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 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.