Inhibition of nitric oxide synthase prevents myocardial protection by ramiprilat.
The objective of this investigation was to determine the role of nitric oxide synthase in the action of the angiotensin-converting enzyme inhibitor, ramiprilat, to reduce myocardial ischemia/reperfusion injury. Ramiprilat, the nitric oxide synthase inhibitor NG-nitro-L-NAME (L-NAME), ramiprilat plus L-NAME, or saline (n = 8 each group), were administered i.v. in intact animal preparations of experimentally induced acute myocardial ischemia. Anesthetized, open-chest rabbits were instrumented for measurement of systemic hemodynamics and left ventricular pressure from which left ventricular +dP/dtmax was derived. Animals were subjected to 30 min of left main coronary artery occlusion (marginal branch) followed by 2 hr of reperfusion. Ramiprilat (50 micrograms/kg) or saline was administered 5 min before reperfusion, and those rabbits receiving L-NAME (100 micrograms/kg/min) were pretreated starting 30 min before occlusion throughout the remainder of the experiment. After reperfusion, myocardial infarct size (IS) was determined via tetrazolium staining and expressed as a percentage of area at risk (AR). IS/AR% was significantly reduced in rabbits administered ramiprilat (19 +/- 3%) compared 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 not significantly different between groups. The results indicate that the effect of ramiprilat to reduce infarct size is abolished by pretreatment with L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)
Hartman
J C
JC
Cardiovascular Diseases Research Unit, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan.
Kurc
G M
GM
Hullinger
T G
TG
Wall
T M
TM
Sheehy
R M
RM
Shebuski
R J
RJ
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D011817:Rabbits; D017257:Ramipril / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; C052549:ramiprilat; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D017257:Ramipril; D019331:NG-Nitroarginine Methyl Ester