ATTENUATION OF MYOCARDIAL STUNNING BY THE ACE-INHIBITOR RAMIPRILAT THROUGH A SIGNAL CASCADE OF BRADYKININ AND PROSTAGLANDINS BUT NOT NITRIC-OXIDE

Background Attenuation of myocardial stunning by several angiotensin-c onverting enzyme (ACE) inhibitors has been demonstrated. However, the signal cascade mediating such protective effect has not been analyzed in detail so far. Methods and Results In a first protocol, we addresse d the role of bradykinin and analyzed the effect of the ACE inhibitor ramiprilat without and with added bradykinin B-2 receptor antagonist H OE 140 on regional myocardial blood flow (colored microspheres) and fu nction (sonomicrometry). Thirty-two enflurane/N2O-anesthetized open-ch est dogs were subjected to 15 minutes of occlusion of the left circumf lex coronary artery (LCx) and 4 hours of subsequent reperfusion. Eight dogs served as placebo controls (group 1), and 8 dogs received ramipr ilat (20 mu g/kg IV) before LCx occlusion (group 2). Eight dogs receiv ed a continuous intracoronary infusion of HOE 140 [0.5 ng/(mL.min) IC] during ischemia and reperfusion (group 3), and in 8 dogs HOE 140 was infused continuously during ischemia and reperfusion, starting 45 minu tes before the administration of ramiprilat (group 4). Mean aortic pre ssure was kept constant with an intra-aortic balloon, and heart rate d id not change throughout the experimental protocols. Under control con ditions and during myocardial ischemia, posterior transmural blood flo w (BF) and systolic wall thickening (WT) were not different in the fou r groups of dogs. However, at 4 hours of reperfusion, WT was still dep ressed in groups 1 (-10+/-20% of control [mean+/-SD]), 3 (-18+/-12% of control), and 4 (-12+/-21% of control), whereas WT in group 2 had rec overed to 55+/-20% of control (P<.05 versus group 1). BF at 4 hours of reperfusion was not different in the four groups of dogs. Thus, the b eneficial effect of ramiprilat on the functional recovery of stunned m yocardium was obviously mediated by bradykinin. Since bradykinin stimu lates the formation of both prostaglandins and nitric oxide, we tested in a second protocol which of these mediators was further involved in the beneficial effects of ramiprilat. Twenty-four additional dogs wer e subjected to 15 minutes of LCx occlusion and 4 hours of reperfusion. Six dogs received the cyclooxygenase inhibitor indomethacin (10 mg/kg IV) (group 5) and 6 dogs a combination of indomethacin with ramiprila t (group 6) before LCx occlusion. Six dogs received the nitric oxide s ynthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg IV) (group 7) and 6 dogs a combination of L-NAME with ramiprilat (gro up 8) before LCx occlusion. BF and WT before and during myocardial isc hemia were not different in groups 5 and 6 and groups 7 and 8. However , at 4 hours of reperfusion, WT was still depressed in groups 5 (-10+/ -38% of control), 6 (-7+/-18% of control), and 7 (-12+/-14% of control ), whereas WT in group 8 had recovered to 47+/-28% of control (P<.05 v ersus group 7). BF at 4 hours of reperfusion was not different in the four groups of dogs. Conclusions In summary, the attenuation of stunni ng by the ACE inhibitor ramiprilat involves a signal cascade of bradyk inin and prostaglandins but not nitric oxide.