Protective effect of imidaprilat, an angiotensin-converting enzyme inhibitor on *OH generation in rat myocardium.
We used a flexibly mounted microdialysis technique to the hearts of rats and examined the protective effect of imidaprilat, an angiotensin-converting enzyme (ACE) inhibitor, on the production of hydroxyl free radical (*OH) generation. A microdialysis probe was implanted into the left ventricular myocardium, and dialysate norepinephrine (NE) concentrations were measured as an index of myocardial interstitial NE levels. Sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was directly infused through a microdialysis probe to detect the generation of *OH reflected by the formation of dihydroxybenzoic acid (DHBA) in rat myocardium. When tyramine (1 mM) was directly infused through the microdialysis probe, the level of NE significantly increased in the dialysate and the level of NE increased by 128 +/- 43%. Imidaprilat (5, 25 and 50 microM) decreased the level of tyramine (1 mM)-induced NE in a concentration-dependent manner. Tyramine clearly produced an increase in *OH formation. In the presence of imidaprilat (50 microM), tyramine failed to increase both 2,3- and 2,5-dihydroxylation. Therefore, the effects of imidaprilat on the *OH generation in the sympathetic nerve blockaded hearts by reserpine treatment were not observed. Moreover, to examine the effect of imidaprilat on *OH formation by ischemia/reperfusion of the myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery. When the heart was reperfused, elevation of NE and 2,3- and 2,5-DHBA in imidaprilat (50 microM)-pretreated animals was not observed in the heart dialysate. Imidaprilat 2.5 mg/kg i.p. pretreatment at 5 h before coronary occlusion significantly blunted the rise of serum creatine phosphokinase and improved the electrocardiogram 2 h after coronary occlusion. These results suggest that imidaprilat, an ACE inhibitor, is associated with cardioprotective effect due to the suppression of NE-induced *OH generation.
Obata
T
T
Department of Pharmacology, Oita Medical University, Japan. tobata@oita-med.ac.jp
Yamanaka
Y
Y
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D015773:Enalaprilat / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D017665:Hydroxyl Radical; D015773:Enalaprilat; C078006:imidaprilat