IMPAIRED VENTILATORY RESPONSES TO HYPOXIA AND HYPERCAPNIA IN MUTANT MICE DEFICIENT IN ENDOTHELIN-1

We studied respiratory functions in mutant mice deficient in endotheli n-1 (ET-1) generated by gene targeting. In conscious adult mice hetero zygous for ET-1 gene mutation (ET(+/-) heterozygous mice), arterial P- O2 was significantly lower, P-CO2 tended to be higher, and pH tended t o be lower than. in wild-type littermates. When these conscious mice b reathed room air, respiratory minute volume and rate, determined by bo dy plethysmography, were not significantly different between the two g roups. However, when ET(+/-) heterozygous mice were subjected to syste mic hypoxia (1:1 air-N-2) or hypercapnia (5% CO2-95% O-2), increases i n respiratory minute volume were significantly attenuated. In consciou s newborn ET(-/-) homozygous mice delivered by cesarean section and tr acheotomized, ventilatory responses to systemic hypoxia and hypercapni a, regularly observed in newborn wild-type mice, were almost totally a bsent. In urethan-anesthetized adult ET(+/-) heterozygous mice, increa ses in phrenic nerve discharges in response to hypoxia and hypercapnia were significantly attenuated. Our results demonstrate that ventilato ry responses to hypoxia and hypercapnia are impaired in ET-1-deficient mice and suggest that endogenous ET-1 participates in the physiologic al control of ventilation.