title: PPARγ dependence of cyclosporine-isoprenaline renovascular interaction: roles of nitric oxide synthase and heme oxygenase.
abstract: We previously showed that cyclosporine (CSA) impairs renal vasodilations caused by β-adrenoceptor activation. This study investigated whether the peroxisome proliferator-activated receptor gamma (PPARγ) and related nitric oxide synthase (NOS)/heme oxygenase (HO) signaling mediates the CSA-β-adrenoceptor interaction. The vasodilatory response elicited by a bolus injection of isoprenaline (1 μmole) in phenylephrine-preconstricted perfused kidneys of rats was reduced after prior infusion of zinc protoporphyrin IX (ZnPP, HO inhibitor) or GW9662 (PPARγ antagonist), suggesting the involvement of PPARγ and HO-derived CO in the isoprenaline response. In contrast, the inhibition of NOS activity by N-nitro-l-arginine methyl ester had no effect on isoprenaline responses. CSA (5 μM) significantly attenuated isoprenaline vasodilations, an effect that was abolished in the presence of GW9662 and accentuated by ZnPP. Also, supplementation with the PPARγ agonist pioglitazone or with l-arginine or hemin, substrates for NOS and HO, respectively, eliminated the unfavorable effect of CSA on isoprenaline vasodilations. The protection conferred by pioglitazone against CSA-evoked attenuation of isoprenaline vasodilations was maintained in N-nitro-l-arginine methyl ester-treated kidneys and disappeared after treatment with ZnPP or GW9662. In conclusion, the activation of the HO/CO/PPARγ cascade is probably the cellular mechanism that underlies the beneficial effect of pioglitazone on the CSA-isoprenaline interaction. Further, the facilitation of the HO/CO or NOS/NO pathway seems to offset this harmful effect of CSA.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
authors.forename: Hanan M
authors.initials: HM
authors.lastname: El-Gowelli
authors.forename: Khaled S
authors.initials: KS
authors.lastname: Abd-Elrahman
authors.forename: Evan I
authors.initials: EI
authors.lastname: Saad
authors.forename: Sahar M
authors.initials: SM
authors.lastname: El-Gowilly
authors.forename: Abdel-Galil A
authors.initials: AG
authors.lastname: Abdel-Galil
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: El-Mas
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D047495:PPAR gamma; D011943:Receptors, Adrenergic, beta; D045162:Thiazolidinediones; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D007545:Isoproterenol; D000077205:Pioglitazone