title: Atorvastatin prevents endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats: role of cyclooxygenase 2-derived contracting prostanoids.
abstract: We investigated the effect of atorvastatin on cyclooxygenase (COX) contribution to endothelial dysfunction in spontaneously hypertensive rat (SHR) mesenteric resistance arteries. Atorvastatin (10 mg/kg per day, oral gavage) or its vehicle was administered for 2 weeks to male SHR or Wistar-Kyoto rats. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In Wistar-Kyoto rats, relaxation to acetylcholine was inhibited by N(G)-nitro-L-arginine methyl ester and unaffected by SC-560 (COX-1 inhibitor), DuP-697 (COX-2 inhibitor), or ascorbic acid. In SHRs, the response to acetylcholine was attenuated, less sensitive to N(G)-nitro-L-arginine methyl ester, unaffected by SC-560, and enhanced by DuP-697 or SQ-29548 (thromboxane-prostanoid receptor antagonist) to a similar extent. Endothelium-dependent relaxation was normalized by ascorbic acid or apocynin (NADPH oxidase inhibitor), which also restored the inhibition by N(G)-nitro-L-arginine methyl ester. In atorvastatin-treated SHRs, relaxation to acetylcholine was normalized, fully sensitive to N(G)-nitro-L-arginine methyl ester, and not affected by SC-560, DuP-697, SQ 29548, or antioxidants. Dihydroethidium assay showed an increased intravascular superoxide generation in SHRs, which was abrogated by atorvastatin. RT-PCR revealed a COX-2 induction in SHR arteries, which was downregulated by atorvastatin. The release of prostacyclin and 8-isoprostane was higher from SHR than Wistar-Kyoto mesenteric vessels. COX-2 inhibition and apocynin decreased 8-isoprostane without affecting prostacyclin levels. Atorvastatin increased phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS(1177), and inducible NO synthase levels in SHR mesenteric vessels and decreased 8-isoprostane release. In conclusion, COX-2-derived 8-isoprostane contributes to endothelial dysfunction in SHR mesenteric arteries. Atorvastatin restores NO availability by increasing phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS(1177), and inducible NO synthase levels and by abrogating vascular NADPH oxidase-driven superoxide production, which also results in a downregulation of COX-2-dependent 8-isoprostane generation.
authors.affiliation: Department of Internal Medicine, University of Pisa, Pisa, Italy. a.virdis@med.unipi.it
authors.forename: Agostino
authors.initials: A
authors.lastname: Virdis
authors.forename: Rocchina
authors.initials: R
authors.lastname: Colucci
authors.forename: Daniele
authors.initials: D
authors.lastname: Versari
authors.forename: Narcisa
authors.initials: N
authors.lastname: Ghisu
authors.forename: Matteo
authors.initials: M
authors.lastname: Fornai
authors.forename: Luca
authors.initials: L
authors.lastname: Antonioli
authors.forename: Emiliano
authors.initials: E
authors.lastname: Duranti
authors.forename: Elena
authors.initials: E
authors.lastname: Daghini
authors.forename: Chiara
authors.initials: C
authors.lastname: Giannarelli
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
authors.forename: Stefano
authors.initials: S
authors.lastname: Taddei
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000069059:Atorvastatin; D015153:Blotting, Western; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006538:Heptanoic Acids / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000503:physiopathology; D011336:Probability; D011453:Prostaglandins / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D006538:Heptanoic Acids; D011453:Prostaglandins; D011758:Pyrroles; D008315:Malondialdehyde; D012313:RNA; D000069059:Atorvastatin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2