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J Appl Physiol 87: 1266-1271, 1999;
8750-7587/99 $5.00
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Vol. 87, Issue 4, 1266-1271, October 1999

INVITED REVIEW
Targeted deletion of the neutral endopeptidase gene alters ventilatory responses to acute hypoxia in mice

H. Grasemann1, B. Lu2, A. Jiao1, J. Boudreau1, N. P. Gerard2, and G. T. De Sanctis1

1 Combined Program in Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, and 2 Ina Sue Perlmutter Laboratory, Children's Hospital, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02115

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% O2 in N2 and 8% O2 in N2. Deletion of the NEP gene caused marked alterations in both the magnitude and composition of the hypoxic ventilatory response to both 8% O2 in N2 and 12% O2 in N2, 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% O2 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.

substance P; unanesthetized mice; control of breathing


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