DOSE-DEPENDENT SEPARATION OF DOPAMINERGIC AND ADRENERGIC EFFECTS OF EPININE IN HEALTHY-VOLUNTEERS

Epinine (N-methyl-dopamine, the active metabolite of ibopamine), is a full agonist at dopamine (DA)-receptors and alpha- and beta-adrenocept ors. To study whether in vivo DA-receptor mediated effects can be sepa rated from alpha- and beta-adrenoceptor effects we compared in 10 male volunteers the effects of i.v. epinine (0.5; 1; 2; 4 mu g/kg/min for 15 min each) on DA-receptor (changes in serum prolactin)- and alpha- a nd beta-adrenoceptor (changes in systolic [P-syst] and diastolic blood pressure [P-diast] and heart rate)-mediated effects with those of dop amine before and after propranolol (5 mg i.v. 45 min pre-infusion), bi soprolol (15 mg p.o. 2 h preinfusion) and domperidone (10 mg p.o. 1 h pre-infusion). At the 0.5 and 1 mu g doses dopamine and epinine did no t affect [P-syst], P-diast and heart rate but significantly decreased prolactin levels. At the higher dose both dopamine and epinine signifi cantly increased P-syst and heart rate, while only epinine significant ly increased P-diast. In addition, both dopamine and epinine significa ntly increased diuresis and natriuresis; in contrast, only dopamine, b ut not epinine, dose-dependently increased plasma noradrenaline levels . Domperidone did not affect dopamine- and epinine-evoked blood pressu re- and heart rate-changes, but antagonized their prolactin-effects (a t 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 abolish ed by bisoprolol and was converted into a heart rate-decrease by propr anolol. We conclude that in 0.5 and 1 mu g doses (plasma levels of 20- 80 nmol/l) epinine acts only at DA-receptors. Thus, ibopamine in thera peutically recommended doses (3 x 100 mg/day with peak plasma epinine- levels of 50-80 nmol/l) very likely activates only DA-receptors. In hi gher doses, however, epinine like dopamine - activates alpha- and beta -adrenoceptors whereby epinine has a stronger alpha-adrenoceptor agoni stic activity than dopamine. Moreover, part of the dopamine-effects ar e indirect via release of endogenous noradrenaline whereas epinine-eff ects do not appear to include an indirect component.