Effect of type A and B monoamine oxidase selective inhibition by Ro 41–1049 and Ro 19–6327 on dopamine outflow in rat kidney slices

Abstract

1 The influence of pargyline and of selective inhibitors of type A and B monoamine oxidase (MAO), Ro 41-1049 and Ro 19-6327 respectively, on the outflow of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in slices of rat renal cortex loaded with exogenous L-3,4-dihydroxyphenylalanine (L-DOPA) was examined. Dopamine and DOPAC in the tissues and in the effluent were assayed by means of h.p.l.c. with electrochemical detection. 2 The levels of newly-formed dopamine and DOPAC in the perifusate decreased progressively with time. In control conditions, DOPAC/dopamine ratios in the perifusate were 3 to 5 fold those in the tissue and were found to increase progressively with time. The addition of pargyline (100 ItM), produced a marked decrease in the outflow levels of DOPAC (45 to 54% reduction) and significantly increased the levels of dopamine in the effluent (102 to 158% increase); DOPAC/dopamine ratios in the perifusate remained stable throughout the perifusion and were similar to those found in the tissues. The addition of the MAO-A inhibitor Ro 41-1049 to the perifusion fluid also significantly decreased DOPAC outflow (41% to 54% reduction) and increased dopamine outflow (19% to 80% increase). In the presence of Ro 41-1049 DOPAC/dopamine ratios in the perifusate were lower (P<0.01) than in controls; in contrast with the effect of pargyline, this ratio was found to increase (P < 0.01) throughout the perifusion period. Ro 19-6327 did not reduce the outflow of DOPAC, but significantly increased (by 40-60%) that of dopamine. In the presence of Ro 19-6237, the proportion of DOPAC to dopamine in the perifusate was similar to that of controls and significantly increased throughout the perifusion; however, this increase was less than that observed in the control group. 3 When benserazide (50 JAM) was added to the perifusion fluid, the levels of both dopamine and DOPAC in the effluent were similar to those observed in the absence of benserazide. However, in the presence of benserazide, DOPAC/dopamine ratios in the perifusate did not increase with time. In conditions of decarboxylase inhibition, the effects of pargyline, Ro 41-1049 and Ro 19-6327 on dopamine and DOPAC outflow were less pronounced than in experiments conducted in the absence of benserazide. 4 In conclusion, the results presented here show that the fraction of newly-formed dopamine which leaves the compartment where the synthesis has occurred is a constant source for deamination into DOPAC. The results provide evidence favouring the view that MAO-A is the main form of the enzyme involved in this process; however, the data described here suggest that dopamine would also have access to MAO-B.

Reduced Urinary Excretion of Dopamine and Metabolites in Chronic Renal Parenchymal Disease

“…Altogether, the present data suggest that changes in renal dopamine production cannot be responsible for the increased fractional excretion of sodium in patients with impaired renal function and may instead favour sodium retention and thus increase blood pressure in these conditions. Previous studies provided evidence that in rat kidney newly formed dopamine is significantly inactivated, namely through deamination to DOPAC by MAO [6,10,12,18]. In addition, it has been shown that the human kidney is endowed with a greater activity of MAO than in the rat kidney [19].…”

“…Evidence has been gathered that at least 90% of urinary dopamine has its origin in the kidney [8] and the urinary levels of free dopamine are used as the main parameter for the assessment of dopamine formation in renal tissues [9]. However, it is well recognised now that under in vitro conditions newly formed dopamine in the rat and the human kidney undergoes extensive deamination to 3,4-dihydroxyphenylacetic acid (DOPAC), by monoamine oxidase (MAO) [6,[10][11][12]; a small amount of the amine is converted to homovanillic acid (HVA) by both MAO and catechol-Omethyltransferase (COMT) and a minor amount is methylated to 3-metoxytyramine (3-MT) [11]. Because daily urinary excretion of both DOPAC and HVA is several-fold that of the parent amine [13,14], these two amine metabolites may represent useful parameters for the assessment of renal dopaminergic system activity.…”

Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice

“…Urine concentrations of noradrenaline were quantified by means of HPLC with electrochemical detection, as previously described (Pestana and Soares-da-Silva, 1994). The lower limits of detection of noradrenaline ranged from 350 to 500 fmol.…”

Renal Dopaminergic System Activity in the Rat Remnant Kidney

“…At the level of the proximal tubule, the overall increase in sodium excretion produced by dopamine results from the inhibition of two main sodium transport mechanisms at the basolateral and apical membranes, Na + ,K + -ATPase and Na + -H + exchanger, respectively [6]. Dopamine of renal origin has also been found to undergo extensive deamination to 3,4-dihydroxyphenylacetic acid (DOPAC), O -methylation to 3-methoxytyramine (3-MT) and deamination plus O -methylation to homovanillic acid (HVA) [7,8,9] and the high levels of metabolic enzymes such as type A and B monoamine oxidases (MAO-A and MAO-B) and catechol- O -methyltransferase (COMT) have also been considered important determinants in the overall availability of renal dopamine.…”