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.) f or 14 days produced an increase in both systolic (SEP) and diastolic ( DBP) blood pressure by 60 and 25 mmHg, respectively. The urinary excre tion of dopamine, DOPAC and HVA was reduced from day 5-6 of CsA admini stration onwards (dopamine from 19 to 46%, DOPAC from 16 to 48%; HVA f rom 18 to 42%). In vehicle-treated rats, the urinary excretion of dopa mine and DOPAC increased (from 7 to 60%) from day 5 onwards; by contra st, the urinary excretion of HVA was reduced (from 27 to 60%) during t he second week. 2 No significant difference was observed between the V -max and K-m values of renal aromatic L-amino acid decarboxylase (AAAD ) in rats treated with CsA for 7 and 14 days or with vehicle. 3 K-m an d V-max of monoamine oxidase types A and B did not differ significantl y between rats treated with CsA for 7 and 14 days or with vehicle. 4 M aximal catechol-O-methyltransferase activity (V-max) in homogenates of renal tissues obtained from rats treated with CsA for 7 or 14 days wa s significantly higher than that in vehicle-treated rats; K-m (22.3 +/ - 1.5 mu M) values for COMT did not differ between the three groups of rats. 5 The accumulation of newly-formed dopamine and DOPAC in cortic al tissues of rats treated with CsA for 14 days was three to four time s higher than in controls. The outflow of both dopamine and DOPAC decl ined progressively with time and reflected the amine and amine metabol ite tissue contents. No significant difference was observed between th e DOPAC/dopamine ratios in the perifusate of renal tissues obtained fr om CsA- and vehicle-treated rats. In addition, no significant differen ces were observed in k values or in the slope of decline of both DA an d DOPAC between experiments performed with CsA and vehicle-treated ani mals. 6 The V-max for the saturable component of L-3,4-dihydroxyphenyl alanine (L-DOPA) uptake in renal tubules from rats treated with CsA wa s twice that of vehicle-treated animals. K-m in CsA- and vehicle-treat ed rats did not differ. 7 The decrease in the urinary excretion of sod ium and an increase in blood pressure during CsA treatment was accompa nied by a reduction in daily urinary excretion of dopamine. This appea rs to result from a reduction in the amount of L-DOPA made available t o the kidney and does not involve changes in tubular AAAD, the availab ility of dopamine to leave the renal cells and dopamine metabolism. Th e enhanced ability of the renal tissues of CsA-treated animals to synt hesize dopamine, when exogenous L-DOPA is provided, results from an en hanced activity of the uptake process of L-DOPA in renal tubular cells .