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 thi s study was to characterize their relaxant effects on the human internal ma mmary artery (IMA) and the gastroepiploic artery (GEA) and to test the hypo thesis that their combination may have greater than additive relaxant effec ts. In organ baths, the relaxant effects of enoximone and dobutamine were t ested on rings of LMA (n = 86) precontracted with U46619 (a thromboxane A(2 ) 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 w ere tested on rings of IMA (n = 24) precontracted with U46619 or NE. With r espect to maximal relaxations induced by papaverine (10(-4) M), enoximone ( less than or equal to 10(-3) M) caused full relaxations of IMA precontracte d with NE, U46619, or KCl. Dobutamine (less than or equal to 10(-3) M) caus ed full relaxations of IMA precontracted with NE or KCl but only 46% (95% C I, 27-65) relaxation in the rings precontracted with U46619. Similar patter ns of relaxation were observed in GEA rings, with dobutamine inducing parti al relaxation in GEA precontracted with U46619. The pD(2) values of enoximo ne and dobutamine were both significantly lower in segments precontracted w ith U46619, The in vitro threshold relaxant concentrations were in the uppe r limits or over the range of therapeutic plasma concentrations. The relaxa nt effect of the combination was significantly more important than the theo retic additive effect in IMA contracted with U46619 or NE. Enoximone and do butamine are potent in vitro vasodilators but exert weak relaxant effects i n IMA and GEA at concentrations in the therapeutic range. There is, however , a greater than additive vasorelaxant effect of the combination, suggestin g that the vasorelaxant effect of the combination, in addition to the addit ive inotropic effect, may be beneficial to patients undergoing coronary byp ass grafting.