Dose-dependent separation of dopaminergic and adrenergic effects of epinine in healthy volunteers

Abstract

Epinine (N-methyl-dopamine, the active metabolite of ibopamine), is a full agonist at dopamine (DA)-receptors and α- and \-adrenoceptors. To study whether in vivo DA-receptor mediated effects can be separated from α- and \-adrenoceptor effects we compared in 10 male volunteers the effects of i.v. epinine (0.5; 1; 2; 4 μg/kg/min for 15 min each) on DA-receptor (changes in serum prolactin)- and α- and \-adrenoceptor (changes in systolic [P_syst] and diastolic blood pressure [P_diast] and heart rate)-mediated effects with those of dopamine before and after propranolol (5 mg i.v. 45 min pre-infusion), bisoprolol (15 mg p.o. 2 h preinfusion) and domperidone (10 mg p.o. 1 h pre-infusion). At the 0.5 and 1 μg doses dopamine and epinine did not affect P_syst P_diast and heart rate but significantly decreased prolactin levels. At the higher dose both dopamine and epinine significantly increased P_syst and heart rate, while only epinine significantly increased P_diast. In addition both dopamine and epinine significantly increased diuresis and natriuresis; in contrast, only dopamine, but not epinine, dose-dependently increased plasma noradrenaline levels. Domperidone did not affect dopamine- and epinine-evoked blood pressure-and heart rate-changes, but antagonized their prolactin-effects (at least at the lower doses). Bisoprolol and propranolol significantly reduced dopamine-induced P_syst- and heart rate-increases to about the same extent. Propranolol enhanced epinine-induced P_syst-and P_diast-increases while bisoprolol reduced epinine-evoked P_syst-increase but not P_diast-increase. Epinine-induced heart rate-increase was abolished by bisoprolol and was converted into a heart rate-decrease by propranolol. We conclude that in 0.5 and 1 μg doses (plasma levels of 20–80 nmol/1) epinine acts only at DA-receptors. Thus, ibopamine in therapeutically recommended doses (3 × 100 mg/day with peak plasma epinine-levels of 50–80 nmol/1) very likely activates only DA-receptors. In higher doses, however, epinine -like dopamine - activates α- and \-adrenoceptors whereby epinine has a stronger α-adrenoceptor agonistic activity than dopamine. Moreover, part of the dopamine-effects are indirect via release of endogenous noradrenaline whereas epinine-effects do not appear to include an indirect component.