Enoximone Potentiates the Positive Inotropic Effects of Beta-1- and Beta-2-Adrenoceptor Stimulation in Human Atrial Myocardium

Abstract

The aim of these studies was to determine whether phosphodiesterase inhibition by enoximone is able to regulate differentially β₁ and β₂-adrenoceptor (AR)-mediated inotropic effects. Strips of human right atrial myocardium were stimulated with noradrenaline plus ICI 118,551 (selective β₁-AR stimulation) or adrenaline plus CGP 20,712A (selective β₂-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 β₁-blocker-treated patients, enoximone potentiated the responses to both β₁-AR and β₂-AR stimulation. There was a fall in -log EC₅₀ (mol/l) of 0.7 ± 0.2 (mean ± SEM; n = 6) for β₁-AR stimulation and of 0.6 ± 0.1 (n= 10) for β₂-AR stimulation. The potentiation of β₂-AR responses in non-β-blocker-treated patients was similar with a fall in -log EC₅₀ (mol/l) of 0.5 ± 0.1 (n = 6). The extent of potentiation was not significantly different between β₁-AR and β₂-AR stimulation, nor between β₁-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 β₁- and β₂-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 β₁ blockers.