Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 771, Angers, France.
Hypertension. 2010 Feb;55(2):339-44. doi: 10.1161/HYPERTENSIONAHA.109.140236. Epub 2009 Dec 21.
Angiotensin II has a key role in the control of resistance artery tone and local blood flow. Angiotensin II possesses 2 main receptors. Although angiotensin II type 1 receptor is well known and is involved in the vasoconstrictor and growth properties of angiotensin II, the role of the angiotensin II type 2 receptor (AT2R) remains much less understood. Although AT2R stimulation induces vasodilatation in normotensive rats, it induces vasoconstriction in pathological conditions involving oxidative stress and cyclooxygenase 2 expression. Thus, we studied the influence of cyclooxygenase 2 on AT2R-dependent tone in diabetes mellitus. Mesenteric resistance arteries were isolated from Zucker diabetic fatty (ZDF) and lean Zucker rats and studied using in vitro using wire myography. In ZDF rats, AT2R-induced dilation was lower than in lean rats (11% versus 21% dilation). Dilation in ZDF rats returned to the control (lean rats) level after acute superoxide reduction (Tempol and apocynin), cyclooxygenase 2 inhibition (NS398), or thromboxane A(2) synthesis inhibition (furegrelate). Cyclooxygenase 2 expression and superoxide production were significantly increased in ZDF rat arteries compared with arteries of lean rats. After chronic treatment with Tempol, AT2R-dependent dilation was equivalent in ZDF and lean rats. Chronic treatment of ZDF rats with NS398 also restored AT2R-dependent dilation to the control (lean rats) level. Plasma thromboxane B(2) (thromboxane A(2) metabolite), initially high in ZDF rats, was decreased by chronic Tempol and by chronic NS398 to the level found in lean Zucker rats. Thus, in type 2 diabetic rats, superoxide and thromboxane A(2) reduced AT2R-induced dilation. These findings are important to take into consideration when choosing vasoactive drugs for diabetic patients.
血管紧张素 II 在控制阻力血管张力和局部血流方面起着关键作用。血管紧张素 II 具有 2 种主要受体。虽然血管紧张素 II 型 1 受体是众所周知的，并且参与血管紧张素 II 的血管收缩和生长特性，但血管紧张素 II 型 2 受体（AT2R）的作用仍然知之甚少。虽然 AT2R 刺激在正常血压大鼠中引起血管舒张，但在涉及氧化应激和环氧化酶 2 表达的病理条件下，它会引起血管收缩。因此，我们研究了环氧化酶 2 对糖尿病中 AT2R 依赖性张力的影响。从 Zucker 糖尿病肥胖（ZDF）和瘦 Zucker 大鼠中分离出肠系膜阻力血管，并使用体外线描法进行研究。在 ZDF 大鼠中，AT2R 诱导的扩张小于瘦大鼠（扩张 11%对 21%）。在急性超氧化物还原（Tempol 和 apocynin）、环氧化酶 2 抑制（NS398）或血栓素 A2 合成抑制（furegrelate）后，ZDF 大鼠的扩张恢复到对照（瘦大鼠）水平。与瘦大鼠的动脉相比，ZDF 大鼠的动脉中环氧化酶 2 表达和超氧化物产生显著增加。在 ZDF 大鼠中进行慢性 Tempol 治疗后，AT2R 依赖性扩张与瘦大鼠相当。慢性 NS398 治疗 ZDF 大鼠也将 AT2R 依赖性扩张恢复到对照（瘦大鼠）水平。ZDF 大鼠中的血浆血栓素 B2（血栓素 A2 代谢物）最初较高，经慢性 Tempol 和 NS398 治疗后降低至瘦 Zucker 大鼠中的水平。因此，在 2 型糖尿病大鼠中，超氧化物和血栓素 A2 降低了 AT2R 诱导的扩张。在为糖尿病患者选择血管活性药物时，这些发现非常重要。
