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CARDIOVASCULAR ANESTHESIA

Interaction of L-Arginine and Phosphodiesterase Inhibitors in Vasodilation of the Porcine Internal Mammary Artery

Department of Anesthesiology, San Francisco Veterans Administration Medical Center and Department of Anesthesiology, University of California–San Francisco, San Francisco, California

Address correspondence and reprint requests to Arthur Wallace, MD, PhD, VAMC Anesthesia (129), 4150 Clement St., San Francisco, CA 94121. Address e-mail to awallace{at}best.com

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°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 (EC₅₀) was 3.8E-05M (n = 6) when given alone and 4.4E-05M (n = 6) with L-NMA. Milrinone had EC₅₀ = 6.0E-06M alone (n = 6) and 2.8E-05M (n = 6) with L-NMA. Zaprinast (EC₅₀ = 6.5E-05M, n = 6) and sildenafil (EC₃₀ = 1.8E-05M, n = 6) were synergistic with L-arginine. L-NMA blocked their effects, increasing the EC₅₀ for zaprinast to 9.9E-03M and the EC₃₀ 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.

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