Cardiovascular and renal hemodynamic effects of A-68930 in the conscious dog: a comparison with fenoldopam.
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.
Christie
M I
MI
Fisons plc, Department of Pharmacology, Loughborough, Leicestershire, United Kingdom.
Smith
G W
GW
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D003243:Consciousness; D004285:Dogs; D015259:Dopamine Agents / Q000494:pharmacology*; D018818:Fenoldopam; D006439:Hemodynamics / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D017447:Receptors, Dopamine D1 / Q000187:drug effects
D001552:Benzazepines; D002839:Chromans; D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C065380:A 68930; D018818:Fenoldopam