Kobayashi T, Nogami T, Taguchi K, Matsumoto T, Kamata K
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, Japan.
Br J Pharmacol. 2008 Dec;155(7):974-83. doi: 10.1038/bjp.2008.327. Epub 2008 Aug 18.
Mechanisms associated with the enhanced contractile response to endothelin-1 in hyperinsulinaemic diabetes have been examined using the rat aorta. Functions for angiotensin II, endothelin-1 receptor expression and extracellular signal-regulated kinase (ERK) have been investigated.
Streptozotocin-induced diabetic rats were infused with angiotensin II or, following insulin treatment, were treated with losartan, an angiotensin II receptor antagonist. Contractions of aortic strips with or without endothelium, in response to endothelin-1 and angiotensin II, were examined in vitro. Aortic ET(A) receptors and ERK/MEK expression were measured by western blotting.
Insulin-treated diabetic rats exhibited increases in plasma insulin, angiotensin II and endothelin-1. The systolic blood pressure and endothelin-1-induced contractile responses in aortae in vitro were enhanced in insulin-treated diabetic rats and blunted by chronic losartan administration. LY294002 (phosphatidylinositol 3-kinase inhibitor) and/or PD98059 (MEK inhibitor) diminished the enhanced contractile response to endothelin-1 in aortae from insulin-treated diabetic rats. ET(A) and ET(B) receptors, ERK-1/2 and MEK-1/2 protein expression and endothelin-1-stimulated ERK phosphorylation were all increased in aortae from insulin-treated diabetic rats. Such increases were blunted by chronic losartan administration. Endothelin-1-induced contraction was significantly higher in aortae from angiotensin II-infused diabetic rats. angiotensin II-infusion increased ERK phosphorylation, but the expression of endothelin receptors and ERK/MEK proteins remained unchanged.
These results suggest that the combination of high plasma angiotensin II and insulin with a diabetic state induced enhancement of endothelin-1-induced vasoconstriction, ET(A) receptor expression and ERK expression/activity in the aorta. Losartan improved both the diabetes-related abnormalities and the diabetic hypertension.
利用大鼠主动脉研究了高胰岛素血症糖尿病中与内皮素-1收缩反应增强相关的机制。对血管紧张素II、内皮素-1受体表达及细胞外信号调节激酶（ERK）的功能进行了研究。
给链脲佐菌素诱导的糖尿病大鼠输注血管紧张素II，或在胰岛素治疗后，用血管紧张素II受体拮抗剂氯沙坦进行治疗。体外检测有无内皮的主动脉条对内皮素-1和血管紧张素II的收缩反应。通过蛋白质印迹法测定主动脉ET(A)受体及ERK/MEK的表达。
胰岛素治疗的糖尿病大鼠血浆胰岛素、血管紧张素II和内皮素-1水平升高。胰岛素治疗的糖尿病大鼠体外主动脉的收缩压和内皮素-1诱导的收缩反应增强，而长期给予氯沙坦可使其减弱。LY294002（磷脂酰肌醇3激酶抑制剂）和/或PD98059（MEK抑制剂）可减弱胰岛素治疗的糖尿病大鼠主动脉对内皮素-1增强的收缩反应。胰岛素治疗的糖尿病大鼠主动脉中ET(A)和ET(B)受体、ERK-1/2和MEK-1/2蛋白表达以及内皮素-1刺激的ERK磷酸化均增加。长期给予氯沙坦可使其减弱。在输注血管紧张素II的糖尿病大鼠主动脉中，内皮素-1诱导的收缩明显更高。输注血管紧张素II可增加ERK磷酸化，但内皮素受体及ERK/MEK蛋白的表达保持不变。
这些结果表明，高血浆血管紧张素II和胰岛素与糖尿病状态相结合可导致主动脉中内皮素-1诱导的血管收缩增强、ET(A)受体表达及ERK表达/活性增强。氯沙坦可改善糖尿病相关异常及糖尿病性高血压。
