EFFECTS OF THE ET(B)-SELECTIVE ANTAGONIST IRL-2500 IN CONSCIOUS SPONTANEOUSLY HYPERTENSIVE AND WISTAR-KYOTO RATS

The pharmacologic profile of a novel and selective ET(B) antagonist, I RL 2500 N-methyl-(D)-(4-phenylphenyl)-alanyl-L-tryptophan) was examine d in conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. The initial vasodepressor response to endothelin-l (ET-1) and IRL 1620 (0.5 nmol/kg, i.v.) was significantly reduced in conscio us WKY rats pretreated with IRL 2500 (10 mg/kg, i.v.). The secondary a nd sustained presser response to these agonists, however, was not alte red by IRL 2500. The linear peptide antagonist BQ 788, although also i nhibiting the initial depressor responses, attenuated the secondary pr esser response to IRL 1620 and potentiated the presser response to ET- 1. IRL 2500, administered alone to naive conscious SHRs produced a -37 +/- 8 mm Hg reduction in blood pressure, followed by a secondary pres ser response (+ 38 +/- 7 mm Hg) with a duration exceeding 90 min. Pret reatment with either the ET(A)-selective antagonist BQ 123 or with the nonselective ET(A)/ET(B) antagonist SB 209670 resulted in marked pote ntiation of the depressor response and significant attenuation of the secondary rise in pressure. These results indicate that in the conscio us rat, IRL 2500 acts as an ET(B1)-selective antagonist. In addition, ET(A) receptor activation contributes to the sustained presser respons e to IRL 2500 in the conscious SHR. Furthermore, IRL 2500 may also exe rt a non-ET receptor-mediated vasodilatation in the SHR.