Assessment of renal dopaminergic system activity during cyclosporine A administration in the rat.
1. Administration of cyclosporine A (CsA; 50 mg kg-1 day-1, s.c.) for 14 days produced an increase in both systolic (SBP) and diastolic (DBP) blood pressure by 60 and 25 mmHg, respectively. The urinary excretion of dopamine, DOPAC and HVA was reduced from day 5-6 of CsA administration onwards (dopamine from 19 to 46%, DOPAC from 16 to 48%; HVA from 18 to 42%). In vehicle-treated rats, the urinary excretion of dopamine and DOPAC increased (from 7 to 60%) from day 5 onwards; by contrast, the urinary excretion of HVA was reduced (from 27 to 60%) during the second week. 2. No significant difference was observed between the Vmax and Km values of renal aromatic L-amino acid decarboxylase (AAAD) in rats treated with CsA for 7 and 14 days or with vehicle. 3. Km and Vmax of monoamine oxidase types A and B did not differ significantly between rats treated with CsA for 7 and 14 days or with vehicle. 4. Maximal catechol-O-methyltransferase activity (Vmax) in homogenates of renal tissues obtained from rats treated with CsA for 7 or 14 days was significantly higher than that in vehicle-treated rats; Km (22.3 +/- 1.5 microM) values for COMT did not differ between the three groups of rats. 5. The accumulation of newly-formed dopamine and DOPAC in cortical tissues of rats treated with CsA for 14 days was three to four times higher than in controls. The outflow of both dopamine and DOPAC declined progressively with time and reflected the amine and amine metabolite tissue contents. No significant difference was observed between the DOPAC/dopamine ratios in the perifusate of renal tissues obtained from CsA- and vehicle-treated rats. In addition, no significant differences were observed in k values or in the slope of decline of both DA and DOPAC between experiments performed with CsA and vehicle-treated animals. 6. The Vmax for the saturable component of L-3,4-dihydroxyphenylalanine (L-DOPA) uptake in renal tubules from rats treated with CsA was twice that of vehicle-treated animals. Km in CsA- and vehicle-treated rats did not differ. 7. The decrease in the urinary excretion of sodium and an increase in blood pressure during CsA treatment was accompanied by a reduction in daily urinary excretion of dopamine. This appears to result from a reduction in the amount of L-DOPA made available to the kidney and does not involve changes in tubular AAAD, the availability of dopamine to leave the renal cells and dopamine metabolism. The enhanced ability of the renal tissues of CsA-treated animals to synthesize dopamine, when exogenous L-DOPA is provided, results from an enhanced activity of the uptake process of L-DOPA in renal tubular cells.
Pestana
M
M
Institute of Pharmacology and Therapeutics, Faculty of Medicine, Porto, Portugal.
Vieira-Coelho
M A
MA
Pinto-do-O
P C
PC
Fernandes
M H
MH
Soares-da-Silva
P
P
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism* / Q000652:urine; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects*; D002394:Catechol O-Methyltransferase / Q000378:metabolism / Q000652:urine; D003404:Creatinine / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism* / Q000652:urine; D006719:Homovanillic Acid / Q000378:metabolism* / Q000652:urine; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism / Q000652:urine; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D014508:Urea / Q000378:metabolism
D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D016572:Cyclosporine; D014508:Urea; D012964:Sodium; D003404:Creatinine; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D011188:Potassium; D004298:Dopamine; D006719:Homovanillic Acid