Cellular characterization of the pharmacological selectivity and tachyphylactic properties of denopamine for the human beta adrenergic receptors.

The pharmacological properties of the cardiotonic agent denopamine toward human beta-1 and beta-2 adrenergic receptors (AR) were assessed in a heterologous expression system. In whole cells radiolabeled with the nonselective beta antagonist [125I]iodopindolol, denopamine displayed a 7-fold lower inhibition constant for the beta-1 than for the beta-2 AR. Similarly, denopamine exhibited a 7-fold greater potency to stimulate the adenylyl cyclase activity in cells expressing the beta-1 AR than in cells expressing the beta-2 subtype, which confirmed the subtype selectivity of this drug. The maximal stimulation of adenylyl cyclase activity by denopamine was less than 10% of that produced by isoproterenol at both receptor subtypes, which indicated that denopamine is a weak partial agonist. The extent of beta-1 AR desensitization induced by denopamine was then compared with that induced by the full agonist isoproterenol. By contrast with isoproterenol, preincubation with denopamine for 20 min did not induce any decrease in the responsiveness of the receptor to subsequent stimulation nor did it promote any sequestration of the receptor. A 24-hr pretreatment with denopamine produced a time-dependent reduction in the number of beta-1 AR with a rate of down-regulation slower than that produced by isoproterenol. These data therefore indicate that denopamine is a beta-1 adrenergic selective agonist with low intrinsic activity that is less prone than full agonists to cause desensitization. This may explain the long-lasting cardiotonic effects of denopamine compared with those of full agonists.