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.