BENEFICIAL ACUTE EFFECTS OF SELECTIVE MODULATION OF RENAL DOPAMINE SYSTEM BY GAMMA-L-GLUTAMYL-L-DOPA IN RABBITS WITH CONGESTIVE-HEART-FAILURE

Gamma-L-Glutamyl-L-dopa (gludopa) is a dopamine (DA) Prodrug with a hi gh degree of renal selectivity. We compared the acute renal effects of gludopa in conscious control rabbits (n = 6) and rabbits with doxorub icin-induced congestive heart failure (CHF, n = 5). Normal saline and gludopa 25 and 100 mug/kg/min were infused intravenously (i.v.), each for 60 min. One week later, the same protocol was followed except that the DA-1 antagonist SCH 23390 was given i.v. in a dose of 0.3 mg/kg 1 0 min before gludopa infusion. An additional control group (n = 6) rec eived the DA-1 antagonist alone and saline vehicle infusion throughout the study period. In both control and CHF groups, gludopa elicited si gnificant and similar increases in urine flow (70, 62%), sodium excret ion (127, 98%), and renal blood flow (RBF) (33, 27%), and decreased re nal vascular resistance (RVR) (- 23, - 38%). All these changes were ab olished by previous DA-1 antagonism with SCH 23390. Blood pressure (BP ), heart rate (HR), and hindlimb blood flow (HBF) remained unchanged d uring gludopa infusion in both groups. In the control group, but not i n the CHF group, plasma renin activity (PRA) increased during gludopa infusion; this was not influenced by DA-1 antagonism. In normal rabbit s (n = 6), treatment with SCH 23390 alone had no significant effect on renal excretory function or haemodynamics. During gludopa administrat ion, plasma DA concentration was not significantly altered, whereas ur ine DA excretion and renal DA content were markedly increased. Intrare nal conversion of gludopa to DA was significantly less in CHF rabbits as compared with the control group. Acute administration of gludopa pr oduced renal vasodilation, natriuresis, and diuresis in rabbits with d oxorubicin-induced CHF, similar to that observed in normal rabbits. Th ese responses were mediated by intrarenally generated DA through DA-1 receptors.