DOBUTAMINE ANTAGONIZES EPINEPHRINES BIOCHEMICAL AND CARDIOTONIC EFFECTS - RESULTS OF AN IN-VITRO MODEL USING HUMAN-LYMPHOCYTES AND A CLINICAL-STUDY IN PATIENTS RECOVERING FROM CARDIAC-SURGERY

Background Patients may receive more than one positive inotropic drug to improve myocardial function and cardiac output, with the assumption that the effects of two drugs are additive. The authors hypothesized that combinations of dobutamine and epinephrine would produce additive biochemical and hemodynamic effects. Methods: The study was performed in two parts. Phase 1 used human lymphocytes in an in vitro model of cyclic adenosine monophosphate (cAMP) generation in response to dobuta mine (10(-8) to 10(-4) M) or epinephrine (10(-9) M to 10(-5) M), and d obutamine and epinephrine together, Phase 2 was a clinical study in pa tients after aortocoronary artery bypass in which isobolographic analy sis compared the cardiotonic effects of dobutamine (1.25, 2.5, or 5 mu g.kg(-1).min(-1)) or epinephrine (10, 20, or 40 ng.kg(-1).min(-l)), a lone or in combination. Results: In phase 1, dobutamine increased cAMP production 41%, whereas epinephrine increased cAMP concentration appr oximate to 200%. However, when epinephrine (10(-6) IM) and dobutamine were combined, dobutamine reduced cAMP production at concentrations be tween 10(-6) to 10(-4) hr (P = 0.001), In patients, 1.25 to 5 mu g.kg( -1).min(-1) dobutamine increased the cardiac index (CI) 15-28%. Epinep hrine also increased the CI with each increase in dose. However, combi ning epinephrine with the two larger doses of dobutamine (2.5 and 5 mu g.kg(-1).min(-1)) did not increase the CI beyond that achieved with e pinephrine and the lowest dose of dobutamine (1.25 mu g.kg(-1).min(-1) ). In addition, the isobolographic analysis for equieffective concentr ations of dobutamine and epinephrine suggests subadditive effects. Con clusions: Dobutamine inhibits epinephrine-induced production of cAMP i n human lymphocytes and appears to be subadditive by clinical and isob olographic analyses of the cardiotonic effects. These findings suggest that combinations of dobutamine and epinephrine may be less than addi tive.