INHIBITORY EFFECTS OF ENDOTHELIN-3 ON ANTIDIURESIS AND NOREPINEPHRINEOVERFLOW INDUCED BY STIMULATION OF RENAL NERVES IN ANESTHETIZED DOGS

The effects of endothelin-3 (ET-3) on changes in renal hemodynamics, u rine formation, and norepinephrine (NE) overflow induced by renal nerv e stimulation (RNS) were examined in anesthetized dogs, RNS at a law f requency (0.5-2.0 Hz) produced significant decreases in urine flow (UF ), urinary excretion of sodium (UNaV), and fractional excretion of sod ium (FENa). and increased the NE secretion rate (NESR) without affecti ng systemic or renal hemodynamics, RNS al a high frequency (2.5-5.0 Hz ), which diminishes renal hemodynamics by causing renal vasoconstricti on, affected urine formation and NESR more potently than did low-frequ ency RNS. When ET-3 (2.0 ng/kg/min) was infused into the renal artery, there was a slight and transient increase in renal blood flow (RBF); this response was followed by a gradual reduction, ET-3 infusion tende d to increase the basal levels of UF without affecting UNaV, indicatin g the excretion of hypotonic urine with administration of this peptide . During ET-3 infusion, low-frequency RNS-induced antidiuretic action was significantly attenuated. Simultaneously, increase in NESR elicite d by low-frequency RNS was markedly suppressed. Qualitatively similar results were observed in the case of high-frequency RNS. In addition, high-frequency RNS-induced decreases in the glomerular filtration rate (GFR) and the filtration fraction (FF) were suppressed by ET-3 infusi on. These findings suggest that ET-3 suppresses renal responses to sti mulated renal noradrenergic neurotransmission by inhibiting the releas e of NE. These findings, together with our previous findings, suggest that ET-3 (and/or ET-1) functions as an inhibitory modulator of the re nal noradrenergic nervous system through the prejunctional ETB-recepto r mechanism.