Targeted deletion of the neutral endopeptidase gene alters ventilatory responses to acute hypoxia in mice.
Neutral endopeptidase (NEP) is one of the major endopeptidases responsible for the inactivation of substance P in the carotid body, a neurotransmitter shown to be important in the transduction of hypoxic stimuli. Ventilatory responses to acute hypoxia were measured by indirect plethysmography in unanesthetized, unrestrained wild-type mice and in mice in which the NEP gene was deleted (NEP -/-). Ventilation was measured while the animals breathed room air: 12% O(2) in N(2) and 8% O(2) in N(2). Deletion of the NEP gene caused marked alterations in both the magnitude and composition of the hypoxic ventilatory response to both 8% O(2) in N(2) and 12% O(2) in N(2), compared with the wild-type mice (C57BL/6J) on the same genetic background as the NEP -/- mice. Treatment of C57BL/6J mice with thiorphan, a NEP inhibitor, resulted in a greater ventilatory response to 8% O(2) because of a significantly greater shortening of expiratory time. The results of these studies demonstrate that NEP plays an important role in modifying the expression of the ventilatory response to acute hypoxia.
Grasemann
H
H
Combined Program in Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Lu
B
B
Jiao
A
A
Boudreau
J
J
Gerard
N P
NP
De Sanctis
G T
GT
D000208:Acute Disease; D000818:Animals; D017353:Gene Deletion; D018390:Gene Targeting; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D012119:Respiration / Q000187:drug effects; D015244:Thiorphan / Q000494:pharmacology
D011480:Protease Inhibitors; D015244:Thiorphan; D015260:Neprilysin