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 P-O2 was significantly lower, P-CO2 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-N-2) or hypercapnia (5% CO2-95% O-2), 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.