Interaction of L-arginine and phosphodiesterase inhibitors in vasodilation of the porcine internal mammary artery.
We tested the hypothesis that L-arginine (the substrate for nitric oxide production)-combined with amrinone, milrinone (Type III phosphodiesterase [PDE] inhibitors), zaprinast, or sildenafil (Type V PDE inhibitors)-would vasodilate synergistically. Internal mammary artery segments were excised from anesthetized swine, divided into rings, and suspended in a tissue bath at 37 degrees C. Force of contraction was measured during dose-response testing of combinations of L-arginine and amrinone, milrinone, zaprinast, or sildenafil. Amrinone and milrinone were additive to L-arginine. N(G)-methyl-L-arginine (L-NMA) inhibited the effects of milrinone but not amrinone. The effective concentration of amrinone eliciting 50% relaxation (EC(50)) was 3.8E-05M (n = 6) when given alone and 4. 4E-05M (n = 6) with L-NMA. Milrinone had EC(50) = 6.0E-06M alone (n = 6) and 2.8E-05M (n = 6) with L-NMA. Zaprinast (EC(50) = 6.5E-05M, n = 6) and sildenafil (EC(30) = 1.8E-05M, n = 6) were synergistic with L-arginine. L-NMA blocked their effects, increasing the EC(50) for zaprinast to 9.9E-03M and the EC(30) for sildenafil to 6.1E+02M. In conclusion, L-arginine is additive to the vasodilation of the type III PDE inhibitors, amrinone and milrinone, but synergistic with the type V PDE inhibitors, zaprinast and sildenafil.


CONCLUSIONS
Amrinone and milrinone, Type III cAMP-dependent phosphodiesterase inhibitors, are additive to L-arginine-dependent vasodilation. Zaprinast and sildenafil, Type V cGMP-dependent phosphodiesterase inhibitors, are synergistic with L-arginine.
Wallace
A W
AW
Department of Anesthesiology, San Francisco Veterans Administration Medical Center and Department of Anesthesiology, University of California-San Francisco, San Francisco, California, USA. awallace@best.com
Tom
W L
WL
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D006152:Cyclic GMP / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008323:Mammary Arteries / Q000187:drug effects* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D019323:omega-N-Methylarginine; D001120:Arginine; D006152:Cyclic GMP