title: A novel cardioprotective agent, JTV-519, is abolished by nitric oxide synthase inhibitor on myocardial metabolism in ischemia-reperfused rabbit hearts.
abstract: 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 (31P-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.
authors.affiliation: First Department of Internal Medicine, Kinki University School of Medicine, Osakasayama, Japan. int1@med.kindai.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kawabata
authors.forename: Kizuku
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Kinji
authors.initials: K
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011312:Pressure; D011817:Rabbits; D013841:Thiazepines / Q000494:pharmacology*; D016277:Ventricular Function, Left
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D013841:Thiazepines; C109183:K201 compound; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester