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 alpha- and beta-adrenoceptors. To study whether in vivo DA-receptors mediated effects can be separated from alpha- and beta-adrenoceptor effects we compared in 10 male volunteers the effects of i.v. epinine (0.5; 1; 2; 4 micrograms/kg/min for 15 min each) on DA-receptor (changes in serum prolactin)- and alpha- and beta-adrenoceptor (changes in systolic [Psyst] and diastolic blood pressure [Pdiast] 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 pre-infusion) and domperidone (10 mg p.o. 1 h pre-infusion). At the 0.5 and 1 microgram doses of dopamine and epinine did not effect Psyst, Pdiast and heart rate but significantly decreased prolactin levels. At the higher dose both dopamine and epinine significantly increased Psyst and heart rate, while only epinine significantly increased Pdiast. 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 Psyst- and heart rate-increases to about the same extent. Propranolol enhanced epinine-induced Psyst- and Pdiast-increases while bisoprolol reduced epinine-evoked Psyst-increase but not Pdiast-increase. Epinine-induced heart rate-increase was abolished by bisoprolol and was converted into heart rate-decrease by propranolol. We concluded that in 0.5 and 1 microgram doses (plasma levels of 20-80 nmol/l)epinine acts only at DA-receptors. Thus, ibopamine in therapeutically recommended doses (3 x 100 mg/day with peak plasma epinine-levels of 50-80 nmol/l) very likely activates only DA-receptors. In higher doses, however, epinine-like dopamine-activates alpha- and beta-adrenoceptors whereby epinine has a stronger alpha-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.

Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes

“…3T3-L1cells may also express D 2 R (35) ( Figure 1). Dopamine and some dopamine receptor agonists are also able to stimulate α-and β-adrenergic receptors in the cardiovascular system and in adipocytes (11,23,24,35,36 ) and this effect in vivo is observed at a higher dopamine dose in human (37). Dopamine also suppresses leptin release in 3T3-L1 cells but the effect is blocked not by the dopamine receptor antagonists but by propranolol, indicating the involvement of β-adrenergic receptors (11).…”

Cardiac overexpression of the human 5-HT4receptor in mice

“…Epinephrine and norepinephrine levels in plasma and whole heart tissue as well as 5-HT levels in whole heart tissue were estimated by HPLC with fluorometric detection (13). Hearts were perfused with buffer in the Langendorff mode for 20 min to wash the coronaries free of blood.…”

Effects of domperidone on digital laminar microvascular blood flow in clinically normal adult horses

“…48 In humans, epinine reportedly has a dose-dependent separation of dopaminergic and adrenergic effects whereby low doses of dopamine and epinine exert effects only at dopamine receptors but do not activate αor β-adrenoceptors. 49 At higher doses, dopamine and epinine appear to have a different pattern of receptor activation: although dopamine exerts a mild β1-adrenoceptor stimulating effect because it lacks β2and α-adrenoreceptor activity, epinine appears to activate β1-, β2-, and α-adrenoceptors to approximately the same degree. 49 It is possible that there are 2 interconvertible states of central dopamine-2 receptors containing high-and lowaffinity binding sites 50 ; these 2 sites of the dopamine-2 receptors might also be present in the peripheral vasculature.…”

“…49 At higher doses, dopamine and epinine appear to have a different pattern of receptor activation: although dopamine exerts a mild β1-adrenoceptor stimulating effect because it lacks β2and α-adrenoreceptor activity, epinine appears to activate β1-, β2-, and α-adrenoceptors to approximately the same degree. 49 It is possible that there are 2 interconvertible states of central dopamine-2 receptors containing high-and lowaffinity binding sites 50 ; these 2 sites of the dopamine-2 receptors might also be present in the peripheral vasculature. Central dopamine-2 receptors also appear to have 2 functionally independent, distinct, G-protein coupling domains, 51 as they are coupled to multiple transduction pathways, and these pathways may be activated by different receptor states.…”