Enoximone potentiates the positive inotropic effects of beta-1- and beta-2-adrenoceptor stimulation in human atrial myocardium.
The aim of these studies was to determine whether phosphodiesterase inhibition by enoximone is able to regulate differentially beta 1- and beta 2-adrenoceptor (AR)-mediated inotropic effects. Strips of human right atrial myocardium were stimulated with noradrenaline plus ICI 118,551 (selective beta 1-AR stimulation) or adrenaline plus CGP 20,712A (selective beta 2-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 beta 1-blocker-treated patients, enoximone potentiated the responses to both beta 1-AR and beta 2-AR stimulation. There was a fall in -log EC50 (mol/l) of 0.7 +/- 0.2 (mean +/- SEM; n = 6) for beta 1-AR stimulation and of 0.6 +/- 0.1 (n = 10) for beta 2-AR stimulation. The potentiation of beta 2-AR responses in non-beta-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 beta 1-AR and beta 2-AR stimulation, nor between beta 1-blocker-treated patients and non-beta-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 beta 1- and beta 2-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 beta 1 blockers.
Hall
J A
JA
Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge, UK.
Latimer
M
M
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017335:Enoximone; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011412:Propanolamines; C026777:ICI 118551; D017335:Enoximone; C049763:CGP 20712A; D003981:Diazoxide