Effects of ketamine on contraction and synthesis of inositol 1,4,5-trisphosphate in smooth muscle of the rabbit mesenteric artery.
BACKGROUND
Ketamine acts directly on vascular smooth muscle, causing relaxation. It has been suggested that the mechanism underlying this action involves an interference with transmembrane Ca2+ influx and an inhibition of Ca2+ release from intracellular Ca2+ stores. In vascular smooth muscle cells, agonist-induced Ca2+ release is thought to be mediated by an intracellular second messenger, inositol 1,4,5-trisphosphate (InsP3). To investigate the site at which ketamine acts on agonist-induced contraction, the authors studied the effects of ketamine on contraction and on the synthesis of InsP3 in smooth muscles of the rabbit mesenteric artery.


METHODS
Changes in isometric tension of smooth muscle fibers were measured by attaching a thin circular strip from the rabbit mesenteric artery to a strain gauge. To measure the norepinephrine (NE)-induced production of InsP3, smooth muscle strips of the rabbit mesenteric artery were exposed to the agents and homogenized. Inositol 1,4,5-trisphosphate in the supernatant fractions was then assayed.


RESULTS
Ketamine dose-dependently inhibited contractions induced by high K+, NE, and histamine in normal Krebs solution. Ketamine also inhibited the NE- or histamine-induced contraction in Ca(2+)-free solution containing 2 mM ethylene-glycol bis-(beta-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), indicating that this drug inhibits agonist-induced Ca2+ release from intracellular stores. Norepinephrine (10 microM) transiently increased the synthesis of InsP3 in Ca(2+)-free solution, and ketamine (0.1-1.0 mM) inhibited this effect, in a dose-dependent manner.


CONCLUSIONS
These results indicate that, in the rabbit mesenteric artery, ketamine inhibits agonist-induced Ca2+ release through its inhibitory action on the agonist-induced synthesis of InsP3. Thus, it is possible that ketamine interferes with the synthesis of intracellular second messengers.
Kanmura
Y
Y
Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Kajikuri
J
J
Itoh
T
T
Yoshitake
J
J
D000818:Animals; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits
D007649:Ketamine; D015544:Inositol 1,4,5-Trisphosphate