Role of endothelin-1 in the yenal injury of hypertension

在各种实验性高血压模型中，我们探讨了内皮素(ET)在脱氧皮质酮醋酸酯(DOCA)盐诱导的大鼠高血压和肾损伤发病机制中的作用。给药2周后，分别给予选择性ET-A受体拮抗剂ABT627或选择性ETB受体拮抗剂A-192621治疗2周，检测大鼠的全身和肾功能指标。DILY应用ABT-627几乎完全消除了高血压和肾功能不全的发展，并明显改善了心血管肥厚。肾小球、肾小管和肾小动脉均有坏死。相反，A-192621虽不影响DOCA盐性高血压的形成，但可加重肾功能障碍和组织损伤。A-192621可显著促进心血管肥厚的发生。这些结果有力地支持了ET_A受体介导的作用在DOCA-盐源性高血压发病机制中的重要作用。另一方面，在这种高血压模型中，ET_B受体介导的作用可能对血管和肾脏损伤具有保护作用。我们还发现，在DOCA-盐诱导的高血压大鼠，肠系膜动脉对去甲肾上腺素的收缩反应增强。ET_B受体拮抗剂使这种增强作用减弱到正常血压动物的水平。因此，在DOCA盐诱导的高血压大鼠肠系膜动脉中，局部产生的ET-1可能通过刺激ET_B受体参与上述增强作用。此外，蛋白激酶C系统似乎也参与了这种现象

Among various experimental hypertensive models, we investigated the involvement of endothelin (ET) in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt-induced hypertesion and renal injury in rats. Two weeks after the start of DOCA-salt treatment, the rats were given ABT-627, a selective ET\A receptor antagonist or A-192621, a selective ET_B receptor antagonist for 2 weeks, and their systemic and renal functional parameters were examined. The dily administration of ABT-627 almost completely abolished the development of hypertension and renal dysfunction, and markedly improved the cardiovascular hypertrophy. There were nolesions in glomeruli, tubles and renal small arteries. In contrast, althouth A-192621 did not affect the development of DOCA-salt-induced hypertension, renal dysfunction and tissue injury were deteriorated by this agent. The develpoment of cardiovascular hypertrophy was significantly enhanced by A-192621.These results strongly support the view thet ET_A receptormediated action plays an important role in the pathogenesis of DOCA-salt-induced hypertension. On the other hand, it seems likely that hte ET_B receptor-mediated action protects against vascular and renal injuries, in this model of hypertensionWe also found that the contractile responses to noreinephrine were enhanced in mesenteric arteries of DOCA-salt-induced hypertensive rats. This enhancement was declined to the level seen with normotensive animals by ET_B receptor antagonist. Thus, in mesenteric arteries of DOCA-salt-induced hypertensive rats, locally generated ET-1 may contribute to the above enhancement via stimulation of ET_B receptor. In addition, the protein kinase C system seems to be involved in this phenomenon