KS-C370G 在正常及糖尿病大鼠之降血糖及心血管作用評估

Abstract

It is well known that the complication of cardiovascular disease is a major cause of death in diabetic patients. The present study was planned to examine the hypoglycemic and cardiovascular effects of a synthetic caffeic acid derivative “KS-C370G” on normal, type 1 and type 2 diabetic rats. In normal Wistar rats, KS-C370G was found to exert hypoglycemic effect at oral doses ranging from 0.01 to 1 mg/kg. The hypoglycemic effect reached maximum at 0.05 mg/kg. The average percentage decrease of plasma glucose measured at 90 min after 0.05 mg/kg of KS-C370G was 32.0 ± 3.0 % (n=8, P<0.05 vs control glucose level). In diabetic rats, significant hypoglycemic effects by 0.5 mg/kg of KS-C370G were observed (Type 1 diabetic rats: -13.8 ± 4.3 %, n=7, P<0.05; Type 2 diabetic rats: -20.0 ± 3.4 %, n=6, P<0.05). The hypoglycemic effect of KS-C370G (1 mg/kg) in normal Wistar rats was associated with a significant increase of plasma insulin level from 7.7 ± 1.0 uIU/ml to 14.9 ± 3.4 uIU/ml (n=8, P<0.05). The intravenous glucose tolerance test (IGTT) on the normal Wistar rats revealed that treatment with KS-C370G enhanced glucose utilization. KS-C370G increased the coronary flow on Langendorff perfused rat hearts of normal Wistar and diabetic rats in vitro (normal Wistar rats, 0.3 uM, increased coronary flow rate from 11.8 ± 1.0 to 13.2 ± 1.4 ml/min, n=5, P<0.05; Type 1 diabetic rats: 1 uM, increased coronary flow rate from 10.3 ± 0.6 to 11.9 ± 0.9 ml/min, n=9, P<0.05; Type 2 diabetic rats: 0.1 uM, increased coronary flow rate from 10.8 ± 0.8 to 11.9 ± 0.9 ml/min, n=4, P<0.05). Since the increase of coronary flow of KS- C370G was partly suppressed by pretreatment of the perfused heart with 10 uM L-NAME, it was probable that part of the increase of coronary flow by KS-C370G may be related to increase of NO synthesis or release. In aortic strips precontracted with 1 uM phenylephrine or 80 mM potassium, KS-C370G exerted concentration-dependent vasorelaxation at concentration ranging from 3 to 300 uM. In type 1 diabetic rats, chronic therapy with KS-C370G (3 mg/kg, i.p., b.i.d.) for 4 weeks resulted in an increase of basal coronary flow from 7.2 ± 0.2 ml/min (n=4) to 11.2 ± 0.5 ml/min (n=5, P<0.05). This therapeutic effect was comparable to the effect of insulin (1 IU/kg, i.p., b.i.d.) for 4 weeks. In conclusion, KS-C370G was found to have hypoglycemic activity and beneficial effects on coronary flow of diabetic rats. The mechanisms for the hypoglycemic effect and improvement of coronary flow of this agent in diabetic rats remain to be clarified.