Chen Jia, He Liang, Liu Xuemei, Dinger Bruce, Stensaas Larry, Fidone Salvatore
Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah 84108-1256, USA.
Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1257-62. doi: 10.1152/ajplung.00419.2006.
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 untreated animals 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.
先前的实验反复证明，暴露于慢性低氧环境（CH）会在哺乳动物颈动脉体中引发显著的结构变化和化学感受超敏反应。此外，最近的研究表明，CH会上调氧敏感的I型细胞中的神经活性肽内皮素（ET）。本研究通过同时将大鼠暴露于低压CH（B(P)=380托）和波生坦（一种强效非肽拮抗剂，可阻断ET(A)和ET(B)受体）来研究ET在适应性过程中的可能作用。颈动脉体重量表明，14天的CH诱导器官增大，而在波生坦处理的大鼠中这种反应减弱（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，波生坦基本消除了CH诱导的化学感受细胞小叶增生以及结缔组织基质的扩张。与CH相关的血管扩张未被该药物改变。在暴露于3天CH的未处理动物中，增殖细胞核抗原（PCNA，一种有丝分裂标记物）在氧敏感的I型细胞小叶以及小叶外血管和结缔组织细胞中的表达增加。在波生坦处理的动物中，PCNA表达的发生率显著降低（P<0.05）。对颈动脉窦神经（CSN）活性的体外评估表明，在CH 9天后基础和低氧诱发的化学感受活性增强在同时用波生坦处理时显著减弱（P<0.001）。总体而言，我们的数据与以下假设一致，即CH诱导的颈动脉体适应性至少部分是由涉及ET受体的信号通路介导的。
