Cardiovascular and renal hemodynamic effects of A-68930 in the conscious dog: a comparison with fenoldopam

MI Christie and GW Smith

Fisons plc, Department of Pharmacology, Loughborough, Leicestershire, United Kingdom.

The renal hemodynamic and cardiovascular effects of the novel dopamine (DA) D1 receptor agonist A-68930 (5-6-dihydroxy-3-phenyl-1-aminomethyl- isochroman hydrochloride) were studied in the chronically instrumented conscious dog. Intravenous infusion of A-68930, fenoldopam or DA produced a fall in renal vascular resistance and a rise in renal blood flow (RBF), with hypotension and tachycardia. Both compounds were more potent than DA at increasing RBF. By the i.v. route, A-68930 was calculated to be 12 times more potent than fenoldopam. At the end of a submaximal infusion, the effects of A-68930 on RBF declined with a half- time of 14.8 +/- 2.5 min, significantly longer than that of fenoldopam (2.9 +/- 0.5 min) or DA (1.4 +/- 0.4 min). After p.o. dosing, A-68930 was calculated to be 84 times more potent than fenoldopam at increasing RBF. Furthermore, the A-68930-induced increase in RBF took longer to return to base line (5-6 hr) than after an equieffective p.o. dose of fenoldopam (1-2 hr). The effects of p.o. A-68930 were blocked by the DA1 antagonist, SCH 23390 [7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-(1H)-3-benzazepine hydrochloride], consistent with an action at the DA1 receptor. These data indicate that A-68930 is a potent, p.o.- active DA1 agonist in the conscious dog with a longer duration of action than fenoldopam.

Volume 268, Issue 2, pp. 565-570, 02/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics