a control group, a JTV-519 group perfused with JTV-519, and a JTV-519 +L-NAME group perfused with a combination of JTV-519 and L-NAME. During ischemia, the JTV-519 group showed a significant inhibition of the decrease in adenosine triphosphate (ATP) compared with both the control and JTV-519 + L-NAME groups (p<0.01); the levels of ATP were 20 6, 56 9, and 40+/-4% in the control group, JTV-519 group, and JTV-519 + L-NAME group, respectively. Both the JTV-519 group and JTV-519+L-NAME group showed a significant inhibition of the increase in left ventricular end-diastolic pressure (LVEDP) compared with the control group (p<0.01). After postischemic reperfusion, the JTV-519 group again showed a significant improvement of ATP as compared with both the control and JTV-519+L-NAME groups (p<0.01); the ATP levels were 52+/-4, 82 3, and 64+/-3% in the control group, JTV-519 group, and JTV-519+L-NAME group. In conclusion, JTV-519 has a significant beneficial effect on myocardial energy metabolism during both ischemia and reperfusion. This beneficial effect was dependent on NO synthase. Furthermore, JTV-519 showed significant potential for improving myocardial relaxation during ischemia. This effect was not dependent on NO synthase.