title: Store-operated Ca2+ influx in airway smooth muscle: Interactions between volatile anesthetic and cyclic nucleotide effects.
abstract: BACKGROUND
  Volatile anesthetics produce bronchodilation in part by depleting sarcoplasmic reticulum Ca stores in airway smooth muscle (ASM). Other bronchodilatory drugs are known to act via cyclic nucleotides (cyclic adenosine 3',5'-cyclic monophosphate, cyclic guanosine 3',5'-cyclic monophosphate). Intracellular Ca regulation in ASM involves plasma membrane Ca influx, including that triggered by sarcoplasmic reticulum Ca depletion (store-operated Ca entry [SOCE]). The authors hypothesized that anesthetics and bronchodilatory agents interact in inhibiting SOCE, thus enhancing ASM relaxation.
  
  
  METHODS
  In enzymatically dissociated porcine ASM cells imaged using fluorescence microscopy, sarcoplasmic reticulum Ca was depleted by 1 microm cyclopiazonic acid in 0 extracellular Ca, nifedipine, and potassium chloride (preventing Ca influx through L-type channels and SOCE). Extracellular Ca was rapidly reintroduced to selectively activate SOCE in the presence or absence of 1 minimum alveolar concentration (MAC) halothane, isoflurane, or sevoflurane. Anesthetic interference with SOCE regulation by cyclic nucleotides was examined by activating SOCE in the presence of (1) 1 microm acetylcholine, (2) 100 microm dibutryl cyclic adenosine 3',5'-cyclic monophosphate, or (3) 100 microm 8-bromo-cyclic guanosine 3',5'-cyclic monophosphate.
  
  
  RESULTS
  SOCE was enhanced by acetylcholine, whereas volatile anesthetics and both cyclic nucleotides partially inhibited Ca influx. Preexposure to 1 or 2 MAC anesthetic (halothane > isoflurane > sevoflurane) inhibited SOCE. Only halothane and isoflurane inhibited acetylcholine-induced augmentation of Ca influx, and significantly potentiated cyclic nucleotide inhibition such that no influx was observed in the presence of anesthetics and cyclic nucleotides.
  
  
  CONCLUSIONS
  These data indicate that volatile anesthetics prevent sarcoplasmic reticulum refilling by inhibiting SOCE and enhancing cyclic nucleotide blunting of Ca influx in ASM. Such interactions likely result in substantial airway relaxation in the presence of both anesthetics and bronchodilatory agents such as beta agonists or nitric oxide.
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
authors.forename: Adeyemi
authors.initials: A
authors.lastname: Iyanoye
authors.forename: Binnaz
authors.initials: B
authors.lastname: Ay
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology; D008738:Methyl Ethers / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000077149:Sevoflurane; D013552:Swine
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; C016276:8-bromocyclic GMP; D000077149:Sevoflurane; D003994:Bucladesine; D007530:Isoflurane; D006152:Cyclic GMP; D000109:Acetylcholine; D006221:Halothane