Suppression of noradrenaline spillover by the dopamine prodrug gamma-L-glutamyl-L-dopa: a central effect?

Abstract

The DA prodrug gamma-L-glutamyl-L-dopa (gludopa) has a high degree of renal selectivity with 2-step conversion to DA in the kidney. The effects of gludopa, with and without DA-2 receptor blockade, on renal and total noradrenaline (NA) spillover, were studied in two groups of rabbits. Eight rabbits received gludopa infusion (25 and 100 micrograms/kg/min and 8 received an infusion of gludopa and DA-2 receptor antagonist, YM-09151 (50 micrograms/kg i.v.). Renal and total NA spillover rates were measured by 3H-NA tracer method before and after gludopa infusion. Brain NA, DA, gludopa and L-dopa content were measured after gludopa infusion in 5 rabbits; control values for tissue catecholamine and drug levels were obtained in 5 untreated rabbits. Gludopa infusion markedly increased kidney DA content (300-fold) and DA excretion (6000-fold) but had little effect on plasma DA. It produced a dose-related fall in mean (+/- SEM) renal NA spillover (21.6 +/- 3.7 to 10.6 +/- 2.7, 7.2 +/- 2.7 ng/min, p < 0.01). Even greater falls were observed in total NA spillover after gludopa (43.1 +/- 10.2 to 19.7 +/- 3.4, 9.4 +/- 1.8 ng/min, p < 0.01). DA-2 receptor antagonism had no influence on the effects of gludopa on either renal or total NA spillover. Significant amounts of gludopa were detected in the brain after drug infusion (0.28 +/- 13 nmol/g brain tissue). Gludopa, a putative renal selective dopamine prodrug with effects mediated via DA-1 receptors also significantly inhibits both renal and extra-renal NA spillover. This effect is not a DA-2 effect but may be mediated centrally.