Functional angiotensin and endothelin, but not thromboxane, pathways are necessary for the hypertension and ‎baroreflex dysfunction caused by cyclosporine in rats (LB565)

Abstract

We investigated the effects of pharmacologic interventions that selectively interrupt angiotensin II (Ang II), endothelin (ET), or ‎thromboxane (TXA2) signaling on CSA‐evoked hypertension and arterial baroreflex impairment in conscious rats. Baroreflex ‎curves relating changes in heart rate (HR) to increases (phenylephrine, PE) or decreases (sodium nitroprusside, SNP) in blood ‎pressure (BP) were constructed and slopes of the curves were taken as a measure of baroreflex sensitivity (BRSPE and BRSSNP). ‎CSA (25 mg/kg/day i.p., 7 days) significantly increased BP and HR and attenuated reflex HR responses and slopes of the ‎baroreflex curves generated by PE and SNP. Concurrent blockade of ETA (atrasentan) or AT1 receptors (losartan), or inhibition of ‎angiotensin converting enzyme (captopril) reduced the hypertensive, but not the tachycardic, effect of CSA. Further, atrasentan ‎reversed the CSA‐evoked impairment in both BRSPE and BRSSNP whereas losartan or captopril selectively improved BRSPE. The ‎blockade of TXA2 receptors by terutroban failed to alter the detrimental effects of CSA on BP or baroreflex gain. It is concluded ‎that the facilitation of Ang II and ETA, but not TXA2, signaling contributes, at least partly, to the rise in BP caused by CSA ‎possibly via the inhibition of reflex HR control. The study highlights some potential therapeutic modalities for the control of the ‎adverse effects of CSA on hemodynamics.‎