Y. Kanmura et al., EFFECTS OF KETAMINE ON CONTRACTION AND SYNTHESIS OF INOSITOL 1,4,5-TRISPHOSPHATE IN SMOOTH-MUSCLE OF THE RABBIT MESENTERIC-ARTERY, Anesthesiology, 79(3), 1993, pp. 571-579
Background. Ketamine acts directly on vascular smooth muscle, causing
relaxation. It has been suggested that the mechanism underlying this a
ction involves an interference with transmembrane Ca2+ influx and an i
nhibition of Ca2+ release from intracellular Ca2+ stores. In vascular
smooth muscle cells, agonist-induced Ca2+ release is thought to be med
iated by an intracellular second messenger, inositol 1,4,5- trisphosph
ate (InsP3). To investigate the site at which ketamine acts on agonist
-induced contraction, the authors studied the effects of ketamine on c
ontraction and on the synthesis of InsP3 in smooth muscles of the rabb
it mesenteric artery. Methods: Changes in isometric tension of smooth
muscle fibers were measured by attaching a thin circular strip from th
e rabbit mesenteric artery to a strain gauge. To measure the norepinep
hrine (NE)-induced production of InsP3, smooth muscle strips of the ra
bbit mesenteric artery were exposed to the agents and homogenized. Ino
sitol 1,4,5-trisphosphate in the supernatant fractions was then assaye
d. Results: Ketamine dose-dependently inhibited contractions induced b
y high K+, NE, and histamine in normal Krebs solution. Ketamine also i
nhibited the NE- or histamine-induced contraction in Ca2+-free solutio
n containing 2 mm ethylene-glycol bis-(beta-aminoethylether)-N,N,N',N'
-tetraacetic acid (EGTA), indicating that this drug inhibits agonist-i
nduced Ca2+ release from intracellular stores. Norepinephrine (10 mum)
transiently increased the synthesis of InsP3 in Ca2+ -free solution,
and ketamine (0.1-1.0 mm) inhibited this effect, in a dose-dependent m
anner. Conclusions: These results indicate that, in the rabbit mesente
ric 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 intracellu
lar second messengers.