Suppression of noradrenaline spillover by the dopamine prodrug gamma-L-glutamyl-L-dopa: a central effect?
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.
McGrath
B P
BP
Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Wang
Z Q
ZQ
Shimizu
K
K
Way
D
D
Secombe
J
J
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D003864:Depression, Chemical; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011355:Prodrugs / Q000494:pharmacology*; D011817:Rabbits; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000097:blood
D001549:Benzamides; D018492:Dopamine Antagonists; D011355:Prodrugs; D017448:Receptors, Dopamine D2; C017342:gamma-glutamyl DOPA; D004295:Dihydroxyphenylalanine; C030265:nemonapride; D004298:Dopamine; D009638:Norepinephrine; D010130:p-Aminohippuric Acid