mdl-100907 and Hypercholesterolemia

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.. 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.. 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.. 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.

Topics: Animals; Hypercholesterolemia; Ischemia; Isonipecotic Acids; Male; Models, Animal; Muscle, Skeletal; Oxygen; Physical Conditioning, Animal; Rabbits; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Spectroscopy, Near-Infrared

We investigated the effects of serotonin (5-HT), SL65.0472 (7-fluoro-2-oxo-4-[2-[4-thieno[3,2-c]pyridine-4-yl)piperazin-1-yl]ethyl]-1,2-dihydroquinoline-1-acetamide, a 5-HT(1B)/5-HT(2A) receptor antagonist) and ketanserin (a 5-HT(2A) receptor antagonist) during exercise-induced cardiac ischemia in conscious dogs. Dogs were administered a hypercholesterolemic diet and an inhibitor of nitric oxide synthetase to produce chronic endothelial dysfunction. Myocardial ischemia was induced by a treadmill exercise test associated with limitation of left anterior descending coronary blood flow. Infusion of serotonin during exercise produced dose-related cardiovascular changes (after 10 microg/kg/min; heart rate +27+/-6 bpm, systolic blood pressure +18+/-3 mm Hg, left circumflex coronary blood flow +64+/-8 ml/min, myocardial segment length shortening in the ischemic zone -5.9+/-1.9%, P<0.05). SL65.0472 blocked serotonin-induced increases in blood pressure, rate pressure product and circumflex coronary artery flow (100 microg/kg i.v., P<0.05) and reduced serotonin-induced ischemic myocardial segment length shortening (300 microg/kg i.v., P<0.05). Ketanserin (30-300 microg/kg i.v.) had no significant effect on any serotonin-induced changes during exercise. Thus, SL65.0472 opposes serotonin-induced myocardial dysfunction in a dog model of exercise-induced ischemia.

Topics: Animals; Dogs; Endothelium, Vascular; Female; Hemodynamics; Hypercholesterolemia; Infusions, Intravenous; Ketanserin; Myocardial Ischemia; Physical Conditioning, Animal; Piperazines; Quinolines; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists