Cardiovascular actions of inhibitors of endothelium-derived relaxing factor (nitric oxide) formation/release in anesthetized dogs.
NG-monomethyl-L-arginine (NMA) and NG-nitro-L-arginine (NNA), both of which are inhibitors of nitric oxide (endothelium-derived relaxing factor, EDRF) production from L-arginine, have been shown to be pressor agents in vivo. This study compared the cardiac and vascular responses to intraaortic administration of NMA and NNA in anesthetized dogs. NMA at doses of 3, 10, 30 and 100 mg kg-1 i.a. increased systemic vascular resistance and decreased cardiac output; mean arterial pressure increased by 10 mm Hg (at 100 mg kg-1 dose). Heart rate did not change. NNA, administered at doses of 1, 3, 10 and 30 mg kg-1 i.a. produced similar cardiovascular actions and was equipotent to NMA. Pretreatment with indomethacin abolished the pressor response to NMA; however, systemic vasoconstriction and cardiac depression still occurred. Increasing mean arterial pressure by phenylephrine infusion to levels much greater than produced by NMA and NNA caused only small reductions in cardiac output. NMA did not reduce coronary blood flow, but instead caused a transient flow increase. Therefore, systemic administration of NMA and NNA result in pronounced systemic vasoconstriction and cardiac depression with only a small pressor response in anesthetized dogs. The cardiac depression did not result from elevated arterial pressure nor was it due to coronary vasoconstriction and reduced myocardial oxygen supply/demand ratio.
Klabunde
R E
RE
Department of Pharmacology, Abbott Laboratories, Abbott Park, IL 60064.
Ritger
R C
RC
Helgren
M C
MC
D000758:Anesthesia; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D019335:Nitroarginine; D014661:Vasoconstriction / Q000187:drug effects; D019323:omega-N-Methylarginine
D019335:Nitroarginine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D007213:Indomethacin