[Metabolism and vascular effects of gammaglutamyl L-dopa on the isolated kidney of the rat].
The gammaglutamyl L-dopa (or gludopa), a dopamine (DA) prodrug, may be usefull in antihypertensive therapy as an orally active specific renal vasodilator. Indeed, gludopa is selectively metabolized in vivo by the kidney. This is the consequence of the sequential action of two renal enzymes, gamma-glutamyl transpeptidase (gamma-GT) and aromatic L-amino acid decarboxylase. The aim of this work was to elucidate, in vitro, the factors regulating its metabolism and to characterize its renal vascular effects. The rat kidney was isolated and perfused at constant flow in a closed circuit with a modified Krebs-Henseleit solution (BSA 6g/100 ml). Gludopa injection (10(-5) M) led to generation of DA (measured by gaz chromatography/mass spectrometry) in the venous effluent (134 +/- 39 ng/ml, n = 3) and in the urine (257 +/- 107 ng/mn/g). In non filtering kidneys, the level of DA in recirculating medium was depressed (47 +/- 5 ng/ml, n = 5; p less than 0.05). Glomerular filtration and access to the gamma-GT localized on the brush border membrane of proximal tubular cells are thus important for optimal metabolism of gludopa. Vascular effects of gludopa were studied on the isolated rat kidney after reestablishing vascular tone by continuous perfusion with prostaglandin F2 alpha (10(-8) M/mn) and after inhibition of alpha- and beta-adrenoceptors. Gludopa (3 X 10(-6) to 4 X 10(-5) M) induced dose-dependent renal vasodilation. At 4 X 10(-5) M, the renal response (30 +/- 3 p. 100 of the relaxation induced by 10(-4) M of papaverine) was similar to that elicited by DA at 20 fold lower concentration.(ABSTRACT TRUNCATED AT 250 WORDS)