Vasorelaxant actions of enoximone, dobutamine, and the combination on human arterial coronary bypass grafts.
Enoximone (a type III-selective phosphodiesterase inhibitor) and dobutamine (a beta-receptor agonist) are positive inotropic drugs frequently used in the postoperative management of coronary bypass surgery. The purpose of this study was to characterize their relaxant effects on the human internal mammary artery (IMA) and the gastroepiploic artery (GEA) and to test the hypothesis that their combination may have greater than additive relaxant effects. In organ baths, the relaxant effects of enoximone and dobutamine were tested on rings of IMA (n = 86) precontracted with U46619 (a thromboxane A2 mimetic), norepinephrine (NE), or KCl. The relaxant effects of dobutamine and enoximone also were tested on rings of GEA (n = 42) precontracted with U46619 and NE. The effect of the combination of enoximone and dobutamine were tested on rings of IMA (n = 24) precontracted with U46619 or NE. With respect to maximal relaxations induced by papaverine (10(-4) M), enoximone (< or =10(-3) M) caused full relaxations of IMA precontracted with NE, U46619, or KCI. Dobutamine (< or =10(-3) M) caused full relaxations of IMA precontracted with NE or KCI but only 46% (95% CI, 27-65) relaxation in the rings precontracted with U46619. Similar patterns of relaxation were observed in GEA rings, with dobutamine inducing partial relaxation in GEA precontracted with U46619. The pD2 values of enoximone and dobutamine were both significantly lower in segments precontracted with U46619. The in vitro threshold relaxant concentrations were in the upper limits or over the range of therapeutic plasma concentrations. The relaxant effect of the combination was significantly more important than the theoretic additive effect in IMA contracted with U46619 or NE. Enoximone and dobutamine are potent in vitro vasodilators but exert weak relaxant effects in IMA and GEA at concentrations in the therapeutic range. There is, however, a greater than additive vasorelaxant effect of the combination, suggesting that the vasorelaxant effect of the combination, in addition to the additive inotropic effect, may be beneficial to patients undergoing coronary bypass grafting.
Cracowski
J L
JL
Laboratory of Pharmacology, Faculté de Médecine de Grenoble, La Tronche, France. Jean-Luc.Cracowski@ujf-grenoble.fr
Stanke-Labesque
F
F
Chavanon
O
O
Blin
D
D
Mallion
J M
JM
Bessard
G
G
Devillier
P
P
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D001026:Coronary Artery Bypass; D004280:Dobutamine / Q000494:pharmacology*; D004357:Drug Synergism; D017335:Enoximone / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008323:Mammary Arteries / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D013270:Stomach / Q000098:blood supply; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects
D002316:Cardiotonic Agents; D014662:Vasoconstrictor Agents; D004280:Dobutamine; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017335:Enoximone; D009638:Norepinephrine