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

Abstract

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.

A novel and simple method for endotracheal intubation of mice

“…The observed arterial pO 2 and pCO 2 of the mechanically ventilated mice in this study had values similar to mice that underwent 40 min of open chest operation and were mechanically ventilated (Guo et al 1998). Tracheostomy is often used to achieve mechanical ventilation in models where the animal is killed at the end of the experiment (Kuwaki et al 1996, Georgakopoulos et al 1998, Kubota et al 1998. The intubation technique reported here can be carried out by experienced operators in about the same time it takes to complete tracheostomy, but without causing unnecessary trauma.…”

Impaired Ventilatory Responses to Hypoxia in Mice Deficient in Endothelin-Converting-Enzyme-1

“…Second, unanesthetized mutant mice deficient in ET-1 have impaired ventilatory responses to chemical stimuli. The homozygous tracheotomized newborns show practically no responses to hypercapnia and hypoxia (they die within 15-30 min if they are not tracheotomized), and the heterozygous adult mice show significantly weaker responses to chemical stimuli than their wild-type littermates (5).…”

Neural control of breathing: insights from genetic mouse models

“…Null mutant newborn mice lacking Edn1 (a potent vasoconstrictor peptide) and the endothelin receptor a (Ednra) had blunted ventilatory responses to hypoxia (15,45). Furthermore, heterozygous mutant newborn mice lacking endothelin-converting-enzyme 1 (Ece1) allele exhibited abnormal hyperpneic ventilatory responses to hypoxia (71).…”

“…Studies looking at respiratory phenotypes in newborn mice with targeted gene deletions have started to establish links between the expression of specific genes and the development of carbon-dioxide sensitivity (see Table 2). Null mutant newborn mice lacking the Edn1 and Ednra genes had blunted ventilatory responses to hypercapnia (45,46). Ret ("rearranged during transfection") is a transmembrane tyrosine kinase signaling receptor for members of the glial cell line-derived neurotrophic factor (GDNF) family of ligands.…”