ENDOTHELIN RECEPTOR SUBTYPES IN THE PATHOGENESIS OF ANGIOPLASTY-INDUCED NEOINTIMA FORMATION IN THE RAT - A COMPARISON OF SELECTIVE ET(A) RECEPTOR ANTAGONISM AND DUAL ET(A)/ET(B) RECEPTOR ANTAGONISM USING BQ-123 AND SB-204670

The present study compared the vasculoprotective efficacy of acute and chronic endothelin (ET) ET(A) or dual ET(A/B) receptor antagonism in the rat common carotid artery (RCCA) model using BQ-123 and SB 209670. Acute intra-arterial infusion (0.1 mg/kg/min) for 2 h at the time of angioplasty of either BQ-123 or SB 209670 did not attenuate the neointima lesion formation observed 2 weeks after angioplasty (neointima:media ratios of 137% and 116% of control, respectively). In contrast, chronic administration of SB 209670 (bolus i.p. injection, 2.5 mg/kg b.i.d.) attenuated lesion formation (neointima:media ratio inhibited by 52% relative to vehicle control; p < 0.05). An identical dosage regimen of BQ-123 did not exhibit significant vasculoprotection (neointima:media ratio of 128% vehicle control). However, this dosage regimen of BQ-123 was associated with significant and selective ET(A) receptor antagonism. The systemic presser response to exogenous ET-1 administration was inhibited by 91% (p < 0.05), whereas the associated depressor response was not different from that observed in vehicle-treated rats. Therefore, since chronic administration of pharmacologic doses of the ET(A)-selective antagonist BQ-123 does not prevent lesion formation in the RCCA model, whereas the ET(A)/B receptor antagonist SB 209670 is vasculoprotective, the data implicate a significant role for the ET(B) receptor subtype, either exclusively or in concert with ET(A) receptor activation, in the pathogenesis of neointima formation in the rat.