title: The dopamine prodrug, gludopa, decreases both renal and extrarenal noradrenaline spillover in conscious rabbits.
abstract: 1. Renal and total noradrenaline (NA) spillover rates were examined under control conditions and during graded infusions of gludopa (gamma-L-glutamyl-L-dopa) in conscious rabbits. 2. Gludopa infusion at 25 and 100 micrograms/kg per min did not alter mean arterial pressure (MAP) and heart rate (HR), but had significant dose-related effects on the renal dopamine (DA) system. At the high dose there were pronounced increases in urinary DA excretion (> 6000-fold) and renal DA content (> 100-fold); renal NA content doubled. 3. Renal venous DA increased after gludopa infusion, but arterial plasma DA concentrations were not significantly changed. Mean arterial plasma gludopa and L-dopa concentrations reached 890, 3190 ng/mL and 3, 10 ng/mL at low and high doses, respectively. 4. Gludopa resulted in a pronounced dose-dependent fall in renal NA spillover, which at 100 micrograms/kg per min accounted for almost half of the reduction in overall NA spillover rate. 5. The significant falls in renal and extrarenal NA spillover rate during gludopa infusion are consistent with suppression of renal and overall sympathetic activity. Gludopa-induced inhibition of renal NA spillover is likely to be due to the actions of DA generated in the kidney on presynaptic DA-2 and alpha-2 receptors. A central sympathoinhibitory mechanism may explain the reduced total NA spillover.
authors.affiliation: Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Shimizu
authors.forename: D
authors.initials: D
authors.lastname: Way
authors.forename: J
authors.initials: J
authors.lastname: Secombe
authors.forename: B P
authors.initials: BP
authors.lastname: McGrath
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D004298:Dopamine / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007980:Levodopa / Q000097:blood; D008297:Male; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism*; D011817:Rabbits
chemical_list: D007980:Levodopa; C017342:gamma-glutamyl DOPA; D004295:Dihydroxyphenylalanine; D004298:Dopamine; D009638:Norepinephrine