Impaired ventilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1. Kuwaki, Tomoyuki, Wei-Hua Cao, Yukiko Kurihara, Hiroki Kurihara, Guang-Yi Ling, Makoto Onodera, Ki-Hwan Ju, Yoshio Yazaki, and Mamoru Kumada. Department of Physiology and Third Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113, Japan
APStracts 2:0346R, 1995.
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 mixture of air and N2) or hypercapnia (5% CO2 and 95% O2), increases in respiratory minute volume were significantly attenuated. In conscious newborn ET-/- homozygous mice delivered by cesarian sections and tracheotomized, ventilatory responses to systemic hypoxia and hypercapnia, regularly observed in newborn wild-type mice, were almost totally absent. In urethane-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. 

Received 7 June 1995; accepted in final form 11 December 1995.
APS Manuscript Number R350-5.
Article publication pending Am. J. Physiol. (Regulatory Integrative
Comp. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 December 95