KS-C370G 在正常及糖尿病大鼠之降血糖及心血管作用評估

Abstract

目前已知心血管疾病是造成糖尿病死亡的主要原因之一。本篇在探討咖啡酸衍生物 KS-C370G 在正常、STZ 誘導的第一型糖尿病大鼠及胰島素誘導的第二型糖尿病大鼠之降血糖作用及其對心血管系統之影響。 本篇實驗結果發現：KS-C370G 在正常之大鼠有很強的降血糖作用 (口服 0.05 mg/kg 九十分鐘後，血糖值減少32.0 ± 1.1 %，n=8，P<0.05)，在糖尿病大鼠中也有明顯的降血糖作用 (第一型糖尿病鼠：口服0.5 mg/kg 九十分鐘後，血糖值減少 13.8 ± 4.3 %，n=7，P<0.05；第二型糖尿病鼠：口服 0.5 mg/kg九十分鐘後，血糖值減少20.0 ± 3.4 %，n=6，P<0.05)，而KS-C370G之降血糖作用可能部分與增加胰島素之分泌有關 (正常大鼠口服KS-C370G 1 mg/kg，30分鐘後，血中胰島素的量由 7.7 ± 1.0 增加至14.9 ± 3.4 uIU/ml，n=8，P<0.05)。在正常大鼠進行葡萄糖耐受性試驗 (IGTT)，發現在 KS-C370G 存在下，可增加大鼠對葡萄糖之利用率。 KS-C370G在離體定壓灌流之大鼠心臟可增加正常及糖尿病鼠冠狀動脈之流速 (正常大鼠：0.3 uM，使流速由 11.8 ± 1.0增加至 13.2 ± 1.4 ml/min，n=5，P<0.05；第一型糖尿病鼠：1 uM，流速由 10.3 ± 0.6 增加至 11.9 ± 0.9 ml/min，n=9，P<0.05；第二型糖尿病鼠：0.1 uM，流速由 10.8 ± 0.8 增加至 11.9 ± 0.9 ml/min，n=4，P<0.05)，此作用可能與一氧化氮之增加有關 (在L-NAME 10 uM存在下，正常Wistar大鼠之冠狀動脈流速需要KS-C370G 10 uM才有明顯增加：流速由 5.5 ± 0.7 ml/min，n=6，增加至 7.4 ± 0.8 ml/min，n=5，P<0.05)。 KS-C370G 對 Phenylephrine 1 uM 或高鉀 80 mM 引起之血管收縮均可產生放鬆作用；KS-C370G 10 至 100 uM 存在下使 Phenylephrine 引起血管收縮之濃度-反應相關曲線平行右移。 在 STZ 誘導的第一型糖尿病鼠長期投與KS-C370G治療 (腹腔注射KS-370G 3 mg/kg，每天兩次，持續四週) 後，可明顯看到第一型糖尿病大鼠之冠狀動脈流速改善之情形 (流速由 7.2 ± 0.2 ml/min，n=4，增加至 11.2 ± 0.5 ml/min，n=5，P<0.05)。 由以上結果可知KS-C370G對於糖尿病之心血管併發症，可能有改善的效果。而關於KS-C370G 對糖尿病鼠心血管功能改善之詳細機轉，仍待進一步之探討。

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.