Concomitant antagonism of endothelial and vascular smooth muscle cell ETBreceptors for endothelin induces hypertension in the hamster

Abstract

In the vascular system, endothelin (ET) type B (ET_B) receptors for ET-1 are located on endothelial and on venous and arterial smooth muscle cells. In the present study, we investigated the hemodynamic effects of chronic ET_Breceptor blockade at low and high doses in the Syrian Golden hamster. After 16 days of gavage with A-192621 (0.5 or 30 mg·kg⁻¹·day⁻¹), a selective ET_Breceptor antagonist, hamsters were anesthetized with a mixture of ketamine and xylazine (87 and 13 mg/kg im, respectively), and basal mean arterial blood pressure (MAP) and pressor responses to exogenous ET-1 were evaluated. The lower dose of A-192621 (0.5 mg·kg⁻¹·day⁻¹) did not modify basal MAP, whereas the higher dose (30 mg·kg⁻¹·day⁻¹) increased MAP and plasma ET levels. Radio-telemetry recordings confirmed the increase in MAP induced by the higher dose of A-192621 in conscious hamsters. On the other hand, although the lower dose of A-192621 was devoid of intrinsic pressor effects, it markedly reduced the transient hypotensive phase induced by intravenously injected IRL-1620, a selective ET_Breceptor agonist. Finally, A-192621 (0.5 mg·kg⁻¹·day⁻¹) alone or A-192621 (30 mg·kg⁻¹·day⁻¹) + atrasentan (6 mg·kg⁻¹·day⁻¹), a selective ET_Areceptor antagonist, potentiated the pressor response to exogenous ET-1. Our results suggest that, in the hamster, ET_Breceptors on vascular smooth muscle cells are importantly involved in the clearance of endogenous ET-1, whereas the same receptor type on the endothelium is solely involved in the vasodilatory responses to the pressor peptide. Blockade of endothelial and vascular smooth muscle cell ET_Breceptors triggers a marked potentiation of ET_A-dependent increases in systemic resistance.