Studies on the Nature of the Antagonistic Actions of Dopamine and 5-Hydroxytryptamine in Renal Tissues

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The present work examines the possibility of whether the reciprocal effects of dopamine (DA) and 5-hydroxytryptamine (5-HT) are only dependent on the antagonistic nature of the signal resulting from the activation of their specific receptors or may also result from a competitive type of inhibiton at different levels of the synthetic and metabolic pathways shared by DA and 5-HT. Studies performed in isolated proximal convoluted tubules (PCT) have shown that L-5-HTP and L-DOPA use the same transporter in order to be taken up into the cell and both L-DOPA and L-5-HTP exert a competitive type of inhibition upon their cellular uptake. The decrease in the formation of 5-HT in isolated PCT induced by L-DOPA reflects most probably a reduction in the intracellular availability of L-5-HTP. However, in experiments conducted in homogenates of PCT L-DOPA was found to be a better substrate for AAAD than L-5-HTP. Appart from sharing a common synthetic pathway, DA and 5-HT also share a common metabolic pathway; type A monoamine oxidase (MAO-A), the predominant form of MAO in rat renal tissues, converts DA into 3, 4-dihydroxyphenylacetic acid (DOPAC) and 5-HT into 5-hydroxyindolacetic acid (5-HIAA). However, in contrast to 5-HT, DA can be metabolized by MAO-B and catechol-O-methyltransferase. Inhibition of MAO-A was found to produce a 2-fold increase in the urinary excretion of 5-HT; this increase in the urinary excretion of 5-HT was accompanied by an unexpected reduction in the urinary excretion of DA. It is possible that the increased availability of 5-HT might have compromised the ability of the DA outward transfer to extrude the amine into the urine. Depending on the degree of sodium loading, the increased urinary excretion of 5-HT during MAO-A inhibition is accompanied by antinatriuresis and increased urine osmolality. This antinatriuretic effect does not appears to be due to a reduction on the availability of DA, but to result from an increased availability of 5-HT. In fact, this antinatriuretic effect can be antagonized in a concentration dependent manner by the selective 5-HT1A receptor antagonist (+) WAY 100135, but not by ketanserin. It is possible that stimulation of Na+-K+-ATPase might be relevant for the antinatriuretic effect of endogenous renal 5-HT, in contrast to the inhibitory effects of DA on the enzyme. In fact, we have recently found that the 5-HT1A receptor agonist 8-OH-DPAT increases Na+-K+-ATPase activity with a EC50 value of 355nM; this effect can be antagonized by (+) WAY 100135 with a IC50 value of 20nM. It is possible, therefore, to conclude that the nature of the antagonistic effects of DA and 5-HT in renal tissues does not only depends on the reciprocal effects related to the activation of their specific receptors, but has also to do with the availability of their amino acid precursors and the ability of the amines to leave the cellular compartment. (Hypertens Res 1995; 18 Suppl. I: S47-S51)

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