Inhibition of Vasoconstriction by Phosphodiesterase III Inhibitor Milrinone in Human Conduit Arteries Used as Coronary Bypass Grafts

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Abstract
Summary We wished to determine the effect of phosphodiesterase III (PDE III) inhibitor milrinone on human arteries used as coronary bypass grafts. Human internal mammary artery segments (IMA, n = 109) taken from 25 patients were studied. Concentration-relaxation curves for milrinone were established in IMA precontracted with four vasoconstrictors [K+, endothelin-1 (ET-1), U46619, and phenylephrine (PE)]. In IMA rings incubated with therapeutic plasma concentrations of milrinone (7 and 70 μM) for 10 min, concentration-contraction curves for the four vasoconstrictors were constructed. Milrinone caused a complete relaxation in U46619, ET-1, PE (100%), or K+ (97.7%)-precontracted IMA. The EC50 value was higher against K+ (-5.31 ± 0.27 log M) than PE (-6.20 ± 0.25 log M, p = 0.036) or endothelin-1 (-6.41 ± 0.28 log M, p = 0.018). Pretreatment with milrinone decreased the contraction induced by ET-1 from 186.0 ± 23.3 to 66.9 ± 9.6% (p = 0.002) and that induced by PE from 140.6 ± 27.6 to 54.1 ± 7.0% (p = 0.03) and shifted the EC50 7.6-fold higher (p = 0.003). Treatment of milrinone reduced the K+ and U46619 contraction (p < 0.05) at lower concentrations (between 10 and 80 mM for K+ and -8.5 and -7.5 log M for U46619) and shifted the concentration-contraction curves rightward (2.56-fold higher for K+, p < 0.0001; 3.18-fold higher for U46619, p = 0.007). Denudation of endothelium did not affect the milrinone-induced relaxation. These results demonstrate that milrinone is a potent vasodilator of human conduit arteries used as coronary bypass grafts and may have a slight selectivity with greater potency to receptor stimulants than to the depolarizing agent K+. The results may prove a particular indication for milrinone for use in patients receiving arterial grafts for coronary bypass.

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