INHIBITION OF NITRIC-OXIDE SYNTHASE PREVENTS MYOCARDIAL PROTECTION BYRAMIPRILAT

The objective of this investigation was to determine the role of nitri c oxide synthase in the action of the angiotensin-converting enzyme in hibitor, ramiprilat, to reduce myocardial ischemia/reperfusion injury. Ramiprilat, the nitric oxide synthase inhibitor N-G-nitro-L-NAME (L-N AME), ramiprilat plus L-NAME, or saline (n = 8 each group), were admin istered i.v. in intact animal preparations of experimentally induced a cute myocardial ischemia. Anesthetized, open-chest rabbits were instru mented for measurement of systemic hemodynamics and left ventricular p ressure from which left ventricular +dP/dt(max) was derived. Animals w ere subjected to 30 min of left main coronary artery occlusion (margin al branch) followed by 2 hr of reperfusion. Ramiprilat (50 mu g/kg) or saline was administered 5 min before reperfusion, and those rabbits r eceiving L-NAME (100 mu g/kg/min) were pretreated starting 30 min befo re occlusion throughout the remainder of the experiment. After reperfu sion, myocardial infarct size (IS) was determined via tetrazolium stai ning and expressed as a percentage of area at risk (AR). IS/AR% was si gnificantly reduced in rabbits administered ramiprilat (19 +/- 3%) co mpared to those receiving saline (39 +/- 2%), ramiprilat plus L-NAME ( 43 +/- 4%) or L-NAME alone (43 +/- 2%; mean +/- S.E.M.; P < .05). AR as a percent of total left ventricular mass was not different between any of the four treatment groups. Systemic hemodynamic effects were no t significantly different between groups. The results indicate that th e effect of ramiprilat to reduce infarct size is abolished by pretreat ment with L-NAME. Because earlier data suggest that ramiprilat protect s myocardium by elevating bradykinin, this new result implies that the protection may be related to increased nitric oxide production mediat ed by bradykinin.