Interactions of three inotropic agents, ASL-7022, dobutamine and dopamine, with α- and β-adrenoceptors in vitro

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Abstract
Three inotropic agents, ASL-7022, dobutamine and dopamine, were evaluated for their α-and β-adrenoceptor mediated effects in vitro in a variety of isolated organs and in radioligand binding studies. All compounds were α1-adrenoreceptor agonists in rat and guinea pig aortae, but the rank orders of potency were exactly opposite in these two tissues. Only the rank potency order of dobutamine>ASL-7022>dopamine obtained in rat aorta was consistent with the results obtained in radioligand binding studies to α1-adrenoreceptors in rat cerebral cortex and to previous results obtained in vivo in the pithed rat. The results obtained in guinea pig aorta did not parallel the radioligand binding studies in rat brain or our previous results in pithed rat, and suggests that species differences exist between postsynaptic vascular α1-adrenoreceptors in rat and guinea pig aorta, consistent with previous conclusions. ASL-7022 was found to be a potent α2-adrenoreceptor agonist in field-stimulated guinea pig ileum, and was approximately 10-fold more potent than dobutamine in this respects, which was also confirmed by radioligand binding studies to α2-adrenoreceptors in rat cerebral cortex. The β1-adrenoreceptor mediated effects of these compounds were evaluated in guinea pig atria, where the rank order of potency was dobutamine>ASL-7022>dopamine. An identical rank order of affinity was established for these compounds by displacement of 3H-dihydroalprenolol from β1-adrenoreceptors in rat cerebral cortex. The β1-adrenoreceptor mediated effects of dobutamine and ASL-7022 in guinea pig atria were completely direct in nature and not secondary to the release of endogenous catecholamines. In contrast, a major component of the β1-adrenoreceptor mediated tachycardia produced by dopamine in guinea pig atria was indirect in nature as evidenced by the marked attenuation in potency that occurred following catecholamine depletion with reserpine. All three compounds elicited β2-adrenoreceptor mediated inhibition of tone in rat uterus, with the rank order of potency being ASL-7022>dobutamine>dopamine. Again, this rank order of β2-adrenoreceptor potency was also reflected in β2-adrenoreceptor affinity as assessed by displacement of 3H-dihydroalprenolol from β2-adrenoreceptors in rat cerebellum. Based on these results, it may be concluded that for α-adrenoceptors, dobutamine is a selective β2-adrenoreceptor agonist, ASL-7022 is a selective α2-adrenoreceptor agonist, and dopamine is a nonselective α-adrenoceptor agonist. For β-adrenoceptor mediated effect, ASL-7022 is a selective α2 agonist, while dobutamine and dopamine are nonselective β-adrenoceptor agonists. It is likely that the complex inotropic and hemodynamic activities of ASL-7022, dobutamine and dopamine result from the sum of their individual effects at the α-and β-adrenoceptor subtypes.