title: Sevoflurane enhances nitroglycerin tolerance in rat aorta: implications for the desensitization of soluble guanylate cyclase possibly through the additive generation of superoxide anions and/or hydroxyl radicals within vascular smooth muscle.
abstract: Nitroglycerin (TNG) tolerance, defined as an impaired vasodilation response to TNG, has been recently demonstrated to be associated with increased production of reactive species. We designed this study to investigate the mechanisms that mediate TNG tolerance and to compare the effects of sevoflurane and isoflurane on the development of TNG tolerance. Tension changes in rat aortic rings without endothelium were recorded. The cumulative relaxant responses to TNG (10(-8)-10(-5) M) were assessed in phenylephrine-contracted rings. To induce TNG tolerance, the rings were then incubated in the bathing solution containing TNG (10(-5) M) for 30 min in the presence or absence of each anesthetic (1 to 3 MAC). After washout of TNG and anesthetic, the second response to TNG was obtained. Some rings were pretreated with oxygen radical scavengers or sulfhydryl supplements. The first and the second responses to TNG were compared. Sevoflurane at 3 MAC, but not sevoflurane at smaller concentrations or isoflurane, enhanced TNG tolerance when administered in combination with TNG. Sevoflurane alone had no effect on TNG tolerance. The enhancement of TNG tolerance in the case of a combined sevoflurane and TNG treatment was inhibited in the presence of oxygen radical scavengers or at a smaller oxygen concentration (25%). Sevoflurane at a concentration of 3 MAC in hyperoxic condition enhances the development of TNG tolerance, possibly by additive generation of superoxide anions or hydroxyl radicals within vascular smooth muscle.
  
  
  CONCLUSIONS
  The effects of sevoflurane and isoflurane on the development of nitroglycerin (TNG) tolerance were investigated in isolated rat aorta. TNG tolerance was induced by incubation of the vascular tissue in the bathing media containing TNG (10-5 M) for 30 min. Sevoflurane, but not isoflurane, enhances TNG tolerance, possibly by additive generation of oxygen-derived free radicals.
authors.affiliation: Department of Anesthesiology, Wakayama, Medical University, Wakayama, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kakutani
authors.forename: Koji
authors.initials: K
authors.lastname: Ogawa
authors.forename: Shizue
authors.initials: S
authors.lastname: Iwahashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mizumoto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hatano
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006162:Guanylate Cyclase / Q000378:metabolism*; D017665:Hydroxyl Radical / Q000378:metabolism*; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology*; D010100:Oxygen / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D000077149:Sevoflurane; D013481:Superoxides / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D000975:Antioxidants; D008738:Methyl Ethers; D013481:Superoxides; D017665:Hydroxyl Radical; D000077149:Sevoflurane; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D010100:Oxygen