title: Mechanism of sarpogrelate action in improving cardiac function in diabetes.
abstract: Although sarpogrelate, a 5-HT(2A) receptor antagonist, has been reported to exert beneficial effects in diabetes, the mechanisms of its action are not understood. In this study, diabetes was induced in rats by an injection of streptozotocin (65 mg/kg) and the animals were assessed 7 weeks later. Decreased serum insulin as well as increased serum glucose, cholesterol, and triglyceride levels in diabetic animals were associated with increased blood pressure and heart/body weight ratio. Impaired cardiac performance in diabetic animals was evident by decreased heart rate, left ventricular developed pressure, rate of pressure development, and rate of pressure decay. Treatment of diabetic animals with sarpogrelate (5 mg/kg) or insulin (10 units/kg) daily for 6 weeks attenuated the observed changes in serum insulin, glucose, and lipid levels as well as blood pressure and cardiac function by varying degrees. Protein content for membrane glucose transporters (GLUT-1 and GLUT-4) was depressed in diabetic heart; the observed alteration in GLUT-4 was partially prevented by both sarpogrelate and insulin, whereas that in GLUT-1 was attenuated by sarpogrelate only. Incubation of myoblast cells with sarpogrelate and insulin stimulated glucose uptake; these effects were additive. 5-hydroxytryptamine was found to inhibit glucose-induced insulin release from the pancreas; this effect was prevented by sarpogrelate. These results suggest that sarpogrelate may improve cardiac function in chronic diabetes by promoting the expression of membrane glucose transporters as well as by releasing insulin from the pancreas.
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface General Hospital Research Center, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Goyal
authors.forename: Vijayan
authors.initials: V
authors.lastname: Elimban
authors.forename: Yan-Jan
authors.initials: YJ
authors.lastname: Xu
authors.forename: Hideo
authors.initials: H
authors.lastname: Kumamoto
authors.forename: Nobuakira
authors.initials: N
authors.lastname: Takeda
authors.forename: Naranjan S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D002320:Cardiovascular Physiological Phenomena; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D004353:Drug Evaluation, Preclinical; D051275:Glucose Transporter Type 4 / Q000502:physiology; D006321:Heart / Q000503:physiopathology*; D007328:Insulin / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D051379:Mice; D032446:Myoblasts / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013386:Succinates / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D051275:Glucose Transporter Type 4; D007328:Insulin; D013386:Succinates; C064294:sarpogrelate