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) 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 microM) 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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Grantham Hospital, Department of Surgery, University of Hong Kong, Hong Kong.
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D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D001158:Arteries / Q000187:drug effects* / Q000294:innervation; D002317:Cardiovascular Agents / Q000494:pharmacology; D001026:Coronary Artery Bypass; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone; D010656:Phenylephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D002317:Cardiovascular Agents; D019332:Endothelin-1; D010726:Phosphodiesterase Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011728:Pyridones; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone