Am. J. Respir. Cell Mol. Biol., Volume 20, Number 4, April, 1999 620-630

Localization and Distribution of Endothelin Receptor Subtypes in Pulmonary Vasculature of Normal and Hypoxia-Exposed Rats

Sanae Soma, Hideki Takahashi, Masashi Muramatsu, Masahiko Oka, and Yoshinosuke Fukuchi

Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan

To clarify the roles of two different endothelin (ET) receptors in the pulmonary vasculature, the localization and distribution of endothelin-A (ET_A) and ET_B receptors were investigated in rat lung under normal and hypoxic conditions by an immunohistochemical method. We also carried out in situ hybridization for ET_B receptor. In normal rats, ET_A receptor is localized in the media of the pulmonary artery and vein with predominant distribution in such proximal segments as elastic arteries and large muscular arteries. ET_B receptor is expressed in the intima and media of pulmonary vessels. The distribution of ET_B receptor in the media predominates in the distal segments of the pulmonary artery, whereas its distribution in the intima is greater in the proximal segments. Immunoreactivity for ET_A receptor increases in the media of the distal segments of the pulmonary artery after exposure to hypobaric hypoxia. Semiquantitative evaluation showed immunoreactivity for ET_A receptor in the pulmonary arteries accompanying the terminal bronchioles, respiratory bronchioles, and alveolar ducts to be increased by 2.5-, 5-, and 20-fold after 14 d exposure to hypoxia, respectively. The messenger RNA and immunoreactivity for ET_B receptor increased significantly in the intima of the distal segments of pulmonary artery after 7 and 14 d exposure to hypoxia. These results suggest that the vasoconstrictive effects of ET-1 are exerted mainly through ET_A receptor in the proximal segments of the pulmonary artery and vein, whereas its effects in the distal segments are mediated by ET_A and ET_B receptors in normal rats. ET_A receptors that increase in resistance arteries after exposure to hypoxia appear to play an important role in the vascular remodeling associated with hypoxic pulmonary hypertension. Because ET_B receptors in the endothelium mediate ET-1-induced vasodilatory effects, the increase in endothelial ET_B receptors may counteract the development of hypoxic pulmonary hypertension.

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