Impaired ventilatory responses to hypoxia in mice deficient in endothelin-converting-enzyme-1.
Endothelin-converting-enzyme (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to mature endothelin-1. Most homozygous ECE-1-/- embryos die in utero and show severe craniofacial, enteric, and cardiac malformations precluding ventilatory function assessment. In contrast, heterozygous ECE-1+/- embryos develop normally. Their respiratory function at birth has not been studied. Taking into account previous respiratory investigations in mice with endothelin-1 gene disruption, we hypothesized that ECE-1-deficient mice may have impaired ventilatory control. We analyzed ventilatory responses to hypercapnia (8% CO(2)) and hypoxia (10% O(2)) in newborn and adult mice heterozygous for ECE-1 deficiency (ECE-1+/-) and in their wild-type littermates (ECE-1+/+). Ventilation, breath duration, and tidal volume were measured using whole-body plethysmography. Ventilatory responses to hypoxia were significantly weaker in ECE-1+/- than in ECE-1+/+ newborn mice (percentage ventilation increase: 1 +/- 25% versus 33 +/- 29%, p = 0.010). Baseline breathing variables and ventilatory responses to hypercapnia were normal in the ECE-1+/- newborn mice. No differences were observed between adult ECE-1+/- and ECE-1+/+ mice. We conclude that ECE-1 is required for normal ventilatory response to hypoxia at birth.
Renolleau
S
S
Laboratoire de Neurologie et Physiologie du Développement and Service de Physiologie, Hôpital Robert Debré, Paris, France.
Dauger
S
S
Vardon
G
G
Levacher
B
B
Simonneau
M
M
Yanagisawa
M
M
Gaultier
C
C
Gallego
J
J
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D005838:Genotype; D006579:Heterozygote; D000860:Hypoxia / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012119:Respiration
D017931:DNA Primers; C120591:Ecel1 protein, mouse; D008666:Metalloendopeptidases