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.