title: Atorvastatin preconditioning attenuates the production of endothelin-1 and prevents experimental vasospasm in rats.
abstract: OBJECTIVE
  Induced endothelin-1 (ET-1) production and decreased nitric oxide synthase (NOS) bioavailability have been found in aneurysmal subarachnoid hemorrhage (SAH). Atorvastatin is recognized to have pleiotropic effects including increasing NOS bioavailability as well as reducing inflammation and oxidative damage other than reducing dyslipidemia. This study is of interest to examine the effect of atorvastatin on ET-1/endothelial nitric oxide synthase (eNOS) in experimental SAH.
  
  
  METHODS
  A rodent double-hemorrhage SAH model was employed. Animals were randomly assigned as sham-operated, SAH, vehicle plus SAH, 5 mg/day atorvastatin treatment plus SAH and 5 mg/day atorvastatin precondition plus SAH groups. Administration with atorvastatin (5 mg/day) was initiated 1 week before (precondition) and 24 hr later (treatment). Cerebrospinal fluid samples were collected at 72 hr after second SAH. ET-1 (ELISA) was measured. The basilar arteries (BAs) were harvested and sliced, and their cross-sectional areas were measured. Radiolabeled NOS assay kit was used to detect eNOS.
  
  
  RESULTS
  Morphologically, convoluted internal elastic lamina, distorted endothelial cells and myonecrosis of the smooth muscle were predominantly observed in the BA of SAH and vehicle-treated SAH groups, which was not detected in the atorvastatin-preconditioned SAH group or the healthy controls. Significant vasospasm was noted in the vehicle group (lumen potency 64.5%, compared with the sham group, p </= 0.01) and less prominent in the atorvastatin treatment group (lumen potency, 76.6%, p < 0.05). In addition, increased ET-1 levels were found in all the animals subject to SAH (SAH only, SAH plus vehicle and SAH plus atorvastatin reversal) except in the atorvastatin precognition group when compared with the healthy controls (no SAH). Likewise, the levels of expressed NOS in BAs is induced in the atorvastatin groups (both atorvastatin treatment and precondition) when compared with that in the SAH group (p < 0.01).
  
  
  CONCLUSIONS
  This study offers first evidence that atorvastatin in the preconditioning status reduces the level of ET-1, which corresponds to its antivasospastic effect in the condition of chronic vasospasm. Although there is increased expression of NOS in both atorvastatin precondition and reversal groups, BA's lumen potency is significantly increased in the atorvastatin precondition group when compared with the SAH group (p < 0.01).
authors.affiliation: College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Zen
authors.initials: CZ
authors.lastname: Chang
authors.forename: Shu-Chuan
authors.initials: SC
authors.lastname: Wu
authors.forename: Chih-Long
authors.initials: CL
authors.lastname: Lin
authors.forename: Shiuh-Lin
authors.initials: SL
authors.lastname: Hwang
authors.forename: Shen-Long
authors.initials: SL
authors.lastname: Howng
authors.forename: Aij-Lie
authors.initials: AL
authors.lastname: Kwan
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019194:Ischemic Preconditioning / Q000379:methods; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000517:prevention & control*
chemical_list: D019332:Endothelin-1; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D009569:Nitric Oxide; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat