title: Phosphatidylinositol 3-kinase inhibition induces vasodilator effect of sevoflurane via reduction of Rho kinase activity.
abstract: OBJECTIVE
  This study was aimed to examine whether a volatile anesthetic sevoflurane in clinical doses reduces vasoconstriction under the inhibition of phosphatidylinositol 3-kinase (PI3K) in the rat and human arteries and whether the intravenous administration of the PI3K inhibitor decreases blood pressure in rats under the sevoflurane inhalation.
  
  
  METHODS
  Rat arteries (n=5-6) and human omental arteries (n=5-6) were subjected to isometric force recordings and western immunoblotting for Rho kinase, mitogen-activated protein kinase, and protein kinase C. Some arteries were incubated with sevoflurane (1.5% or 3%), a selective PI3K inhibitor LY294002 (3×10-6mol/L) or the combination. Mean arterial pressure (MAP) and heart rate (HR) in rats (n=7) were evaluated with or without intravenous injection of LY294002 (3×10-6mol/L) under 2% sevoflurane inhalation.
  
  
  RESULTS
  Sevoflurane with LY294002, but not sevoflurane or LY294002 solely, inhibited the phenylephrine-induced contraction (32% to 52% decrease at phenylephrine [3×10-6mol/L] in rat arteries and [3×10-5mol/L] in human arteries). Sevoflurane (3%) only with LY294002 decreased Rho kinase activity in the rat aorta into 30%. Intravenous LY294002 reduced MAP (8.1-12.4mmHg decrease), but not HR, in rats under 2% sevoflurane inhalation.
  
  
  CONCLUSIONS
  Clinical sevoflurane doses with PI3K inhibition reduce the contraction of rat and human arteries ex vivo resulting from Rho kinase inhibition, and systemic blood pressure of rats in vivo. These results suggest that sevoflurane potentially causes vasodilation and hypotension in patients receiving anti-cancer therapy that inhibits PI3K.
authors.affiliation: Department of Anesthesiology, Aichi Medical University School of Medicine, Aichi, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of and Pharmacology, Aichi Medical University School of Medicine, Aichi, Japan.
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Feng
authors.affiliation: Department of Anesthesiology, Tokushima University Hospital, 3-18-15, Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Satomi
authors.affiliation: Department of Anesthesiology, Tokushima University Hospital, 3-18-15, Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Anesthesiology, Aichi Medical University School of Medicine, Aichi, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Anesthesiology, Aichi Medical University School of Medicine, Aichi, Japan; Department of Anesthesiology, Tokushima University Hospital, 3-18-15, Kuramoto, Tokushima 770-8503, Japan. Electronic address: hkinoshi@krc.biglobe.ne.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kinoshita
mesh_terms: D000368:Aged; D018685:Anesthetics, Inhalation / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage* / Q000494:pharmacology; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077149:Sevoflurane; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D002867:Chromones; D008738:Methyl Ethers; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014665:Vasodilator Agents; D010656:Phenylephrine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077149:Sevoflurane; D058539:Phosphatidylinositol 3-Kinase; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases
keywords: Anesthetics; Phosphatidylinositol 3-kinase; Rho kinase; Sevoflurane