SARAFOTOXIN S6C ELICITS A NON-ET(A) OR NON-ET(B)-MEDIATED PRESSER RESPONSE IN THE PITHED RAT

Sarafotoxin S6c (Sx6c) is reported to evoke depressor and presser effe cts via activation of endothelin (ET) ET(B) receptors located on the e ndothelium and smooth muscle, respectively. We have examined the effec ts of the selective ET(B) receptor antagonist BQ 788 on the fall and r ise in diastolic blood pressure induced by Sx6c (1 nmol/kg, i.v.) in p ithed rats. A dose-dependent reduction in both depressor and presser r esponse was observed. BQ 788 completely ablated the Sx6c-mediated fall in blood pressure at 1 mg/kg. In contrast, the presser response was n ot completely abolished by 10 mg/kg BQ 788 (10 mg/kg: 16.5 +/- 3.0 mm Hg vs. control 49.0 +/- 2.5 mm Hg). Co-administration of the ET(A) rec eptor antagonist BQ 123 (1.5 mg/kg) with BQ 788 produced no further an tagonism of the Sx6c-mediated presser response. BQ 788 plus BQ 123 (1. 5 mg/kg) totally blocked the presser response to ET-1 (0.1 nmol/kg, i. v.) suggesting a difference in the mechanism of action between the two agonists. In conclusion, a portion of the Sx6c-induced pressor respon se is resistant to blockade by known ET(A) and ET(B) receptor antagoni sts. Whether Sx6c acts on a novel ET receptor or produces a nonspecifi c effect remains to be determined.