Lack of amiloride-sensitive transport across alveolar and respiratory epithelium of iNOS(-/-) mice in vivo

The extent to which endogenously generated nitric oxide alters Na+ transpor t across the mammalian alveolar epithelium in vivo has not been documented. Herein we measured alveolar fluid clearance and nasal potential difference s in mice lacking the inducible form of nitric oxide synthase [iNOS; iNOS(- /-)] and their corresponding wildtype controls [iNOS(+/+)]. Alveolar fluid clearance values in iNOS(+/+) and iNOS(-/-) anesthetized mice with normal o xygenation and acid-base balance were similar to 30% of instilled fluid/30 min. In both groups of mice, fluid absorption was dependent on vectorial Na + movement. Amiloride (1.5 mM) decreased alveolar fluid clearance in iNOS(/+) mice by 61%, whereas forskolin (50 muM) increased alveolar fluid cleara nce by 55% by stimulating amiloride-insensitive pathways. Neither agent alt ered alveolar fluid clearance in iNOS(-/-) mice. Hyperoxia upregulated iNOS expression in iNOS(+/+) mice and decreased their amiloride-sensitive compo nent of alveolar fluid clearance but had no effect on the corresponding val ues in iNOS(-/-) mice. Nasal potential difference measurements were consist ent with alveolar fluid clearance in that both groups of mice had similar b aseline values, which were amiloride sensitive in the iNOS(+/+) but not in the iNOS(-/-) mice. These data suggest that nitric oxide produced by iNOS u nder basal conditions plays an important role in regulating amiloride-sensi tive Na+ channels in alveolar and airway epithelia.