Dopexamine: a novel agonist at peripheral dopamine receptors and β₂‐adrenoceptors

Abstract

1 Dopexamine is an agonist at peripheral dopamine receptors and at P2-adrenoceptors.2 Dopexamine has approximately one-third the potency of dopamine in stimulating the vascular DA,-receptor in the dog, resulting in a fall in renal vascular resistance of 20% at 2.3 x 10-8 mol kg-' (i.a.). 3 Prejunctional DA2-receptors are also stimulated by dopexamine, resulting in a reduction of neurogenic vasoconstriction in the rabbit isolated ear artery (IC5o of 1.15 x 10-6 M) and of neurogenic tachycardia in the cat (ID5o of 5.4 x 10-8mol kg-', i.v.), with a potency six and four times less respectively than that of dopamine. 4 By contrast, dopexamine is approximately 60 times more potent than dopamine as an agonist at the P2-adrenoceptor of the guinea-pig isolated tracheal chain, with an EC50 of 1.5 x 10-6 M.5 Both dopexamine and dopamine are weak agonists at the guinea-pig atrial P,-adrenoceptor over the concentration range 10-7 to 10-4 M, but dopexamine has an intrinsic activity ofonly 0.16 relative to dopamine. 6 Dopexamine does not stimulate postjunctional a,-or M2-adrenoceptors in the canine isolated saphenous vein, whereas dopamine is an agonist, approximately 120 times less potent than noradrenaline. 7 Unlike dopamine and salbutamol, dopexamine does not cause arrhythmias in the guinea-pig isolated perfused heart at doses of up to 10 5mol, which is a thousand times the minimum cardiostimulant dose.8 The combination of agonist properties at peripheral dopamine receptors and at V2-adrenoceptors, with little or no activity at a-and P3-adrenoceptors gives dopexamine a novel pharmacological profile. This may confer advantages over dopamine in the treatment of acute heart failure.

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D1‐, β1‐ and β2‐receptor‐mediated responses

“…Equally, lack of desensitization of atrial PI-receptors following 7-day dopexamine infusion was not a surprising result since dopexamine has been reported to be only a weak agonist at the 3,-receptors of the guinea-pig right atria (Mitchell et al, 1987), with an intrinsic activity of only 0.1 relative to isoprenaline (Brown et al, 1985). In the guinea-pig left atria, it was found to have no intrinsic activity and therefore to act as a P1-receptor antagonist (Williams et al, 1990).…”

“…The potency of isoprenaline in the pulmonary artery was approximately 10 fold less than its potency in the left atria and 8 fold less than its potency in right atria. Although the dose of dopexamine was higher (240 pg kg-' h-'), it has been shown that dopexamine is considerably less potent than isoprenaline in producing 12-receptor-mediated relaxation of the guinea-pig uterus, where its intrinsic activity is also less than that of isoprenaline (a = 0.78) (Williams et al, 1990), although it acts as a full agonist in guinea-pig trachea (Brown et al, 1985). Therefore, it is conceivable that the dose of dopexamine may also have been insufficient to induce desensitization of pulmonary arterial P2-receptors, especially if dopexamine acts as a partial agonist in that tissue; partial agonists have been shown to be less effective in producing P-receptor desensitization than full agonists (Pittman et al, 1984;Neve et al, 1985).…”

The haemodynamic and myocardial effects of dopexamine: a new beta 2‐ adrenoceptor and dopaminergic agonist.

“…In animal studies, intravenous dopexamine administration is followed by a moderate fall in blood pressure, an increase in heart rate and left ventricular peak dP/dt.P'-, and renal and mesenteric vasodilation (Brown et al, 1984b(Brown et al, , 1985a.…”

The effects of dopexamine on the cardiovascular system of the dog

“…The cardiovascular effects ofdopexamine were examined and compared with dopamine in pentobarbitone-anaesthetized and in conscious dogs. A preliminary account of this work was presented to the British Pharmacological Society (Brown et al, 1984).…”