title: Mechanisms of direct inhibitory action of isoflurane on vascular smooth muscle of mesenteric resistance arteries.
abstract: BACKGROUND
  Isoflurane has been shown to directly inhibit vascular reactivity. However, less information is available regarding its underlying mechanisms in systemic resistance arteries.
  
  
  METHODS
  Endothelium-denuded smooth muscle strips were prepared from rat mesenteric resistance arteries. Isometric force and intracellular Ca2+ concentration ([Ca2+]i) were measured simultaneously in the fura-2-loaded strips, whereas only the force was measured in the beta-escin membrane-permeabilized strips.
  
  
  RESULTS
  Isoflurane (3-5%) inhibited the increases in both [Ca2+]i and force induced by either norepinephrine (0.5 microM) or KCl (40 mM). These inhibitions were similarly observed after depletion of intracellular Ca2+ stores by ryanodine. Regardless of the presence of ryanodine, after washout of isoflurane, its inhibition of the norepinephrine response (both [Ca2+]i and force) was significantly prolonged, whereas that of the KCl response was quickly restored. In the ryanodine-treated strips, the norepinephrine- and KCl-induced increases in [Ca2+]i were both eliminated by nifedipine, a voltage-gated Ca2+ channel blocker, whereas only the former was inhibited by niflumic acid, a Ca2+-activated Cl- channel blocker. Isoflurane caused a rightward shift of the Ca2+-force relation only in the fura-2-loaded strips but not in the beta-escin-permeabilized strips.
  
  
  CONCLUSIONS
  In mesenteric resistance arteries, isoflurane depresses vascular smooth muscle reactivity by directly inhibiting both Ca2+ mobilization and myofilament Ca2+ sensitivity. Isoflurane inhibits both norepinephrine- and KCl-induced voltage-gated Ca2+ influx. During stimulation with norepinephrine, isoflurane may prevent activation of Ca2+-activated Cl- channels and thereby inhibit voltage-gated Ca2+ influx in a prolonged manner. The presence of the plasma membrane appears essential for its inhibition of the myofilament Ca2+ sensitivity.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Kyushu University, Fukuoka, Japan. akata@kuaccm.med.kyushu-u.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Akata
authors.forename: Tomoo
authors.initials: T
authors.lastname: Kanna
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshino
authors.forename: Shosuke
authors.initials: S
authors.lastname: Takahashi
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000502:physiology; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D003864:Depression, Chemical; D005456:Fluorescent Dyes; D016257:Fura-2; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D002121:Calcium Channel Blockers; D018118:Chloride Channels; D005456:Fluorescent Dyes; D014662:Vasoconstrictor Agents; D012433:Ryanodine; D011189:Potassium Chloride; D007530:Isoflurane; D002118:Calcium; D016257:Fura-2; D009638:Norepinephrine