Crosstalk between central pathways of nitric oxide and carbon monoxide in the hypertensive action of cyclosporine

Although the intermediary role of central neurons in the hypertensive and sympathoexcitatory actions of cyclosporine (CSA) has been recognized in previous studies including our own, the underlying mechanism remains obscure. In this study, we tested the hypothesis that central pathways of nitric oxide (NO) and carbon monoxide (CO) modulate the blood pressure (BP) response elicited by CSA in conscious rats. Hemodynamic effects of CSA were evaluated in absence and presence of maneuvers that inhibit or facilitate biosynthesizing enzymes of NO (NOS) or CO (heme oxygenase, HO). CSA (20 mg/kg i.v.) produced abrupt increases in BP that peaked in 5 min and maintained for at least 45 min. The hypertensive effect of CSA disappeared in rats pretreated intracisternally (i.c.) with Nω-nitro-l-arginine methyl ester (L-NAME, nonselective NOS inhibitor), N5-(1-iminoethyl)-l-ornithine (L-NIO, selective eNOS inhibitor), Nω-propyl-l-arginine (NPLA, selective nNOS inhibitor), or 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, guanylate cyclase inhibitor), suggesting the importance of central eNOS/nNOS/GC cascade in CSA-induced hypertension. L-NAME also abolished the hypotension caused by the sympatholytic drug moxonidine, indicating a tonic sympathoinhibitory action for NO. The inhibition of HO activity by zinc protoporphyrin IX (ZnPP) abrogated the hypertensive action of CSA. The abolition by L-NAME or ZnPP of CSA hypertension was compromised upon simultaneous i.c. exposure to hemin (HO substrate) and l-arginine (NOS substrate), respectively. Together, the interruption of the mutually facilitated NOS/NO and HO/CO pathways and coupled GC/cGMP in central neuronal pools accounts, at least partly, for the hypertensive and perhaps sympathoexcitatory actions of CSA.

► The presence of functional NOS/HO signaling is critical for CSA hypertension. ► Crosstalk between these two enzymatic systems is important for the CSA response. ► Interruption of the eNOS/nNOS/cGMP cascade underlies CSA hypertension.