Dopexamine hydrochloride in the human heart: Receptor binding and effects on cAMP generation

Abstract

Dopexamine hydrochloride is a synthetic catecholamine proposed for the short-term treatment of heart failure and postoperative low cardiac output. The pharmacological profile and anatomical localization of dopexamine binding were investigated in sections of right and left ventricle using [3H]-dopexamine and ligand binding techniques associated with light microscope autoradiography. Its effects on the 3-5-cyclic adenosine monophosphate (cAMP) generating system in membrane particles of the human right or left ventricle were also studied. [3H]-Dopexamine was specifically bound to sections of human right or left ventricle. The binding was time-, temperature- and concentration-dependent and was dissociable. The apparent equilibrium constant of dissociation was 3.5 nM. A decreased [SH]-dopexamine binding capacity from the base to the apex and ventricles was noticeable. The pharmacological profile of [3H]-dopexamine binding to sections of right or left ventricle was consistent with the labelling of both β2-adrenoceptors and dopamine DA-2 receptors. The most potent displacer of [3H]-dopexamine was the β2-adrenoceptor antagonist ICI 118,551 followed by dopamine, noradrenaline and domperidone. The β1-adrenoceptor antagonist metoprolol or the dopamine DA-1 receptor antagonist SCH 23390 were ineffective as displacers of [3H]-dopexamine binding. Light microscope autoradiography revealed the localization of [3H]-dopexamine binding sites within the wall of the human right and left ventricle. The density of silver grains was slightly higher in the right than in the left ventricle and showed a uniform transmural distribution across the ventricular wall. Silver grains, which were located primarily within myocytes, were reduced by about 80-85% by the β2-adrenoceptor antagonist ICI 118,551 and by about 15-20% by the DA-2 receptor antagonist domperidone. The concomitant presence in the incubation medium of [3H]-dopexamine, ICI 118,551 and domperidone reduced the density of silver grains to non-specific values. In membrane particle preparations of right or left ventricle, dopexamine dose-dependently increased cAMP levels. This effect was abolished by the non-selective β-adrenoceptor antagonist ( - )-propranolol or by the β2-selective antagonist ICI 118,551, whereas the DA-1 receptor antagonist SCH 23390 and the DA-2 receptor antagonist domperidone were ineffective. These findings suggest that the cardiac actions of dopexamine in man are mediated through interaction with β2-adrenoceptors and dopamine DA-2 receptors located within myocardial tissue. The activity of the compound on DA-2 receptors is documented by the inhibition of [3H]-dopexamine binding, both in radioligand and autoradiographic experiments, by the DA-2 receptor antagonist domperidone. © 1992 The European Society of Cardiology.