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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Effects of endothelin receptor blockade on hypervasoreactivity in streptozotocin-diabetic rats: vessel-specific involvement of thromboxane A2.
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Effects of endothelin receptor blockade on hypervasoreactivity in streptozotocin-diabetic rats: vessel-specific involvement of thromboxane A2.

机译：内皮素受体阻滞对链脲佐菌素-糖尿病大鼠血管过度反应的影响：血栓烷A2的血管特异性参与。

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摘要

Increased vasoconstrictor response to norepinephrine (NE) and endothelin (ET)-1 in arteries from diabetic animals is ameliorated by chronic endothelin receptor blockade with bosentan and was absent in endothelium-denuded arteries, suggesting the involvement of ET-1 and an endothelium-derived contracting factor such as thromboxane A2 (TxA2). To examine this possibility, we determined the effects of acute blockade of ET receptors or inhibition of TxA2 synthesis on the vascular function of superior mesenteric arteries (SMA) and renal arteries (RA) isolated from nondiabetic and 11-week streptozotocin (STZ) diabetic rats chronically treated with either bosentan or vehicle. Both in vitro incubation with bosentan and a selective ETA receptor blocker, BQ123, eradicated the increase in NE contractile responses in diabetic SMA. Additionally, in vitro incubation with the thromboxane synthase inhibitor, dazmegrel, abrogated the exaggerated NE and ET-1 contractile responses in diabetic SMA. Conversely, in RA, no significant acute effect of bosentan, BQ123, nor dazmegrel on vascular responses to NE was observed. Dazmegrel incubation attenuated the maximum contractile responses to ET-1 in diabetic RA; however, these responses in diabetic RA remained significantly greater than those of other groups. Diabetic RA but not SMA exhibited an enhanced contractile response to the TxA2 analogue U46619, which was corrected by chronic bosentan treatment. Immunohistochemical analyses in diabetic SMA revealed an increase in ETA receptor level that was normalized by chronic bosentan treatment. These data indicate that an interaction between ET-1 and TxA2 may be involved in mediating the exaggerated vasoconstrictor responses in diabetic arteries. Furthermore, the underlying mechanisms appear to be vessel specific.
机译：糖尿病动物对动脉的去甲肾上腺素（NE）和内皮素（ET）-1的血管收缩反应增加，可通过波生坦对内皮素受体的长期阻断得到缓解，内皮剥夺性动脉中血管紧张素缺乏，提示ET-1和内皮源性内皮素参与收缩因子，例如血栓烷A2（TxA2）。为了检验这种可能性，我们确定了急性阻断ET受体或抑制TxA2合成对分离自非糖尿病和11周链脲佐菌素（STZ）糖尿病大鼠的上肠系膜动脉（SMA）和肾动脉（RA）血管功能的影响用波生坦或赋形剂长期治疗。波生坦和选择性ETA受体阻滞剂BQ123的体外温育均消除了糖尿病SMA中NE收缩反应的增加。此外，在体外与血栓烷合酶抑制剂dazmegrel孵育消除了糖尿病SMA中夸大的NE和ET-1收缩反应。相反，在RA中，未观察到波生坦，BQ123或达格美瑞对NE的血管反应有明显的急性作用。 Dazmegrel孵育减弱了糖尿病RA对ET-1的最大收缩反应。然而，糖尿病RA中的这些反应仍然明显高于其他组。糖尿病RA而非SMA表现出对TxA2类似物U46619的增强的收缩反应，其通过慢性波生坦治疗得以纠正。糖尿病SMA中的免疫组织化学分析显示，ETA受体水平升高，这可通过慢性波生坦治疗正常化。这些数据表明，ET-1和TxA2之间的相互作用可能参与介导糖尿病动脉中过度的血管收缩反应。此外，潜在的机制似乎是血管特异性的。

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