INHIBITION OF VASOCONSTRICTION BY PHOSPHODIESTERASE-III INHIBITOR MILRINONE IN HUMAN CONDUIT ARTERIES USED AS CORONARY-BYPASS GRAFTS

We wished to determine the effect of phosphodiesterase III (PDE III) i nhibitor milrinone on human arteries used as coronary bypass grafts, H uman internal mammary artery segments (IMA, n = 109) taken from 25 pat ients were studied. Concentration-relaxation curves for milrinone were established in IMA precontracted with four vasoconstrictors [K+, endo thelin-1 (ET-1), U46619. and phenylephrine (PE)]. In IMA rings incubat ed with therapeutic plasma concentrations of milrinone (7 and 70 mu M) for 10 min, concentration-contraction curves for the four vasoconstri ctors were constructed, Milrinone caused a complete relaxation in U466 19, ET-1, PE (100%), or K+ (97.7%)-precontracted IMA. The EC(50) 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), P retreatment with milrinone decreased the contraction induced by ET-1 f rom 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 EC(50 ) 7.6-fold higher (p = 0.003). Treatment of milrinone reduced the K+ a nd U46619 contraction (p < 0.05) at lower concentrations (between 10 a nd 80 mM for K+ and -8.5 and -7.5 log M for U46619) and shifted the co ncentration-contraction curves rightward (2.56-fold higher for K+, p < 0.0001; 3.18-fold higher for U46619. p = 0.007). Denudation of endoth elium did not affect the milrinone-induced relaxation. These results d emonstrate that milrinone is a potent vasodilator of human conduit art eries 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.