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

Abstract

Three inotropic agents, ASL-7022, dobutamine and dopamine, were evaluated for their alpha- and beta-adrenoceptor mediated effects in vitro in a variety of isolated organs and in radioligand binding studies. All compounds were alpha 1-adrenoceptor 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 greater than ASL-7022 greater than dopamine obtained in rat aorta was consistent with the results obtained in radioligand binding studies to alpha 1-adrenoceptors 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 alpha 1-adrenoceptors in rat and guinea pig aorta, consistent with previous conclusions. ASL-7022 was found to be a potent alpha 2-adrenoceptor agonist in field-stimulated guinea pig ileum, and was approximately 10-fold more potent than dobutamine in this respect, which was also confirmed by radioligand binding studies to alpha 2-adrenoceptors in rat cerebral cortex. The beta 1-adrenoceptor mediated effects of these compounds were evaluated in guinea pig atria, where the rank order of potency was dobutamine greater than ASL-7022 greater than dopamine. An identical rank order of affinity was established for these compounds by displacement of 3H-dihydroalprenolol from beta 1-adrenoceptors in rat cerebral cortex. The beta 1-adrenoceptor 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 beta 1-adrenoceptor 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 beta 2-adrenoceptor mediated inhibition of tone in rat uterus, with the rank order of potency being ASL-7022 greater than dobutamine greater than dopamine. Again, this rank order of beta 2-adrenoceptor potency was also reflected in beta 2-adrenoceptor affinity as assessed by displacement of 3H-dihydroalprenolol from beta 2-adrenoceptors in rat cerebellum. Based on these results, it may be concluded that for alpha-adrenoceptors, dobutamine is a selective alpha 1-adrenoceptor agonist, ASL-7022 is a selective alpha 2-adrenoceptor agonist, and dopamine is a nonselective alpha-adrenoceptor agonist.(ABSTRACT TRUNCATED AT 400 WORDS)

Attenuated Aortic Vasodilation and Sympathetic Prejunctional Facilitation in Epinephrine-Deficient Mice: Selective Impairment of β2-Adrenoceptor Responses

“…One limitation of our experimental design is the limited selectivity of terbutaline and dobutamine at b 2 -and b 1 -adrenoceptors, respectively (Ruffolo et al, 1984;Young et al, 2002;Baker, 2005). This prevents us from using higher nonselective concentrations of those agonists because the mouse aorta relaxes to activation of both subtypes of b-adrenoceptors.…”

Functional and molecular biological evidence for a possible β3‐adrenoceptor in the human detrusor muscle

“…Second, we tested the potencies with which selective agonists for the β‐AR subtypes relaxed the human detrusor muscle. Neither dobutamine, which stimulates both β 1 ‐ and β 2 ‐ARs ( Ozaki et al ., 1982 ; Ruffolo et al ., 1984 ; Ruffolo, 1987 ; Aikawa et al ., 1996 ), nor procaterol, a β 2 ‐AR agonist, produced any significant relaxation at up to 10 −5 M . In fact, the concentration at which dobutamine and procaterol did induce a relaxing effect in our preparation was around 10 −4 M .…”

Pharmacological characterization of β‐adrenoceptors mediating relaxation of the rat urinary bladder in vitro

“…However, they found that the β 1 ‐agonist, dobutamine, was a poor relaxant of rat bladder smooth muscle. Although dobutamine is generally considered to be a β 1 ‐selective agonist, some studies have shown that it also has β 2 ‐agonist and α 1 ‐partial agonist actions ( Ozaki et al ., 1982 ; Ruffolo et al ., 1984 ; Aikawa et al ., 1996 ). In preliminary studies, we found that dobutamine caused a significant relaxation of KCl‐precontracted rat bladder strips with an EC 50 value of 6 μ M (data not shown), similar to that obtained with terbutaline.…”