We evaluated the inotropic actions of levosimendan and epinephrine, both singly and in combination, under isohydric (pH 7.4) and acidotic (pH 7.0) conditions in isolated guinea-pig hearts. Acidosis depressed contractility and myocardial relaxation by 25-30%, and both inotropes were less efficacious at pH 7.0, while their potencies were unaffected. In combination experiments, the presence of levosimendan increased the potency of epinephrine approximately 17-fold (pH 7.4) and 11-fold (pH 7.0), and the presence of epinephrine increased the potency of levosimendan approximately 12-fold (pH 7.4) and approximately 21-fold (pH 7.0). At pH 7.0, both inotropes augmented papillary muscle contraction to a similar extent, but in contrast to epinephrine, levosimendan non-significantly [corrected] raised cAMP levels. In conclusion, combining levosimendan with epinephrine helps to overcome the depressed inotropic actions of epinephrine during acidosis, suggesting that additional studies which might justify clinical evaluation of the concurrent use of the two agents should be performed.