Nitric oxide modulation of central imidazoline I1 receptors accounts for the hypertensive effect of cyclosporine in rats

Abstract

This study tested the hypothesis that the hypertensive action of cyclosporine (CSA) involves interaction with central α2‐receptors and/or I1‐imidazoline receptors and investigated the role of nitric oxide in the interaction. The effect of clonidine (mixed α2/I1‐receptor agonist), moxonidine (I1‐receptor agonist), or guanabenz (α2‐receptor agonist) on CSA hypertension was assessed in conscious rats. CSA (20 mg/kg i.v.) increased BP that continued for at least 45 min. CSA hypertension was inhibited by ganglionic (hexamethonium) or α1‐receptor (prazosin) blockade. Pressor responses to phenylephrine were not affected by CSA, thereby eliminating a possible role for α1‐receptors in CSA hypertension. Intravenous guanabenz (30 μg/kg), clonidine (30 μg/kg), or moxonidine (100 μg/kg) produced similar decreases in BP. Pretreatment with clonidine or moxonidine attenuated CSA hypertension whereas guanabenz had a minimal effect, suggesting a predominant role for I1‐receptor neuronal pathways in the BP effect of CSA. Central administration of moxonidine (80 nmol) into cisterna magna also attenuated CSA hypertension. NOS inhibition by NG‐nitro‐L‐arginine methyl ester abolished BP responses to moxonidine and CSA.Conclusion: facilitation of central I1‐receptor‐NO signaling accounts, at least partly, for CSA hypertension.Supported by Faculty of Pharmacy, Univ. of Alexandria, Egypt.