title: Atorvastatin acutely reduces the reactivity to spasmogens in rat aorta: implication of the inhibition of geranylgeranylation and MYPT-1 phosphorylation.
abstract: Statins are known to display benefits in various diseases independently from their cholesterol lowering properties. In this study, we investigated the acute effects of atorvastatin on vascular reactivity to various spasmogens in isolated rat aorta. The responses to noradrenaline (NA, 10(-8) -10(-4) m), endothelin-1 (ET-1, 10(-10) -10(-7) m), and potassium chloride (KCl, 10-100 mm) were evaluated in aortic rings pretreated with atorvastatin (10(-7) -10(-4) m, 30 min). To verify the mechanism of action, the effects of atorvastatin were studied in the presence of cholesterol precursor, mevalonate (10(-2) m, 45 min), mevalonate-derived isoprenoids, namely geranylgeranyl pyrophosphate (GGPP, 5 × 10(-6) m, 30 min) and farnesyl pyrophosphate (FPP, 5 × 10(-6) m, 30 min), and in the absence of endothelium. In parallel, aortic rings were pretreated with the specific inhibitor of Rho kinase, Y-27632 (10(-7) -10(-6) m). Atorvastatin significantly and concentration-dependently reduced the contractions to spasmogens in rat aorta. This acute inhibitory effect was also evident in endothelium-denuded rings. Pretreatment with mevalonate and GGPP, but not with FPP, reversed the inhibitory effect of atorvastatin (10(-4) m) on NA and ET-1 induced contractions. Similar to atorvastatin, pretreatment with Y-27632 inhibited the contractions to NA and KCl in a concentration-dependent manner. Western blot analysis revealed that both atorvastatin (10(-4) m) and Y-27632 (10(-6) m) pretreatment inhibited the phosphorylation of myosin phosphatase target subunit-1 (MYPT-1) triggered by NA, indicating an inhibitory influence on myosin phosphatase. In conclusion, atorvastatin displayed an acute inhibitory effect on vascular contractility evoked by various spasmogens and the inhibitory effect was possibly mediated by the inhibition of mevalonate and GGPP synthesis as well as the prevention of MYPT-1 phosphorylation induced by Rho/Rho kinase.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit,, Istanbul, Turkey.
authors.forename: Fatoş İlkay
authors.initials: Fİ
authors.lastname: Alp Yildirim
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit,, Istanbul, Turkey.
authors.forename: Deniz
authors.initials: D
authors.lastname: Kaleli Durman
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Gazi University, 06330, Etiler,, Ankara, Turkey.
authors.forename: Eda
authors.initials: E
authors.lastname: Aypar
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Gazi University, 06330, Etiler,, Ankara, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Ark
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit,, Istanbul, Turkey.|Department of Pharmacology, Faculty of Health Sciences, Cyprus International University, Lefkoşa, North Cyprus, Cyprus.
authors.forename: Osman
authors.initials: O
authors.lastname: Özdemir
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit,, Istanbul, Turkey.
authors.forename: Birsel Sönmez
authors.initials: BS
authors.lastname: Uydeş Doğan
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D000069059:Atorvastatin / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D054876:Prenylation / Q000187:drug effects*; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000577:Amides; D019332:Endothelin-1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D012717:Sesquiterpenes; C108830:Y 27632; D011189:Potassium Chloride; C004808:farnesyl pyrophosphate; D000069059:Atorvastatin; D054460:rho-Associated Kinases; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D043263:Myosin-Light-Chain Phosphatase; C002963:geranylgeranyl pyrophosphate; D009638:Norepinephrine
keywords: MYPT-1 phoshorylation; Y-27632; atorvastatin; geranylgeranyl pyrophosphate; rat aorta; vascular reactivity