Chan P, Liu I-M, Tzeng T-F, Yang T-L, Cheng J-T
Divison of Cardiovascular Medicine, Graduate School of Medicine, Taipei Medical University, Taipei City, Taiwan, R.O.C.
Diabetes Obes Metab. 2007 Jan;9(1):39-49. doi: 10.1111/j.1463-1326.2005.00566.x.
We investigated the mechanism(s) by which valsartan, a selective antagonist of angiotensin subtype 1 (AT(1)) receptor, decreased plasma glucose in streptozotocin (STZ)-induced diabetic rats.
The plasma glucose concentration was assessed by the glucose oxidase method. The concentration of beta-endorphin in plasma or medium incubating adrenal medulla was measured using an enzyme-linked immunosorbent assay. The mRNA levels of the subtype 4 form of glucose transporter (GLUT4) in soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in the liver were detected by Northern blotting analysis, while the protein levels of GLUT4 in isolated soleus muscle and hepatic PEPCK were investigated using Western blotting analysis.
A single intravenous injection of valsartan dose-dependently increased plasma beta-endorphin-like immunoreactivity (BER) in parallel with the lowering of plasma glucose concentration in STZ-induced diabetic rats. Naloxone and naloxonazine inhibited the plasma glucose-lowering action of valsartan at doses sufficient to block opioid micro-receptors. In contrast to its action in wild-type diabetic mice, valsartan failed to modify plasma glucose in opioid micro-receptor knockout diabetic mice. Bilateral adrenalectomy in STZ-induced diabetic rats eliminated both the plasma glucose-lowering action and the plasma BER-elevating action of valsartan. In the isolated adrenal medulla of STZ-induced diabetic rats, angiotensin II (Ang II) or valsartan did not affect spontaneous BER secretion. Activation of cholinergic receptors by 1.0 micromol/l acetylcholine (ACh) enhanced BER secretion from the isolated adrenal medulla of STZ-induced diabetic rats, but not in the presence of 1.0 nmol/l Ang II, while valsartan reversed this inhibition by Ang II in a concentration-dependent manner. Treatment of STZ-induced diabetic rats with valsartan (0.2 mg/kg) three times daily for 3 days resulted in an increase in gene expression of GLUT4 in soleus muscle and impeded the reduction of elevated mRNA or protein level of hepatic PEPCK. Both of these effects were blocked by opioid micro-receptor antagonist.
The results suggest that blockade of AT(1) receptor by valsartan may enhance the adrenal beta-endorphin secretion induced by ACh, activating the opioid micro-receptors to increase glucose utilization and/or to decrease hepatic gluconeogenesis, resulting in the reduction of plasma glucose in STZ-induced diabetic rats.
我们研究了血管紧张素1型（AT(1)）受体选择性拮抗剂缬沙坦降低链脲佐菌素（STZ）诱导的糖尿病大鼠血糖的机制。
采用葡萄糖氧化酶法评估血浆葡萄糖浓度。使用酶联免疫吸附测定法测量血浆或培养肾上腺髓质的培养基中β-内啡肽的浓度。通过Northern印迹分析检测比目鱼肌中葡萄糖转运蛋白4亚型（GLUT4）和肝脏中磷酸烯醇式丙酮酸羧激酶（PEPCK）的mRNA水平，同时使用Western印迹分析研究分离的比目鱼肌中GLUT4和肝脏PEPCK的蛋白质水平。
单次静脉注射缬沙坦可使STZ诱导的糖尿病大鼠血浆β-内啡肽样免疫反应性（BER）剂量依赖性增加，同时血浆葡萄糖浓度降低。纳洛酮和纳洛酮嗪在足以阻断阿片类微受体的剂量下可抑制缬沙坦的降血糖作用。与在野生型糖尿病小鼠中的作用相反，缬沙坦未能改变阿片类微受体基因敲除糖尿病小鼠的血糖水平。对STZ诱导的糖尿病大鼠进行双侧肾上腺切除术消除了缬沙坦的降血糖作用和血浆BER升高作用。在STZ诱导的糖尿病大鼠分离的肾上腺髓质中，血管紧张素II（Ang II）或缬沙坦不影响自发的BER分泌。1.0 μmol/L乙酰胆碱（ACh）激活胆碱能受体可增强STZ诱导的糖尿病大鼠分离的肾上腺髓质的BER分泌，但在存在1.0 nmol/L Ang II时则不然，而缬沙坦以浓度依赖性方式逆转了Ang II的这种抑制作用。每天3次用缬沙坦（0.2 mg/kg）治疗STZ诱导的糖尿病大鼠3天，导致比目鱼肌中GLUT4的基因表达增加，并阻止肝脏PEPCK升高的mRNA或蛋白质水平的降低。这两种作用均被阿片类微受体拮抗剂阻断。
结果表明，缬沙坦阻断AT(1)受体可能增强ACh诱导的肾上腺β-内啡肽分泌，激活阿片类微受体以增加葡萄糖利用和/或减少肝脏糖异生，从而降低STZ诱导的糖尿病大鼠的血浆葡萄糖水平。
