Moderate additive effects of endothelin receptor A blockade in Ren-2 transgenic rats subjected to various types of RAS blockade

Abstract

Aims: Chronic endothelin receptor A (ETA) blockade lowered blood pressure (BP) by decreasing angiotensin-dependent vasoconstriction and attenuating calcium influx. We tested whether the addition of ETA blockade to renin-angiotensin system (RAS) blockade would have further effects on the principal vasoactive systems contributing to BP maintenance in Ren-2 transgenic rats (TGR).

Methods: Four-week-old TGR rats were fed with normal-salt diet and given either different renin-angiotensin system (RAS) blockers [angiotensin receptor blocker losartan, angiotensin converting enzyme inhibitor captopril, direct renin inhibitor aliskiren], or ETA blocker (atrasentan) alone, or a combination of atrasentan with RAS blockers for 4weeks. At the end of the study, basal BP and acute BP responses to sequential blockade of renin-angiotensin (RAS), sympathetic nervous (SNS), and nitric oxide (NO) systems were determined in conscious rats. Thereafter, BP responses to acute inhibition of nifedipine-sensitive calcium influx through voltage-dependent calcium channels (L-VDCC) were measured.

Key findings: All RAS blockers similarly decreased BP to normotension, their effects being mediated through substantially attenuated RAS-dependent and moderately decreased SNS-dependent vasoconstriction. Atrasentan alone partially lowered BP, while BP was normalized by combination of atrasentan with either RAS blocker. In combination therapies, BP lowering effects resulted from the attenuation of both RAS- and SNS-dependent vasoconstriction. Moreover, atrasentan-treated groups had substantially reduced NO-dependent vasodilation and significantly decreased calcium influx through L-VDCC.

Conclusions: Although the BP-lowering effect of combined ETA and RAS blockades in TGR is predominantly dependent on the effects exerted by RAS blockade, further effects are attributable to decreased calcium influx due to chronic ETA blockade.

Keywords: Aliskiren; Atrasentan; Captopril; Hypertension; Losartan; Ren-2 transgenic rats.