Role of NADPHox/Rho-kinase signaling in the cyclosporine-NSAIDs interactions on blood pressure and baroreflexes in female rats

Abstract

Aims: 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 effects of CSA are influenced by co-administration of nonsteroidal antiinflammatory drugs (NSAIDs) and if the oxidative NADPH-oxidase (NADPHox)/Rho-kinase (ROCK) pathway mediates this interaction.

Materials and methods: Female rats were treated for 10days with CSA (25mg/kg/day), diclofenac (DIC, COX-1/COX-2 inhibitor, 1mg/kg/day), celecoxib (COX-2 inhibitor, 10mg/kg/day), or their combinations. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed and slopes of the curves were taken as measures of BRS.

Key findings: Compared with control rats, CSA increased BP and reduced reflex chronotropic responses as indicated by the significantly smaller BRS_PE and BRS_SNP values. Similar effects were observed in rats treated with diclofenac alone or combined with CSA. Whereas CSA hypertension was maintained after selective COX-2 inhibition by celecoxib, the concomitant BRS reductions were largely eliminated. NADPHox inhibition by diphenyleneiodonium (DPI) blunted the CSA/DIC-evoked increases and decreases in BP and BRS_PE, respectively. By contrast, fasudil (ROCK inhibitor) had no effect on CSA/DIC hypertension but reversed the associated reductions in both BRS_PE and BRS_SNP.

Significance: Depending on the nature of the cardiovascular response, NADPHox and ROCK 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.

Keywords: Arterial baroreceptors; Blood pressure; Celecoxib (PubChem CID: 2662); Cyclosporine; Cyclosporine A (PubChem CID: 5284373); Diclofenac potassium (PubChem CID: 23667642); Diphenyleneiodonium chloride (PubChem CID: 2733504); Fasudil hydrochloride (PubChem CID: 163751); NADPHoxidase; Nonsteroidal antiinflammatory drugs; Phenylephrine hydrochloride (PubChem CID: 5284443); Rho-kinase; Sodium nitroprusside (PubChem CID: 11963579).