Potential greater than additive vasorelaxant actions of milrinone and nitroglycerin on human conduit arteries

Abstract

1. The mechanism of vasorelaxation for phosphodiesterase III inhibitors is mediated by increase of cAMP whereas for nitrovasodilators, cGMP. The purpose of this study was to test the hypothesis that the phosphodiesterase III inhibitor milrinone and nitroglycerin (NTG) may have greater than additive effects in human arteries. 2. Internal mammary artery segments (IMA, n = 90) taken from 23 patients were studied in organ chambers. The effect of milrinone (3 microM), NTG (10 nM), or the combination was tested in IMA rings precontracted with potassium (K+, 25 mM) or U46619 (10 nM). Concentration-contraction curves for K+ or U46619 were established in other rings treated with milrinone (70 microM), NTG (0.1 microM), or the combination for 10 min. 3. In K(+)-induced contraction, the combination produced more relaxation (45.4%) than did either milrinone (7.9%, P < 0.05) or NTG (3.8%, P < 0.05) alone. This relaxation was significantly more than the theoretical overadditive effect (P < 0.05). Similar results were seen in U46619-induced contraction (94.1% by the combination vs 70.7% by milrinone, P < 0.05, or 36.1% by NTG, P < 0.05). Pretreatment with the combination depressed contraction to a higher extend compared with milrinone alone (P < 0.05) for the K(+)-induced contraction and to NTG alone (P < 0.05) in U46619-induced contraction. Treatment with the combination also shifted EC50 rightward and this shift was significantly more than that caused by treatment with NTG alone (P < 0.05). 4. We conclude that there is a greater than additive vasorelaxant effect of PDE III inhibitors and nitrovasodilators in human conduit arteries. This effect may be beneficial to patients undergoing coronary artery bypass grafting and to other patients requiring these vasodilators. Reduced doses of the vasodilators in concentration may be sufficient to produce vasodilatation similar to that produced by either of them alone at higher concentrations.