AT-1015, a novel serotonin2A receptor antagonist, improves resaturation of exercised ischemic muscle in hypercholesterolemic rabbits.
OBJECTIVE
The effect of AT-1015, a serotonin(2A) receptor antagonist, on the resaturation of ischemic muscle in a hypercholesterolemic rabbit model was examined with near-infrared spectroscopy.


METHODS
New Zealand White male rabbits were fed normal chow or cholesterol-rich chow. Ischemia was induced in the right hindlimb by ligation of the femoral artery, accompanied by balloon injury of the iliac artery. At 3 days after induction of ischemia, the bilateral gastrocnemius muscles were subjected to passive contraction for 2 minutes. The oxygen resaturation time of the gastrocnemius muscle after exercise was measured by near-infrared spectroscopy. AT-1015 was orally administered for 3 days after induction of ischemia. Assay of serotonin level in platelet-poor plasma and histologic examination of muscle and artery were performed in another set of rabbits.


RESULTS
Oxygen resaturation time of the ischemic gastrocnemius was significantly prolonged in hypercholesterolemic rabbits compared with in normal rabbits without AT-1015, whereas there was no difference between both groups of rabbits that were administered AT-1015. Plasma level of serotonin in hypercholesterolemic rabbits was significantly increased compared with that in normal rabbits. No histologic differences were found in both muscle and artery among all groups.


CONCLUSIONS
A serotonin(2A) receptor antagonist improved the oxygen resaturation of ischemic calf muscle after exercise in hypercholesterolemia. The interaction between plasma free serotonin and the serotonin(2A) receptor may play an important role in muscle oxygenation in ischemic limbs.
Department of Surgery, Division of Vascular Surgery, The University of Tokyo, Tokyo, Japan.
Takashi
T
Komiyama
Hideaki
H
Kihara
Ken
K
Hirose
Ryota
R
Yoshimoto
Hiroshi
H
Shigematsu
D000818:Animals; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism*; D007540:Isonipecotic Acids / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects*; D010100:Oxygen / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000502:physiology; D011817:Rabbits; D012701:Serotonin / Q000097:blood; D058830:Serotonin 5-HT2 Receptor Antagonists; D019265:Spectroscopy, Near-Infrared
D007540:Isonipecotic Acids; C411870:N-(2-(4-(5H-dibenzo(a,d)cyclohepten-5-yliden)piperidino)ethyl)-1-formyl-4-piperidinecarboxamide; D058830:Serotonin 5-HT2 Receptor Antagonists; D012701:Serotonin; D010100:Oxygen