The aim of these studies was to determine whether phosphodiesterase inhibition by enoximone is able to regulate differentially β<sub>1</sub> and β<sub>2</sub>-adrenoceptor (AR)-mediated inotropic effects. Strips of human right atrial myocardium were stimulated with noradrenaline plus ICI 118,551 (selective β<sub>1</sub>-AR stimulation) or adrenaline plus CGP 20,712A (selective β<sub>2</sub>-AR stimulation). Concentration-effect curves were determined in the absence or presence of enoximone. Enoximone alone was shown to produce dose-related positive inotropic effects. In tissues from β<sub>1</sub>-blocker-treated patients, enoximone potentiated the responses to both β<sub>1</sub>-AR and β<sub>2</sub>-AR stimulation. There was a fall in -log EC<sub>50</sub> (mol/l) of 0.7 ± 0.2 (mean ± SEM; n = 6) for β<sub>1</sub>-AR stimulation and of 0.6 ± 0.1 (n= 10) for β<sub>2</sub>-AR stimulation. The potentiation of β<sub>2</sub>-AR responses in non-β-blocker-treated patients was similar with a fall in -log EC<sub>50</sub> (mol/l) of 0.5 ± 0.1 (n = 6). The extent of potentiation was not significantly different between β<sub>1</sub>-AR and β<sub>2</sub>-AR stimulation, nor between β<sub>1</sub>-blocker-treated patients and non-β-blocker-treated patients. Further experiments showed that the potentiation by enoximone of the effects of catecholamines was unaltered by diazoxide (n = 6). Enoximone thus causes positive inotropic effects and potentiates the effects of catecholamines acting through both β<sub>1</sub>- and β<sub>2</sub>-AR. These actions are consistent with inhibition of cyclic AMP hydrolysis. The potentiation of the effects of catecholamines by phosphodiesterase inhibition appears unaltered by prior patient therapy with β<sub>1</sub> blockers.