Dobutamine antagonizes epinephrine's 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 dobutamine (10^-8 to 10^-4 M) or epinephrine (10^-9 M to 10^-5 M), and dobutamine and epinephrine together. Phase 2 was a clinical study in patients after aortocoronary artery bypass in which isobolographic analysis compared the cardiotonic effects of dobutamine (1.25, 2.5, or 5 μg · kg^-1 min^-1) or epinephrine (10, 20, or 40 ng · kg^-1 · min^-1), alone or in combination. Results: In phase 1, dobutamine increased cAMP production 41%, whereas epinephrine increased cAMP concentration 200%. However, when epinephrine (10^-6 M) and dobutamine were combined, dobutamine reduced cAMP production at concentrations between 10^{- 6} to 10^-4 M (P = 0.001). In patients, 1.25 to 5 μg · kg^-1 · min^-1] dobutamine increased the cardiac index (CI) 15-28%. Epinephrine also increased the CI with each increase in dose. However, combining epinephrine with the two larger doses of dobutamine (2.5 and 5 μg · kg^-1 min^-1) did not increase the CI beyond that achieved with epinephrine and the lowest dose of dobutamine (1.25 μg · kg^-1 · min^-1) In addition, the isobolographic analysis for equieffective concentrations of dobutamine and epinephrine suggests subadditive effects. Conclusions: Dobutamine inhibits epinephrine- induced production of cAMP in human lymphocytes and appears to be subadditive by clinical and isobolographic analyses of the cardiotonic effects. These findings suggest that combinations of dobutamine and epinephrine may be less than additive.