RESUMO
Dopamine and urodilatin promote natriuresis and diuresis through a common pathway that involves reversible deactivation of renal Na+, K+-ATPase. We have reported that urodilatin enhances dopamine uptake in outer renal cortex through the natriuretic peptide type A receptor. Moreover, urodilatin enhances dopamine-induced inhibition of Na+, K+-ATPase activity. The objective of the present work was to investigate the intracellular signals involved in urodilatin effects on dopamine uptake in renal cortex of kidney rats. We show that urodilatin-elicited increase in ³H-dopamine was blunted by methylene blue (10 µM), a non-specific guanylate cyclase inhibitor, and by phorbol-12-myristate-13-acetate (1 µM), a particulate guanylate cyclase inhibitor, but not by 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (10 µM), a specific soluble guanylate cyclase inhibitor; therefore the involvement of particulate guanylate cyclase on urodilatin mediated dopamine uptake was confirmed. Cyclic guanosine monophosphate and proteinkinase G were also implicated in the signaling pathway, since urodilatin effects were mimicked by the analog 125 µM 8-Br-cGMP and blocked by the proteinkinase G-specific inhibitor, KT-5823 (1 µM). In conclusion, urodilatin increases dopamine uptake in renal cortex stimulating natriuretic peptide type A receptor, which signals through particulate guanylate cyclase activation, cyclic guanosine monophosphate generation, and proteinkinase G activation. Dopamine and urodilatin may achieve their effects through a common pathway that involves deactivation of renal Na+, K+-ATPase, reinforcing their natriuretic and diuretic properties.
Assuntos
Fator Natriurético Atrial/farmacologia , Diuréticos/farmacologia , Dopamina/metabolismo , Rim/metabolismo , Animais , Guanilato Ciclase/metabolismo , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Since renal natriuretic peptide urodilatin (URO) exerts similar natriuretic and diuretic actions to those of atrial natriuretic factor (ANF), we hypothesized that URO regulates renal dopamine (DA) availability, contributing to Na(+), K(+)-ATPase inhibition. URO (1-100 nM) increased (3)H-DA uptake in outer and juxtamedullar renal cortex and medulla slices from Sprague Dawley rats. Hydrocortisone blocked URO-stimulated DA uptake, demonstrating that DA uptake was extraneuronal. The natriuretic peptide receptor type A antagonist anantin blocked URO-dependent increase of (3)H-DA uptake, while the natriuretic peptide receptor type C agonist ANF 4-23-amide did not modify URO effect on DA uptake, suggesting that only natriuretic receptors type A are involved. Co-incubation of URO and ANF did not show additive effects on DA uptake. To test whether URO effect involves changes in Na(+), K(+)-ATPase activity we performed experiments in renal cortex samples of rats with DA synthesis and neuronal uptake inhibited by carbidopa and nomifensine, respectively. When endogenous DA synthesis was inhibited, URO or DA decreased Na(+), K(+)-ATPase activity. URO and DA added together, further decreased Na(+), K(+)-ATPase activity showing an additive effect on the sodium pump. Moreover, hydrocortisone reversed URO-DA over-inhibition of the enzyme, confirming that this inhibition is closely related to URO-stimulation on renal DA uptake. URO and DA could act via a common intracellular pathway to decrease sodium and water tubular reabsorption, contributing to its natriuretic and diuretic effects.