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 high degree of renal selectivity. We compared the acute renal effects of gludopa in conscious control rabbits (n = 6) and rabbits with doxorubicin-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 10 min before gludopa infusion. An additional control group (n = 6) received the DA-1 antagonist alone and saline vehicle infusion throughout the study period. In both control and CHF groups, gludopa elicited significant and similar increases in urine flow (70, 62%), sodium excretion (127, 98%), and renal blood flow (RBF) (33, 27%), and decreased renal vascular resistance (RVR) (-23, -38%). All these changes were abolished by previous DA-1 antagonism with SCH 23390. Blood pressure (BP), heart rate (HR), and hindlimb blood flow (HBF) remained unchanged during gludopa infusion in both groups. In the control group, but not in the CHF group, plasma renin activity (PRA) increased during gludopa infusion; this was not influenced by DA-1 antagonism. In normal rabbits (n = 6), treatment with SCH 23390 alone had no significant effect on renal excretory function or haemodynamics. During gludopa administration, plasma DA concentration was not significantly altered, whereas urine DA excretion and renal DA content were markedly increased. Intrarenal conversion of gludopa to DA was significantly less in CHF rabbits as compared with the control group. Acute administration of gludopa produced renal vasodilation, natriuresis, and diuresis in rabbits with doxorubicin-induced CHF, similar to that observed in normal rabbits. These responses were mediated by intrarenally generated DA through DA-1 receptors.