title: The volatile anesthetic isoflurane inhibits the histamine-induced Ca2+ influx in primary human endothelial cells.
abstract: Although isoflurane is a known vasodilator, the mechanism of isoflurane-induced vasodilation is not clear. One of the most important systems in this context is the nitric oxide (NO)-mediated vasodilation. The activity of this system is regulated by the agonist-induced Ca(2+) influx rather than Ca(2+) release from internal stores. A number of reports have studied the effect of volatile anesthetics on the cytoplasmic calcium concentration signaling in mammalian endothelial cells. However, similar studies using human endothelial cells are lacking. In this study, therefore, we investigated whether isoflurane affects the histamine-induced Ca(2+) influx in primary cultures of human endothelial cells. Using confocal laser scanning microscopy and cells loaded with the Ca(2+) indicator Fluo-3, we studied the effect of isoflurane on the plateau phase of the histamine-induced Ca(2+) influx, which is considered to be due to capacitative Ca(2+) entry. In addition, we measured the ion flux through capacitative Ca(2+) channels directly by using Mn(2+) ions, which, on entering the cell, quench the Fura-2 fluorescence. The results of these two methods were in close agreement and showed a dose-dependent inhibition of the capacitative Ca(2+) entry by isoflurane. Isoflurane apparently depresses NO-mediated vasodilation when the observed inhibition is not compensated for downstream of the endothelial NO synthase activation.
  
  
  CONCLUSIONS
  In response to vasoactive agents, endothelial cells produce nitric oxide (NO), which relaxes the underlying smooth muscle cells. Inhaled anesthetics inhibit this system by an unknown mechanism. Using primary human endothelial cells, we showed that the anesthetic isoflurane depresses a Ca(2+) influx, which is responsible for the activation of the endothelial NO synthase.
authors.affiliation: Department of Anesthesiology, University of Würzburg, Würzburg, Germany.
authors.forename: Piet W L
authors.initials: PWL
authors.lastname: Tas
authors.forename: Christiane
authors.initials: C
authors.lastname: Stöel
authors.forename: Norbert
authors.initials: N
authors.lastname: Roewer
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000502:physiology; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D018613:Microscopy, Confocal; D014471:Umbilical Veins; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D000634:Aminoquinolines; D018685:Anesthetics, Inhalation; D002121:Calcium Channel Blockers; C069657:1-(2-methylphenyl)-4-methylamino-6-methyl-2,3-dihydropyrrolo(3,2-c)quinoline; D006632:Histamine; D007530:Isoflurane; D002118:Calcium