Pathological role of endothelin ET_B receptors

我们利用自然缺失ET_B受体基因的点致死(Sl)大鼠，评价了ET_B受体在DOCA盐诱导的高血压、心血管肥厚和肾脏损伤中的病理作用。当纯合子(sl/sl)和野生型(+/+)大鼠被DOCA-盐处理时，纯合子大鼠比野生型大鼠表现出更早和更高的收缩压升高。慢性应用ET_A受体拮抗剂ABT-627可完全抑制DOCA盐诱导的高血压。纯合子大鼠的肾功能障碍和组织学损伤比野生型大鼠更严重。与野生型大鼠相比，纯合子大鼠血管明显肥大。使用ABT-627可显著改善肾脏和血管损伤。在DOCA盐诱导的高血压中。ET_B受体缺陷型…对DOCA盐性高血压易感性增加及组织损伤与ET-1产生增加及ET_A介导的作用有关更多的大鼠使用相同的动物，我们还评估了内皮素ET-B受体介导的作用在缺血性急性肾功能衰竭(ARF)的发生和维持中的作用。夹闭肾蒂45min后再灌流建立缺血性ARF动物模型。再灌注后24 h，纯合子组和野生型组均可见明显的肾小球功能障碍和组织学损伤，并逐渐恢复。再灌流后7d观察缺血再灌注性肾损伤时，纯合子ARF大鼠肾功能恢复较野生型明显延迟。纯合子大鼠肾缺血再灌流后肾组织ET-1含量升高较野生型大鼠更为明显。因此，ET_B受体介导的Actoins在缺血性ARF的发生发展中不起重要作用，但可能较少参与缺血/再灌注性肾损伤的恢复过程

We evaluated the pathological role of ET_B receptors in DOCA-salt-induced hypertension, cardiovascular hypertrophy and renal damage, using the spotting-lethal (sl) rat which carries a naturally occurring deletion in ET_B receptor gene. When homozygous (sl/sl) and wild-type (+/+) rats were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than wild-type rats. Chronic treatment with ABT-627, an ET_A receptor antagonist, completely suppressed DOCA-salt-induced hypertension in both groups. Renal dysfunction and histologial damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous, compared with wild-type rats. Renal and vaslcular injuries were significantly improved by ABT-627. In DOCA-salt-induced hypertension. Enhanced ET-1 production and ET_A-mediated actions are responsible for the increased susceptivity to DOCA-salt hypertention and tissue injuries in ET_B receptor-defici … More ent ratsUsing same animals, we also evaluated the role of endothelin ET\B-receptor-mediated action in the development and maintenance of ischemic acute renal failure (ARF). Animals were subjected to ischemic ARF by clamping the renal pedicle for 45 min followed by reperfusion. At 24 h after the reperfusion, renal glomerular dysfunction and histological damage were markedly and equally observed both in homozygous and wild-type groups, and these renal njury gradually recovered. When the ischemia/reperfusion-induced renal injury was examined at 7 days after the reperfusion, the recovery in homozygous ARF rats obviously delayed compared with the cases in wild-type animals. Increment of renal endothelin-1 content after the ischemia/reperfusion was more marked in homozygous than in wild-type rats. Thus, ET_B-receptor-mediated actoins do not play an important role in the development of ischemic ARF, but may be involoved in the recovery process from the ischemia/reperfusion-induced renal injury Less