Expression of endothelin-1 in the brain and lung of rats exposed to permanent hypobaric hypoxia.
High-altitude hypoxia causes pulmonary hypertension in humans and animals. Endothelin-1 (ET-1) is a novel and long-lasting vasoconstrictor. However, no study has dealt with the effects of a hypobaric hypoxic environment (HHE) on ET-1 activity in the brain. We examined 134 male rats permanently exposed to the equivalent of 5500 m altitude for 1 to 8 weeks. In these HHE rats, the mean pulmonary arterial pressure was significantly raised. The level of ET-1 protein, measured by enzyme immunoassay, increased rapidly in the lungs on exposure to HHE, but decreased in the brain. The level of ET-1 mRNA, measured by semiquantitative RT-PCR, was raised at 1, 4, and 6 weeks' exposure in the lungs and at 4 or more weeks' exposure in 3 of 8 brain regions. By in situ hybridization and immunohistochemistry of brain sections, ET-1 mRNA and protein were detected in the endothelial cells, neurons, and astrocyte-like cells in control rats. In HHE rats, the immunoreactive intensity for ET-1 protein decreased rapidly with time in these cells within the brain, although a few weakly ET-1 protein-positive cells were detected until 8 weeks' exposure to HHE. Only a few weakly ET-1 mRNA-positive endothelial cells were detected in any HHE rats. Although the reactivity for ET-1 mRNA had decreased significantly in neurons and astrocyte-like cells at 1 and 2 weeks' exposure to HHE, it was again strong in both types of cells at 4 weeks' exposure to HHE. These results raise the possibility that during exposure to HHE, ET-1 production in the lung may play a role in the development of pulmonary hypertension, while a decrease in ET-1 production within the brain may help to protect neurons by preventing or limiting the constriction of cerebral microvessels during the hypoxia induced by HHE.
Kanazawa
Fumiko
F
Biochemical Section, 2nd Division, Aeromedical Laboratory, Japan Air Self-Defense Force, Tachikawa 190-0003, Japan.
Nakanishi
Kuniaki
K
Osada
Hiroshi
H
Kanamaru
Yoshiki
Y
Ohrui
Nobuhiro
N
Uenoyama
Maki
M
Masaki
Yoshinori
Y
Kanatani
Yasuhiro
Y
Hiroi
Sadayuki
S
Tominaga
Susumu
S
Yakata-Suzuki
Ayako
A
Matsuyama
Shigeo
S
Kawai
Toshiaki
T
D000532:Altitude Sickness / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D002534:Hypoxia, Brain / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology
D019332:Endothelin-1; D012333:RNA, Messenger