Lam S Y, Dong X, Chen Y, Leung P S
Department of Physiology, Faculty of Medicine, The University of Hong Kong, Hong Kong.
J Endocrinol. 2002 May;173(2):305-13. doi: 10.1677/joe.0.1730305.
In the present study, the effects of postnatal hypoxemia on the AT1 angiotensin receptor-mediated activities in the rat carotid body were studied. Angiotensin II (Ang II) concentration-dependently increased the chemoreceptor afferent activity in the isolated carotid body. Single- or pauci-fiber recording of the sinus nerve revealed that the afferent response to Ang II was enhanced in the postnatally hypoxic carotid body. To determine whether the increased sensitivity to Ang II is mediated by changes in the functional expression of Ang II receptors in the carotid body chemoreceptors, cytosolic calcium ([Ca2+]i) was measured by spectrofluorimetry in fura-2 acetoxymethyl ester-loaded type I cells dissociated from carotid bodies. Ang II (25-100 nM) concentration-dependently increased [Ca2+]i in the type I cells. The proportion of clusters of type I cells responsive to Ang II was higher in the postnatally hypoxic group than in the normoxic control (89 vs 66%). In addition, the peak [Ca2+]i response to Ang II was enhanced 2- to 3-fold in the postnatally hypoxic group. The [Ca2+]i response to Ang II was abolished by pretreatment with losartan (1 microM), an AT1 receptor antagonist, but not by PD-123177 (1 microM), an AT(2) antagonist. Double-labeling immunohistochemistry confirmed that an enhanced immunoreactivity for AT1 receptor was co-localized to the lobules of type I cells in the hypoxic group. In addition, RT-PCR analysis of subtypes of AT1 receptors showed an up-regulation of AT1a but a down-regulation of AT1b receptors, indicating a differential regulation of the expression of AT1 receptor subtypes by postnatal hypoxia in the carotid body. These data suggest that postnatal hypoxemia is associated with an increased sensitivity of peripheral chemoreceptors in response to Ang II and an up-regulation of AT1a receptor-mediated [Ca2+]i activity of the chemoreceptors. This modulation may be important for adaptation of carotid body functions in the hypoxic ventilatory response and in electrolyte and water homeostasis during perinatal and postnatal hypoxia.
在本研究中，我们研究了出生后低氧血症对大鼠颈动脉体中AT1血管紧张素受体介导活性的影响。血管紧张素II（Ang II）以浓度依赖性方式增加了离体颈动脉体中的化学感受器传入活动。对窦神经进行单纤维或少数纤维记录显示，出生后低氧的颈动脉体中对Ang II的传入反应增强。为了确定对Ang II敏感性的增加是否由颈动脉体化学感受器中Ang II受体功能表达的变化介导，我们通过荧光分光光度法在从颈动脉体分离的用fura-2乙酰氧基甲酯加载的I型细胞中测量了胞质钙（[Ca2+]i）。Ang II（25 - 100 nM）以浓度依赖性方式增加I型细胞中的[Ca2+]i。出生后低氧组中对Ang II有反应的I型细胞簇的比例高于常氧对照组（89%对66%）。此外，出生后低氧组中对Ang II的[Ca2+]i峰值反应增强了2至3倍。用AT1受体拮抗剂氯沙坦（1 microM）预处理可消除对Ang II的[Ca2+]i反应，但用AT(2)拮抗剂PD - 123177（1 microM）预处理则不能。双重标记免疫组织化学证实，低氧组中I型细胞小叶中AT1受体的免疫反应性增强。此外，对AT1受体亚型的RT - PCR分析显示AT1a上调而AT1b受体下调，表明出生后低氧对颈动脉体中AT1受体亚型表达有不同的调节作用。这些数据表明，出生后低氧血症与外周化学感受器对Ang II反应的敏感性增加以及AT1a受体介导的化学感受器[Ca2+]i活性上调有关。这种调节对于围产期和出生后低氧期间颈动脉体功能在低氧通气反应以及电解质和水平衡中的适应可能很重要。
