AJP - Regulatory, Integrative and Comparative Physiology, Vol 270, Issue 6 1279-R1286, Copyright © 1996 by American Physiological Society

ARTICLES

Impaired ventilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1

T. Kuwaki, W. H. Cao, Y. Kurihara, H. Kurihara, G. Y. Ling, M. Onodera, K. H. Ju, Y. Yazaki and M. Kumada
Department of Physiology, Faculty of Medicine, University of Tokyo, Japan.

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.

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