Interaction of L-arginine and phosphodiesterase inhibitors in vasodilation of the porcine internal mammary artery

Anesth Analg. 2000 Apr;90(4):840-6. doi: 10.1097/00000539-200004000-00012.


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.

Implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / pharmacology*
  • Cyclic GMP / physiology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Mammary Arteries / drug effects*
  • Mammary Arteries / physiology
  • Phosphodiesterase Inhibitors / pharmacology*
  • Swine
  • Vasodilation / drug effects*
  • omega-N-Methylarginine / pharmacology


  • Phosphodiesterase Inhibitors
  • omega-N-Methylarginine
  • Arginine
  • Cyclic GMP