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Modulation by NADPH‐ox/Rho‐kinase signaling of the cyclosporine‐NSAIDs interactions on blood pressure and baroreflexes in female rats
Author(s) -
ElMas Mahmoud M,
Ibrahim Karim S,
ElYazbi Ahmed F,
ElGowelli Hanan M
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.848.1
Subject(s) - fasudil , celecoxib , apocynin , chemistry , pharmacology , sodium nitroprusside , baroreflex , nadph oxidase , phenylephrine , blood pressure , endocrinology , medicine , rho associated protein kinase , heart rate , oxidative stress , kinase , nitric oxide , biochemistry
The hypertensive effect of the immunosuppressant drug cyclosporine (CSA) is paralleled, and probably triggered, by impaired arterial baroreceptor sensitivity (BRS). Here we asked if these adverse effects of CSA are influenced by co‐administration of nonsteroidal antiinflammatory drugs (NSAIDs) and if the oxidative NADPH‐ox/Rho‐kinase pathway mediates this interaction. Female rats were treated for 10 days with CSA (25 mg/kg/day), diclofenac (DIC, COX‐1/COX‐2 inhibitor, 1 mg/kg/day), celecoxib (COX‐2 inhibitor, 10 mg/kg/day), or their combinations. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by i.v. doses (1–16 μg/kg) of phenylephrine (PE) or sodium nitroprusside (SNP), respectively, were constructed and slopes of the curve were taken as measures of BRS. Compared with control rats, CSA increased BP and reduced reflex chronotropic responses as indicated by the significantly smaller BRS PE and BRS SNP . Similar effects were observed in rats treated with diclofenac alone or combined with CSA. Whereas CSA hypertension was maintained after COX‐2 inhibition (celecoxib), the concomitant BRS reductions were largely eliminated. NADPH‐ ox inhibition by diphenyleneiodonium blunted the CSA/DIC‐evoked increases and decreases in BP and BRS PE , respectively. By contrast, fasudil (Rho‐kinase inhibitor) had no effect on CSA/DIC hypertension but reversed the associated reductions in both BRS PE and BRS SNP . Cardiac NADPH oxidase II (NOXII), but not Rho kinase (ROKII), protein expression was increased in CSA/diclofenac‐treated rats and this effect disappeared after co‐administration of fasudil or DPI. Together, depending on the nature of the cardiovascular response, NADPH‐ox and Rho‐kinase contribute variably to the worsened cardiovascular profile in CSA/DIC‐treated rats. Further, celecoxib rather than diclofenac could be a better choice as an add‐on therapy to CSA in autoimmune arthritic conditions. Support or Funding Information Supported by the ALEX‐REP Grant Fund, Alexandria University, Egypt (Grant HLTH‐13‐01).