RESUMO
The renin-angiotensin system (RAS) has been implicated in haemodynamic maladaptations of diabetic kidney. Its effects may be modulated by endogenous substances like noradrenaline. Our aim was to study renal vascular response to angiotensin II and the interaction between intrarenal RAS and noradrenergic system at an early diabetic stage. Seven days after alloxan induction of diabetes, concentration-response curves to noradrenaline and angiotensin were generated in isolated, perfused rat kidneys. Percent changes in renal vascular resistance were considered as contractile responses. Diabetic kidneys showed enhanced noradrenaline sensitivity compared to controls. Enalapril and losartan elicited increments in ED(50) of noradrenaline in diabetics (diabetic, 3.4+/-0.2 nmol; diabetic + enalapril, 5.1+/-0.5 nmol, p<0.01 vs. diabetic; diabetic + losartan, 5.5+/-0.7 nmol, p<0.05 vs. diabetic). Maximum response (MR) and sensitivity to angiotensin were augmented in diabetics compared to controls. Prazosin decreased MR and sensitivity in diabetics (MR: control, 156.4%+/-5.1%; diabetic, 262.2%+/-21.1%, p<0.001 vs. control; diabetic + prazosin, 178.8%+/-11.2%, p<0.01 vs. diabetic). Enalapril, losartan and prazosin did not change control responses. At this diabetic stage, renal vasculature presented increased response to angiotensin, and an interaction between renal RAS and noradrenergic system was evidenced. Vascular response to noradrenaline requires the integrity of intrarenal RAS and the participation of AT(1) receptors; alpha(1)-adrenoceptors contribute to vascular response to angiotensin.
Assuntos
Angiotensina II/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Enalapril/farmacologia , Losartan/farmacologia , Norepinefrina/farmacologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The effects of gamma-aminobutyric acid (GABA) agonists were studied in the isolated perfused rat kidney. Perfusions were performed at constant flow with modified Ringer-Krebs solution. The GABAA agonist muscimol (0.1-75 microM) induced an increase in fractional excretion of water and sodium without promoting hemodynamic changes. These tubular changes were inhibited by atropine pretreatment. Thus, a possible modulation of tubular transport mechanisms via GABAA receptors acting on cholinergic system could be suggested. Muscimol was unable to modify the renal vascular resistance either at basal conditions or in noradrenaline-pretreated preparations. However, the GABAA antagonist bicuculline (50 microM) evoked an increased perfusion pressure. Despite the speculation that endogenous GABA could result in a maximal activation of these GABAergic processes, nonspecific binding sites for bicuculline should be considered. The GABAB agonist baclofen (0.05-500 microM) elicited a raised perfusion pressure and diminished glomerular filtration rate, accompanied by an increment in fractional excretion of water, sodium and glucose. These findings suggest a major GABAB receptor-mediated vasoconstriction at the afferent arteriole level. Proximal tubular structures seem to be a biological target for baclofen. GABA (0.05-1000 microM) evoked changes similar to those described for baclofen, although the glomerular filtration rate was not diminished. Data from this study indicate that the GABA system may be involved in the modulation of rat renal function.
Assuntos
Agonistas de Receptores de GABA-A , Agonistas dos Receptores de GABA-B , Rim/efeitos dos fármacos , Animais , Baclofeno/farmacologia , Bicuculina/farmacologia , Rim/fisiologia , Masculino , Muscimol/farmacologia , Perfusão , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/farmacologiaRESUMO
The effects of diazepam were studied in the isolated rat kidney under conditions of constant flow. Kidneys were perfused with modified Ringer-Krebs solution. Diazepam produced a raised fractional excretion of water and sodium without hemodynamic changes, suggesting a direct effect on tubular transport mechanisms. Diazepam decreased renal perfusion pressure in a concentration-dependent fashion when kidneys were pretreated with either noradrenaline or potassium chloride. Similar responses were observed when 7-chloro-5-[4-chloro-phenyl]-1, 3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro 5-4864) or clonazepam was used. These data provide evidence for a relaxant effect of benzodiazepines on preconstricted renal vasculature.