title: Mechanisms of direct inhibitory action of ketamine on vascular smooth muscle in mesenteric resistance arteries.
abstract: BACKGROUND
  Ketamine was previously suggested to relax vascular smooth muscle by reducing the intracellular Ca2+ concentration ([Ca2+]i). However, no direct evidence is available to indicate that ketamine reduces the [Ca2+]i in vascular smooth muscle of systemic resistance arteries.
  
  
  METHODS
  Endothelium-intact or -denuded smooth muscle strips were prepared from rat small mesenteric arteries. Isometric force and [Ca2+]i were measured simultaneously in the fura-2-loaded, endothelium-denuded strips. In some experiments, only isometric force was measured in either the endothelium-intact or beta-escin-treated, endothelium-denuded strips.
  
  
  RESULTS
  In the endothelium-intact strips, lower concentrations (< or = 30 microm) of ketamine slightly enhanced norepinephrine-induced contraction, whereas higher concentrations (> or = 100 microM) of ketamine inhibited both norepinephrine- and KCl-induced contractions. In the fura-2-loaded strips, ketamine (> or = 100 microM) inhibited the increases in both [Ca2+]i and force induced by either norepinephrine or KCl. Ketamine also inhibited the norepinephrine-induced increase in [Ca2+]i after treatment with ryanodine. In the absence of extracellular Ca2+, ketamine notably inhibited the norepinephrine-induced increase in [Ca2+]i, whereas it only minimally inhibited caffeine-induced increase in [Ca2+]i. Ketamine had little influence on the [Ca2+]i-force relation during force development to stepwise increment of extracellular Ca2+ concentration during either KCl depolarization or norepinephrine stimulation. Ketamine did not affect Ca2+-activated contractions in the beta-escin membrane-permeabilized strips.
  
  
  CONCLUSIONS
  The action of ketamine on contractile response to norepinephrine consists of endothelium-dependent vasoconstricting and endothelium-independent vasodilating components. The direct vasorelaxation is largely a result of reduction of[Ca2+]i in vascular smooth muscle cells. The [Ca2+]i-reducing effects are caused by inhibitions of both voltage-gated Ca2+ influx and norepinephrine-induced Ca2+ release from the intracellular stores.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan. akata@kuaccm.med.kyushu-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Akata
authors.forename: K
authors.initials: K
authors.lastname: Izumi
authors.forename: M
authors.initials: M
authors.lastname: Nakashima
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004928:Escin / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005456:Fluorescent Dyes; D016257:Fura-2; D007537:Isometric Contraction / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D011189:Potassium Chloride; D004928:Escin; D007649:Ketamine; D002118:Calcium; D016257:Fura-2; D009638:Norepinephrine