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 endotheli n ETB-receptor agonist, on renal actions and norepinephrine (NE) overf low induced by renal nerve stimulation (RNS) in anesthetized dogs, wit h 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 e xcretion of sodium, and increased NE secretion rate, without affecting systemic and renal hemodynamics. When S6c (1 ng/kg/min) was infused i ntrarenally, 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 re duction. 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 excretio n of NO metabolites, NO2- and NO3-. During S6c infusion, RNS-induced a ntidiuretic action and increases in NE secretion rate were significant ly attenuated. RNS during intrarenal arterial infusion of NOARG (40 mu g/kg/min) led to potent reductions in urine formation and decreased r enal blood flow and glomerular filtration rate. Simultaneously, NE sec retion rate was markedly increased. In the presence of NOARG, S6c-indu ced 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 fi ndings suggest that ET functions as an inhibitory modulator of renal n oradrenergic neurotransmission through ETB-receptor mechanisms, events that may be caused by NO production induced by the peptide.