Interaction of the novel inotropic agent, ASL-7022, with alpha and beta adrenoceptors in the cardiovascular system of the pithed rat: comparison with dobutamine and dopamine

RR Ruffolo and EL Morgan

Three selective inotropic agents, ASL-7022, dobutamine and dopamine, were evaluated for their effects at alpha and beta adrenoceptors in the cardiovascular system of the pithed rat. ASL-7022, dobutamine and dopamine were equipotent as pressor agents in propranolol- and reserpine-pretreated pithed rats; however, the mechanisms involved in their alpha adrenoceptor-mediated pressor effects were markedly different. The pressor response of ASL-7022 was mediated entirely by postsynaptic vascular alpha-2 adrenoceptors, whereas the pressor response of dobutamine was mediated exclusively by postsynaptic vascular alpha-1 adrenoceptors. The pressor response of dopamine was mediated by both postsynaptic vascular alpha-1 and alpha-2 adrenoceptors. All three compounds elicited beta-2 adrenoceptor- mediated vasodepressor responses in pithed rats when vascular tone was elevated by a constant infusion of angiotensin II. In contrast to the equal vasopressor potencies of these compounds, the vasodepressor activities varied by more than two orders of magnitude with ASL-7022 being the most potent and dopamine the least potent. Based on ratios of relative potencies for alpha adrenoceptor-mediated vasopressor effects and beta-2 adrenoceptor-mediated vasodepressor effects, it appears that dobutamine possesses an equal balance between its vasopressor and vasodepressor potencies, such that the net effect in the vasculature is a physiological antagonism with little or no change in blood pressure, consistent with clinical observations and experiments in animals. In contrast, the vasopressor potency of dopamine exceeds its potency as a depressor agent, such that the net effect is vasoconstriction, consistent with clinical and animal studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 229, Issue 2, pp. 364-371, 05/01/1984
Copyright © 1984 by American Society for Pharmacology and Experimental Therapeutics