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 (ETB) 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 ETBreceptor 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 ETBreceptor 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 ETBreceptor 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 ETAreceptor antagonist, potentiated the pressor response to exogenous ET-1. Our results suggest that, in the hamster, ETBreceptors 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 ETBreceptors triggers a marked potentiation of ETA-dependent increases in systemic resistance.