The pharmacologic profile of a novel and selective ETB antagonist, IRL 2500 (N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-alany l-L-tryptophan) was examined in conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. The initial vasodepressor response to endothelin-1 (ET-1) and IRL 1620 (0.5 nmol/kg, i.v.) was significantly reduced in conscious WKY rats pretreated with IRL 2500 (10 mg/kg, i.v.). The secondary and sustained pressor response to these agonists, however, was not altered by IRL 2500. The linear peptide antagonist BQ 788, although also inhibiting the initial depressor responses, attenuated the secondary pressor response to IRL 1620 and potentiated the pressor 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 pressor response (+38 +/- 7 mm Hg) with a duration exceeding 90 min. Pretreatment with either the ETA-selective antagonist BQ 123 or with the nonselective ETA/ETB antagonist SB 209670 resulted in marked potentiation of the depressor response and significant attenuation of the secondary rise in pressure. These results indicate that in the conscious rat, IRL 2500 acts as an ETB1-selective antagonist. In addition, ETA receptor activation contributes to the sustained pressore response to IRL 2500 in the conscious SHR. Furthermore, IRL 2500 may also exert a non-ET receptor-mediated vasodilation in the SHR.