ro-41-0960 and nitecapone

The purpose of this study was to determine the basal levels of dopamine (DA) and to examine the enzymes involved in DA metabolism in different microdissected nephron segments from rat kidneys. Segments were incubated with DA (50 nM) or DA plus monoamine oxidase (MAO) or catechol-O-methyl transferase (COMT) inhibitors. Basal DA levels were higher in the proximal convoluted tubule (PCT, 10.8+/-3.7 pg/mm) and in the medullary collecting duct (MCD, 10.9+/-4.0 pg/mm) than in the medullary thick ascending limb of Henle's loop (MTAL, 4.9+/-0.9 pg/mm) (P<0.05). The percentage of exogenously added DA that was not metabolised was similar in both PCT (67+/-13%) and MCD (65+/-5%) and lower in MTAL (35+/-7%), suggesting that MTAL is a major site of DA metabolism. Inhibition of MAO (pargyline 1 mM) significantly increased the basal content of DA and the percentage of the added non-metabolised DA (to 95+/-10%) in PCT but had no effect on MTAL or MCD. Conversely, inhibition of COMT (nitecapone or Ro-41-0960, both 1 mM) slightly increased the basal levels of DA only in MTAL, whereas the percentage of added DA not metabolised rose to 97+/-10% in MTAL and to 91+/-15% in MCD. COMT inhibition had no effect in PCT. In conscious rats pargyline (50 mg/kg) increased urinary DA from 680+/-34 to 1,128+/-158 ng/d/100 g BW (P<0.01) while nitecapone (40 mg/kg) produced a slight non-significant increment. Our results show that DA is present all along the rat nephron and that renal DA is metabolised continuously and predominantly by MAO in proximal segments, and by COMT in the more distal ones.

Topics: Animals; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine; Kidney Cortex; Kidney Medulla; Kidney Tubules, Collecting; Kidney Tubules, Proximal; Loop of Henle; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Natriuresis; Nephrons; Pargyline; Pentanones; Rats; Rats, Wistar

3-Nitropyrocatechols are very potent and selective inhibitors of catechol-O-methyltransferase (COMT). LD50 values of three of these compounds were assessed after intraperitoneal administration with a special emphasis on interactions with drugs increasing catecholaminergic neurotransmission. LD50 values of the inhibitors varied from 137 mg/kg (Ro 41-0960) to 507 mg/kg (OR-462) and 544 mg/kg (OR-611). The LD50 value of Ro 41-0960 was significantly lower than that of OR-462 and OR-611 (P less than 0.05). At toxic dose levels all inhibitors caused convulsions and hypomotility. OR-462 and OR-611 had statistically significant mortality increasing interaction with 20 mg/kg of nomifensine (P less than 0.05) and the former also with 10 mg/kg of amphetamine (P less than 0.05). Owing to their high therapeutic indexes these compounds can be considered useful new tools in pharmacological research.

Topics: Amphetamine; Animals; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catecholamines; Catechols; Clorgyline; Convulsants; Desipramine; Drug Interactions; Lethal Dose 50; Levodopa; Male; Mice; Motor Activity; Nitriles; Nomifensine; Pentanones; Selegiline; Synaptic Transmission; Yohimbine