Prenalterol (P), a partial adrenergic agonist with functional beta 1-specificity, has been shown to have inotropic effects when given orally and thus represents a potential substitute or adjunct to conventional digitalis therapy (D) in the long-term management of congestive cardiomyopathy (COCM). A direct comparison between both drugs has not been reported. In a blind controlled trial, 15 patients with COCM (NYHA II-III) with sinus rhythm and a left ventricular ejection fraction (LV-EF) of 34.5 +/- 2.6% received consecutively D (0.25-0.5 mg/d), placebo (PLAC), P (slow releases = SR) (80 mg/d SR) and both drugs combined in respective doses. After 4 weeks of therapy with each drug, effects were assessed by gated blood pool scintigraphy at rest (R) and during graded bicycle exercise (EX), systolic time intervals (STI), Holter monitoring and a clinical score. Plasma levels of both drugs and of catecholamines and lactate were also determined. Compared to PLAC, LV-EF was not significantly altered by D at R (34.5 +/- 2.6 vs. 31.9 +/- 2.3%, p = ns), but a shortening of the QS2-interval could be demonstrated (533 +/- 7 vs. 550 +/- 6 msec, p less than 0.05). In contrast, during EX an improvement of LV-EF was observed (34.5 +/- 3 vs. 31.3 +/- 2.8%, p less than 0.05). P alone showed no significant alterations in LV-EF and STI, along with a lack of symptomatic improvement. The addition of D (D + P) resulted in improved left ventricular performance both at R (LV-EF 37.9 +/- 3.3 vs. 31.9 +/- 2.3%, p less than 0.01, QS2 530 +/- 8 vs. 550 +/- 6 msec, p less than 0.01) and during EX (LV-EF 35.3 +/- 2.5 vs. 31.1 +/- 2.8%). Values between D and D + P were not significantly different. No drug or combination improved maximal working capacity. CONCLUSIONS Beneficial effects of chronic treatment with D could be demonstrated in patients with COCM, particularly during EX. Further studies are needed to determine why the acute effects of P are not fully sustained during long-term therapy.