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首页> 外文期刊>American Journal of Physiology >Effect of the endothelin receptor antagonist bosentan on chronic hypoxia-induced morphological and physiological changes in rat carotid body.
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Effect of the endothelin receptor antagonist bosentan on chronic hypoxia-induced morphological and physiological changes in rat carotid body.

机译：内皮素受体拮抗剂波生坦对慢性低氧诱导的大鼠颈动脉形态和生理变化的影响。

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Previous experiments have repeatedly demonstrated that exposure to chronic hypoxia (CH) elicits remarkable structural changes and chemosensory hypersensitivity in the mammalian carotid body. Moreover, recent studies have shown that CH upregulates the neuroactive peptide, endothelin (ET), in oxygen-sensitive type I cells. The present study examines the possible involvement of ET in adaptation by concurrently exposing rats to hypobaric CH (B(P) = 380 Torr) and bosentan, a potent nonpeptide antagonist that blocks ET(A) and ET(B) receptors. Carotid body weight indicated that 14 days of CH induced organ enlargement, a response that was blunted in bosentan-treated rats (CH: 2.54 +/- 0.19-fold increase; CH plus bosentan: 1.92 +/- 0.14-fold increase; P < 0.05). Morphometric studies revealed that bosentan substantially eliminated CH-induced hyperplasia of chemosensory cell lobules as well as expansion of the connective tissue matrix. Vascular dilation associated with CH was not altered by the drug. In untreatedanimals exposed to 3 days of CH, expression of proliferating cell nuclear antigen (PCNA), a marker of mitosis, was increased in lobules of oxygen-sensitive type I cells and in extralobular vascular and connective tissue cells. The incidence of PCNA expression was significantly (P < 0.05) reduced in bosentan-treated animals. In vitro assessments of carotid sinus nerve (CSN) activity showed that enhancement of basal and hypoxia-evoked chemosensory activity following 9 days of CH was significantly (P < 0.001) blunted by concurrent treatment with bosentan. Collectively, our data are consistent with the hypothesis that CH-induced adaptation in the carotid body is at least partially mediated by signaling pathways involving ET receptors.
机译：先前的实验反复证明，暴露于慢性缺氧（CH）会在哺乳动物的颈动脉体内引起显着的结构变化和化学感应超敏反应。此外，最近的研究表明，CH在氧敏感性I型细胞中上调神经活性肽内皮素（ET）。本研究通过将大鼠同时暴露于低压CH（B（P）= 380 Torr）和波生坦（一种有效的非肽拮抗剂，阻断ET（A）和ET（B）受体）来研究ET可能参与的适应性。颈动脉体重表明CH会引起器官扩张14天，这种反应在波生坦治疗的大鼠中减弱（CH：增加2.54 +/- 0.19倍; CH加波生坦：增加1.92 +/- 0.14倍; P < 0.05）。形态计量学研究表明，波生坦基本上消除了CH诱导的化学感觉细胞小叶增生以及结缔组织基质的扩展。与CH相关的血管扩张不会被药物改变。在暴露于CH 3天的未治疗动物中，有氧敏感性I型细胞小叶以及小叶外血管和结缔组织细胞中增殖细胞核抗原（PCNA）（有丝分裂的标志物）的表达增加。在波森坦治疗的动物中，PCNA表达的发生率显着降低（P <0.05）。体外评估颈动脉窦神经（CSN）活性表明，波生坦同时治疗显着（P <0.001）减弱了CH 9天后基础和缺氧引起的化学感觉活性的增强。总的来说，我们的数据与以下假设相符：CH诱导的颈动脉体适应至少部分地由涉及ET受体的信号传导途径介导。

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