Involvement of nitric oxide in endothelin ETB receptor-mediated inhibitory actions on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs

We examined the effect of sarafotoxin S6c (S6c), a selective endothelin ETB-receptor agonist, on renal actions and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) in anesthetized dogs, with or without blockade of endogenous nitric oxide (NO) generation by N-G-nitro-L-arginine (NOARG), a NO synthase inhibitor. RNS (0.5-2.0 Hz) produced significant decreases in urine flow, urinary and fractional excretion of sodium, and increased NE secretion rate, without affecting systemic and renal hemodynamics. When S6c (1 ng/kg/min) was infused intrarenally, there was a slight and transient increase in renal blood flow at 1-2 min after the start of the infusion, without any change in systemic hemodynamics, and this response was followed by a gradual reduction. There was a significant increase in the basal level of urine flow with no effects on urinary and fractional excretion of sodium. In addition, S6c administration elicited an increase in urinary excretion of NO metabolites, NO2- and NO3-. During S6c infusion, RNS-induced antidiuretic action and increases in NE secretion rate were significantly attenuated. RNS during intrarenal arterial infusion of NOARG (40 mu g/kg/min) led to potent reductions in urine formation and decreased renal blood flow and glomerular filtration rate. Simultaneously, NE secretion rate was markedly increased. In the presence of NOARG, S6c-induced suppressive actions on reductions in urine formation and increase in NE secretion rate in response to RNS were markedly attenuated. The peptide did not increase urinary excretion of NO metabolites. These findings suggest that ET functions as an inhibitory modulator of renal noradrenergic neurotransmission through ETB-receptor mechanisms, events that may be caused by NO production induced by the peptide.