John Bates Farmer

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

1 Dopexamine is an agonist at peripheral dopamine receptors and at β2‐adrenoceptors. 2 Dopexamine has approximately one‐third the potency of dopamine in stimulating the vascular DA1‐receptor in the dog, resulting in a fall in renal vascular resistance of 20% at 2.3 × 10−8 mol kg−1 (i.a.). 3 Prejunctional DA2‐receptors are also stimulated by dopexamine, resulting in a reduction of neurogenic vasoconstriction in the rabbit isolated ear artery (IC50 of 1.15 × 10−6 M) and of neurogenic tachycardia in the cat (ID50 of 5.4 × 10−8 mol kg−1, 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 β2‐adrenoceptor of the guinea‐pig isolated tracheal chain, with an EC50 of 1.5 × 10−6 M. 5 Both dopexamine and dopamine are weak agonists at the guinea‐pig atrial β1‐adrenoceptor over the concentration range 10−7 to 10−4 M, but dopexamine has an intrinsic activity of only 0.16 relative to dopamine. 6 Dopexamine does not stimulate postjunctional α1 or α2‐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 10−5 mol, which is a thousand times the minimum cardiostimulant dose. 8 The combination of agonist properties at peripheral dopamine receptors and at β2‐adrenoceptors, with little or no activity at α‐ and β1‐adrenoceptors gives dopexamine a novel pharmacological profile. This may confer advantages over dopamine in the treatment of acute heart failure.

The effects of dopexamine on the cardiovascular system of the dog

1 The cardiovascular effects of dopexamine and dopamine were compared in the anaesthetized and conscious dog by the use of intravenous infusions over the dose range 3 × 10−9 − 10−7 mol kg−1 min−1. 2 In the anaesthetized dog, dopexamine produced a dose‐related fall in blood pressure due to peripheral vasodilatation and a small rise in heart rate and contractility. By contrast, dopamine did not significantly reduce blood pressure but produced a larger dose‐related increase in contractility. At the highest infusion rate (10−7 mol kg−1 min−1) blood pressure and heart rate were increased by dopamine. 3 Dopexamine dilated the renal and mesenteric vascular beds with a potency similar to that of dopamine. Femoral vascular responses produced by both agents were inconsistent but the highest infusion rate of dopamine did produce vasoconstriction. 4 With the aid of selective receptor antagonists (haloperidol, propranolol and bulbocapnine) the vasodepressor activity of dopexamine was shown to be mediated by stimulation of DA2‐, β‐ and DA1‐receptors. The cardiac stimulation and renal vasodilatation produced by both compounds were due to stimulation of β‐adrenoceptors and DA1‐receptors respectively. 5 In the conscious dog, intravenous infusion of dopexamine caused a dose‐related fall in blood pressure, renal vasodilatation and an increase in cardiac contractility and heart rate. Dopamine also increased cardiac contractility, and renal blood flow due to renal vasodilatation but without affecting heart rate. At the highest infusion rate, blood pressure was increased. 6 Dopexamine and dopamine produced a similar incidence of panting and repetitive licking at 3 × 10−8 mol kg−1 min−1 and emesis at 10−7 mol kg−1 min−1, due to stimulation of dopamine receptors in the chemoreceptor trigger zone. 7 Dopexamine produces a different cardiovascular profile from dopamine in the anaesthetized and conscious dog. Both compounds reduce renal vascular resistance, but in contrast to dopamine, dopexamine reduces afterload and produces only mild inotropic stimulation. These differences reflect contrasting activity at adrenoceptors.

The cardiovascular actions of dopexamine hydrochloride, an agonist at dopamine receptors and β2‐adrenoceptors in the dog

The receptor pharmacology of the cardiovascular effects of dopexamine hydrochloride in the anaesthetized dog (given by i.v. infusion of 3 times 10−9‐10−7 mol kg−1 min−1) has been analysed by the use of selective receptor antagonists and of ganglionic blockade. The increases in cardiac output, contractility, and rate were antagonized by the β2‐adrenoceptor antagonist, ICI 118551. Renal blood flow rose secondary to reduction in renal vascular resistance and this was antagonized by SCH 23390, a highly selective DA1‐receptor antagonist. Peripheral vasodilation and reduction of blood pressure were mediated by a combination of DA1 and DA2‐receptor and β2‐adrenoceptor stimulation. In a separate group of dogs, the cardiac stimulant effects of dopexamine HCl were partially reflex and were reduced by ganglion block, revealing responses due to stimulation of cardiac β2‐adrenoceptors. Thus the β2‐adrenoceptor agonist action of dopexamine HCl is not only partly responsible for afterload reduction but also leads to direct cardiac stimulation. From its cardiovascular profile, dopexamine HCl is likely to be of use in acute treatment of heart failure.

FPL 63012AR: a potent D1-receptor agonist.

1 FPL 63012AR is a D1‐receptor agonist in the dog kidney, 10 times as potent as dopamine, reducing renal vascular resistance by 20% with an intra‐arterial dose of 0.42 nmol kg−1. 2 No prejunctional inhibitory D2‐receptor agonist activity was detected in either the isolated ear artery of the rabbit or in the conscious dog as D2‐receptor‐mediated emesis. 3 Unlike dopamine, FPL 63012AR had no significant agonist activity at α1‐, α2‐, β1‐ or β2‐adrenoceptors. 4 FPL 63012AR is a potent inhibitor of [3H]‐noradrenaline uptake (Uptake1) into brain synaptosomes, with an IC50 of 29.5 nm, i.e. 9.2 times more potent than dopamine. 5 The ability to block Uptake1 in the anaesthetised dog was confirmed by inhibition of the tyramine‐induced pressor and inotropic responses. 6 Intravenous infusion of FPL 63012AR in anaesthetized and conscious dogs (0.3 to 3 nmol kg−1 min−1) reduced vascular resistance and increased blood flow to the kidney which was accompanied by hypotension and tachycardia. 7 It is concluded that FPL 63012AR is an example of a novel class of potent agonists at the D1‐receptor. Such compounds may have the potential for use clinically in improving renal perfusion and reducing afterload.