Impaired ventilatory responses to hypoxia in mice deficient in endothelin-converting-enzyme-1

Endothelin-converting-enzyme (ECE-1) catalyzes the proteolytic activation o f big endothelin-1 to mature endothelin-1. Most homozygous ECE-1-/- embryos die in utero and show severe craniofacial, enteric, and cardiac malformati ons precluding ventilatory function assessment. In contrast, heterozygous E CE-1+-/- embryos develop normally. Their respiratory function at birth has not been studied. Taking into account previous respiratory investigations i n mice with endothelin-1 gene disruption, we hypothesized that ECE-1-defici ent mice may have impaired ventilatory control. We analyzed ventilatory res ponses to hypercapnia (8% CO2) and hypoxia (10% O-2) in newborn and adult m ice heterozygous for ECE-1 deficiency (ECE-1+/-) and in their wild-type lit termates (ECE-1+/+). Ventilation, breath duration, and tidal volume were me asured using whole-body plethysmography. Ventilatory responses to hypoxia w ere significantly weaker in ECE-1+/- than in ECE-1+/+ newborn mice (percent age ventilation increase: 1 +/- 25% versus 33 +/- 29%, p = 0.010). Baseline breathing variables and ventilatory responses to hypercapnia were normal i n 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 vent ilatory response to hypoxia at birth.