EFFECTS OF SARAFOTOXIN S6C ON ANTIDIURESIS AND NOREPINEPHRINE OVERFLOW INDUCED BY STIMULATION OF RENAL NERVES IN ANESTHETIZED DOGS

We previously reported that endothelin (ET) may function as an inhibit ory modulator of renal noradrenergic neurotransmission (Suzuki et al., J. Cardiovasc. Pharmacol. 19: 905-910, 1992). In our study, we examin ed the effect of sarafotoxin S6c (S6c), a selective ET, receptor agoni st, on changes in renal function and norepinephrine overflow induced b y renal nerve stimulation (RNS) in anesthetized dogs. RNS at a low fre quency (0.5-2.0 Hz) caused significant decreases in urine flow, urinar y excretion of sodium and fractional excretion of sodium and increased norepinephrine secretion rate, without affecting systemic and renal h emodynamics. RNS at a high frequency (2.5-5.0 Hz), which diminishes re nal hemodynamics, produced more potent decreases in urine formation an d increase in norepinephrine secretion rate than seen with low frequen cy RNS. When S6c (1 ng/kg/min) was infused intrarenally, there was a s light and transient increase in renal blood flow, and then this respon se was followed by a gradual reduction. S6c administration produced in crease in the-basal level of urine flow with no apparent effects on ur inary excretion of sodium and fractional excretion of sodium. During S 6c infusion, low frequency RNS-induced antidiuretic action and increas e in norepinephrine secretion rate were markedly attenuated. Qualitati vely, similar results were observed in the case of high frequency RNS. In addition, high frequency RNS-induced decreases in glomerular filtr ation rate and filtration fraction were significantly suppressed by S6 c infusion. Taken together with our previous findings, it seems likely that ET plays an important role as an inhibitory modulator of renal n oradrenergic neurotransmission, through ET, receptor mechanisms.