title: Cardioprotection with angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor antagonist is not abolished by nitric oxide synthase inhibitor in ischemia-reperfused rabbit hearts.
abstract: Although angiotensin converting enzyme (ACE) inhibitor and/or angiotensin II type 1 (AT1) receptor antagonist can protect the myocardium against ischemia-reperfusion injury, the mechanisms of the effect have not yet been characterized at the cellular level. We here examined the effect of the combination of an ACE inhibitor, temocaprilat, an AT1 receptor antagonist, CV-11974 and/or a nitric oxide synthase inhibitor, L-NAME, on the myocardial metabolism and contraction during ischemia and reperfusion by using phosphorus 31-nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts. After normothermic 20 min global ischemia, postischemic reperfusion of 30 min was carried out. Twenty-one hearts were divided into three experimental groups consisting of 7 hearts each: a Tem+CV group perfused with a combination of temocaprilat and CV-11974; a Tem+CV+L-NAME group perfused with a combination of temocaprilat and CV-11974 plus L-NAME, and a control group. During ischemia, both the Tem+CV group and Tem+CV+L-NAME group showed a significant inhibition of the decrease in adenosine triphosphate (ATP) compared with the control group (p<0.01); the increase in ATP was 50+/-3%, 42+/-4%, and 19+/-4% in the Tem+CV group, Tem+CV+L-NAME group, and control group, respectively. Both experimental groups also 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 Tem+CV group and Tem+CV+L-NAME group again showed a significant improvement of ATP as compared with the control group (p<0.01); the increase in ATP was 73+/-3%, 64+/-3%, and 47+/-4% in the Tem+CV group, Tem+CV+L-NAME group, and control group, respectively, and a significant decrease of LVEDP as compared with the control group (p<0.01). There were no differences in ATP, or LVEDP during ischemia and reperfusion between the Tem+CV group and Tem+CV+ L-NAME group. In conclusion, the combination of temocaprilat and CV-11974 showed significant potential for improving myocardial energy metabolism and relaxation during both myocardial ischemia and reperfusion. This beneficial 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: H
authors.initials: H
authors.lastname: Kawabata
authors.forename: T
authors.initials: T
authors.lastname: Ryomoto
authors.forename: K
authors.initials: K
authors.lastname: Ishikawa
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; 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 / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010477:Perfusion; D011312:Pressure; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles / Q000494:pharmacology*; D013841:Thiazepines / Q000494:pharmacology*; D016277:Ventricular Function, Left
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013841:Thiazepines; C069156:temocaprilat; D019001:Nitric Oxide Synthase; C081643:candesartan; D019331:NG-Nitroarginine Methyl Ester