title: Role of PPAR gamma/nitric oxide synthase signaling in the cyclosporine-induced attenuation of endothelium-dependent renovascular vasodilation.
abstract: Evidence from our laboratory and others suggests a negative effect for cyclosporine A (CSA) on renovascular reactivity. This study investigated the role of peroxisome proliferator-activated receptor gamma (PPAR gamma)/nitric oxide synthase (NOS) signaling in the CSA-induced attenuation of endothelium-dependent vasodilations in phenylephrine-preconstricted perfused kidneys of rats. Bolus injection of carbachol (4 micromoL) reduced the renal perfusion pressure with a peak depressor effect observed at 2 minutes. CSA (5 microM) infusion significantly attenuated the vasodilatory action of carbachol. The specificity of this interaction was verified by the lack of effect of CSA on renal vasodilation caused by papaverine (50 nmol). The carbachol-induced renal vasodilations were also reduced after infusion of N-nitro-L-arginine methyl ester (L-NAME, NOS inhibitor, 100 microM) or 2-chloro-5-nitro-N-phenylbenzamide (GW9662, PPAR gamma antagonist, 1 microM). The attenuation of carbachol vasodilation by CSA was abolished in presence of L-arginine or L-NAME in contrast to no effect for GW9662. Pioglitazone (PPAR gamma agonist, 10 microM) abolished the CSA-induced attenuation of carbachol responses, an effect that was not manifest in presence of GW9662 or l-NAME. These findings suggest that PPAR gamma act tonically to facilitate renovascular dilatory response to endothelial muscarinic receptor activation. More importantly, NOS signaling downstream of PPAR gamma mediates, at least partly, the inhibitory effect of CSA on carbachol vasodilations.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt.
authors.forename: Khaled S
authors.initials: KS
authors.lastname: Abd-Elrahman
authors.forename: Hanan M
authors.initials: HM
authors.lastname: El-Gowelli
authors.forename: Evan I
authors.initials: EI
authors.lastname: Saad
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: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D016572:Cyclosporine / Q000009:adverse effects*; D045462:Endothelium-Dependent Relaxing Factors / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D045462:Endothelium-Dependent Relaxing Factors; D007166:Immunosuppressive Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D016572:Cyclosporine; D002217:Carbachol; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D000077205:Pioglitazone