Arun K H S, Kaul C L, Ramarao P
Cardiovascular and Receptorology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Phase-X, Sector 67, S.A.S. Nagar Mohali 160 062 Punjab, India.
Pharmacol Res. 2004 Dec;50(6):561-8. doi: 10.1016/j.phrs.2004.06.001.
Elevated glucose concentration is implicated to play major role in development of diabetic associated vascular complications. It was previously reported that angiotensin II (Ang II) induced contractile response is enhanced in thoracic aorta of diabetic rats. In the present study, the effect of high glucose (HG, 25 mM) exposure for 2h on Ang II cumulative concentration response curves recorded isometrically was studied in thoracic aortic rings isolated from male Sprague-Dawley rats pretreated with streptozotocin (STZ, 65 mg kg(-1) i.p.) or vehicle at 8 weeks prior to the study. Ang II induced contraction via AT1 receptor was significantly enhanced (by 60 +/- 2 %) in HG exposed thoracic aortic rings isolated from vehicle treated but not STZ treated rats. However, there was no change in the pD2 of Ang II while potassium chloride (KCl) induced contraction was unaltered. Ang II induced contractile response was blocked by valsartan (100 microM, selective AT1 receptor antagonist) but not PD 123,319 (100 microM, selective and potent AT2 receptor antagonist). Exposure of aortic rings from control rats to 25 mM mannitol or sucrose for 2 h did not have any effect on the Ang II induced contraction. Tempol (100 microM, a cell permeable superoxide dismutase mimetic) partially reduced the augmented Ang II response in HG exposed aortic rings, while it did not affect the Ang II responses in normal glucose (NG 5.5 mM) exposed aortic rings isolated from control rats. [3H] Ang II binding at AT1 receptors was unaltered in vascular smooth muscle membranes prepared from thoracic aorta exposed to HG for 2 h compared to NG exposed aortic rings. From our results, we conclude that high glucose concentration augments Ang II mediated contraction via AT1 receptors and reactive oxygen species partly contribute to this augmented contraction.
高血糖浓度被认为在糖尿病相关血管并发症的发展中起主要作用。先前有报道称，糖尿病大鼠胸主动脉中血管紧张素II（Ang II）诱导的收缩反应增强。在本研究中，对从链脲佐菌素（STZ，65 mg kg(-1)腹腔注射）预处理或在研究前8周注射溶媒的雄性Sprague-Dawley大鼠分离的胸主动脉环，研究了高糖（HG，25 mM）暴露2小时对等长记录的Ang II累积浓度反应曲线的影响。在从注射溶媒而非STZ处理的大鼠分离的暴露于HG的胸主动脉环中，Ang II通过AT1受体诱导的收缩显著增强（增强60±2%）。然而，Ang II的pD2没有变化，而氯化钾（KCl）诱导的收缩未改变。Ang II诱导的收缩反应被缬沙坦（100 microM，选择性AT1受体拮抗剂）阻断，但未被PD 123,319（100 microM，选择性强效AT2受体拮抗剂）阻断。将对照大鼠的主动脉环暴露于25 mM甘露醇或蔗糖2小时对Ang II诱导的收缩没有任何影响。Tempol（100 microM，一种细胞可渗透的超氧化物歧化酶模拟物）部分降低了暴露于HG的主动脉环中增强的Ang II反应，而它不影响从对照大鼠分离的暴露于正常葡萄糖（NG 5.5 mM）的主动脉环中的Ang II反应。与暴露于NG的主动脉环相比，从暴露于HG 2小时的胸主动脉制备的血管平滑肌膜中[3H]Ang II与AT1受体的结合未改变。根据我们的结果，我们得出结论，高血糖浓度通过AT1受体增强Ang II介导的收缩，并且活性氧部分促成了这种增强的收缩。
