咖啡酸苯乙基胺在第一型糖尿病大鼠之血糖代謝及心血管之藥理作用

Abstract

前言 糖尿病病人主要症狀為血糖不耐及相關心血管併發症。在動物實驗的研究已有許多治療方法被證明可有效治療糖尿病及相關心血管疾病。蜂膠中主要成分-咖啡酸苯乙基酯 (Caffeic acid phenethyl ester, CAPE) 已在許多研究中被證實可改善血糖代謝、保護心臟缺血/再灌流損傷，及改善糖尿病相關心血管併發症。近期的藥效篩選中發現 CAPE衍生物-咖啡酸苯乙基胺 (Caffeic acid phenethyl amide, CAPA) 在結構上具有較高的穩定性，可在血液中維持較長的半衰期。本論文主要探討CAPA在第一型糖尿病大鼠中之血糖代謝、心血管功能及心臟缺血/再灌流損傷之藥理作用評估。 實驗方法 本研究使用 STZ 誘導之第一型糖尿病大鼠。使用 Langendorff 系統由主動脈反灌流心臟測量冠狀動脈流速；使用胸主動脈測量藥物對血管收縮張力之影響。在心臟/缺血再灌流試驗中，將左冠狀動脈前降支暫時綁緊產生心臟缺血 45 分鐘，再鬆開 2 小時產生心臟再灌流；藥物在再灌流前 30 分鐘給予。最後，使用誘導糖尿病 4 週後之大鼠給予藥物長期治療 4 週測試藥物對糖尿病大鼠相關心血管併發症之改善作用。 實驗結果 口服 0.1 mg/kg CAPA 在正常及糖尿病鼠均可有效降低血糖。離體給予 1–10 μM CAPA 可在正常及糖尿病鼠有效增加冠狀動脈流速，但此作用可被一氧化氮合成酶抑制。在血管張力試驗中，給予 100 μM CAPA 可使 phenylephrine 產生之劑量/反應曲線右移。腹腔注射給予CAPA (3 and 15 mg/kg) 可有效減少心肌缺血/再灌流之損傷體積；給予 dmCAPA (15 mg/kg，無抗氧化能力之 CAPA 衍生物) 或前處理一氧化氮合成酶抑制劑則無保護效果。 在誘導 4 週後之糖尿病鼠給予CAPA (3 mg/kg) 每天腹腔注射兩次持續四週可改善糖尿病降低之冠狀動脈流速，增加血管對 phenylephrine 之反應。每天口服給予 1 mg/kg 持續四週亦可改善糖尿病鼠之心臟功能及缺血/再灌流損傷。 結論 在本研究中發現咖啡酸苯乙基胺在糖尿病大鼠中可降血糖、改善冠狀動脈血流、增加血管反應性及減少心肌缺血/再灌流損傷。主要機轉可能與其抗氧化能力及保存一氧化氮功能有關。其改善糖尿病心血管功能之詳細分子機轉仍需進一步研究。

Background Glucose intolerance and cardiovascular complications are major symptoms in patients with diabetes. Many therapies have proven beneficial in treating diabetes in animals by protecting the cardiovascular system and increasing glucose utilization. Caffeic acid phenethyl ester (CAPE), the major component in extracts of propolis has been shown to ameliorate cardiovascular complications in diabetes. In this study, we evaluated the protective effects of a CAPE analog with more structural stability in plasma, caffeic acid phenethyl amide (CAPA), on glucose homeostasis, cardiovascular function and I/R injury in streptozotocin (STZ)-induced type 1 diabetic rats. Methods Diabetes was induced in 8-week old rats by STZ. Hypoglycemic effects were then assessed in normal and type 1 diabetic rats. In addition, coronary blood flow in Langendorff-perfused hearts was evaluated. The thoracic aorta was used to measure vascular response to phenylephrine. To produce the I/R injury, the left anterior descending coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. Finally, the effect of chronic treatment of CAPA and insulin on coronary artery flow, vascular response to phenylephrine and the cardioprotective effect of chronic treatment of CAPA were analyzed in diabetic rats. Results Oral administration of CAPA decreased plasma glucose in normal and diabetic rats. In normal and diabetic rat hearts, CAPA increased coronary arterial flow rate, and this increase was abolished by NOS inhibitor. In the thoracic aorta, the concentration/response curve of phenylephrine was right-shifted by administration of 100 μM CAPA. Compared to the control group, CAPA administration significantly reduced the myocardial infarct size after I/R. However, 4 weeks of treatment with CAPA started at 4 weeks after STZ induction increased flow rate. In addition, a 4-week CAPA treatment could effectively decrease the infarct size and ameliorate the cardiac dysfunction by pressure-volume loop analysis in STZ-induced diabetic animals. Conclusions CAPA, which is structurally similar to CAPE, induced hypoglycemic activity, increased coronary blood flow and vascular response to phenylephrine in type 1 diabetic rats, exerts cardioprotective activity in I/R injury through its antioxidant property and by preserving nitric oxide levels. On the other hand, chronic CAPA treatment could also ameliorate cardiac dysfunction in diabetic animals. However, the detailed cellular mechanisms need to be further evaluated.