Blockade of endothelin ETA, but not thromboxane, receptors offsets the cyclosporine-evoked hypertension and interrelated baroreflex and vascular dysfunctions

Abstract

The impairment of arterial baroreceptor and vasodilator functions are two major contributors to the hypertensive action of cyclosporine (CSA). In this study, in vivo and in vitro pharmacological studies were performed to investigate whether these effects of CSA are differentially modulated by endothelin and thromboxane signaling. The treatment of rats with CSA (25 mg/kg/day i.p.) for 7 consecutive days caused significant increases in blood pressure (BP), attenuated reflex heart rate (HR) responses to vasopressor (phenylephrine, PE) and vasodepressor (sodium nitroprusside, SNP) agents, and reduced cumulative vasorelaxant responses elicited by acetylcholine (Ach, 1×10-9-1×10-5 M) in PE-precontracted isolated aortas. These effects of CSA were blunted after concurrent i.p. administration of atrasentan (selective ETA blocker, 10 mg/kg/day), but not terutroban (thromboxane receptor blocker, 10 mg/kg/day). Moreover, atrasentan reversed the reductions in aortic protein expression of eNOS caused by CSA whereas terutroban was without effect. We also report that the favorable effect of atrasentan on CSA-evoked impairment in aortic Ach responsiveness disappeared in rats treated simultaneously with L-NAME (NOS inhibitor, 10 mg/kg/day) but not BQ 788 (ETB receptor blocker, 0.1 mg/kg/day) or indomethacin (cycloxygenase inhibitor, 5 mg/kg/day). Together, the data implicate endothelin ETA receptors in baroreflex and vascular derangements which predispose to the hypertensive effect of CSA. Moreover, the facilitation of NOS, but not ETB receptors or cycloxygenase-derived prostanoids, signaling is pivotal for advantageous effect of atrasentan on the aortic CSA-Ach interaction. © 2014 Elsevier B.V.