Impaired ventilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1.
We studied respiratory functions in mutant mice deficient in endothelin-1 (ET-1) generated by gene targeting. In conscious adult mice heterozygous for ET-1 gene mutation (ET+/- heterozygous mice), arterial PO2 was significantly lower, PCO2 tended to be higher, and pH tended to be lower than in wild-type littermates. When these conscious mice breathed room air, respiratory minute volume and rate, determined by body plethysmography, were not significantly different between the two groups. However, when ET+/- heterozygous mice were subjected to systemic hypoxia (1:1 air-N2) or hypercapnia (5% CO2-95% O2), increases in respiratory minute volume were significantly attenuated. In conscious newborn ET-/- homozygous mice delivered by cesarean section and tracheotomized, ventilatory responses to systemic hypoxia and hypercapnia, regularly observed in newborn wild-type mice, were almost totally absent. In urethan-anesthetized adult ET+/- heterozygous mice, increases in phrenic nerve discharges in response to hypoxia and hypercapnia were significantly attenuated. Our results demonstrate that ventilatory responses to hypoxia and hypercapnia are impaired in ET-1-deficient mice and suggest that endogenous ET-1 participates in the physiological control of ventilation.
Kuwaki
T
T
Department of Physiology, Faculty of Medicine, University of Tokyo, Japan.
Cao
W H
WH
Kurihara
Y
Y
Kurihara
H
H
Ling
G Y
GY
Onodera
M
M
Ju
K H
KH
Yazaki
Y
Y
Kumada
M
M
D000818:Animals; D000831:Animals, Newborn; D004594:Electrophysiology; D016232:Endothelins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006935:Hypercapnia / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010791:Phrenic Nerve / Q000503:physiopathology; D012119:Respiration
D016232:Endothelins