RESUMEN
BACKGROUND AND AIMS: Unlike the intestine of normal subjects, small-intestinal epithelia of cystic fibrosis patients and cystic fibrosis transmembrane conductance regulator protein-null (CFTR(-)) mice do not respond to stimulation of intracellular cyclic adenosine monophosphate with inhibition of electroneutral NaCl absorption. Because CFTR-mediated anion secretion has been associated with changes in crypt cell volume, we hypothesized that CFTR-mediated cell volume reduction in villus epithelium is required for intracellular cyclic adenosine monophosphate inhibition of Na(+)/H(+) exchanger (primarily Na(+)/H(+) exchanger 3) activity in the proximal small intestine. METHODS: Transepithelial (22)Na flux across the jejuna of CFTR(+), CFTR(-), the basolateral membrane Na(+)/K(+)/2Cl(-) co-transporter protein NKCC1(+), and NKCC1(-) mice were correlated with changes in epithelial cell volume of the midvillus region. RESULTS: Stimulation of intracellular cyclic adenosine monophosphate resulted in cessation of Na(+)/H(+) exchanger-mediated Na(+) absorption (J(ms)(NHE)) in CFTR(+) jejunum but had no effect on J(ms)(NHE) across CFTR(-) jejunum. Cell volume indices indicated an approximately 30% volume reduction of villus epithelial cells in CFTR(+) jejunum but no changes in CFTR(-) epithelium after intracellular cyclic adenosine monophosphate stimulation. In contrast, cell shrinkage induced by hypertonic medium inhibited J(ms)(NHE) in both CFTR(+) and CFTR(-) mice. Bumetanide treatment to inhibit Cl(-) secretion by blockade of the Na(+)/K(+)/2Cl(-) co-transporter, NKCC1, of stimulated CFTR(+) jejunum prevented maximal volume reduction of villus epithelium and recovered approximately 40% of J(ms)(NHE). Likewise, J(ms)(NHE) and cell volume were unaffected by intracellular cyclic adenosine monophosphate stimulation in NKCC1(-) jejuna. CONCLUSIONS: These findings show a previously unrecognized role of functional CFTR expressed in villus epithelium: regulation of Na(+)/H(+) exchanger 3-mediated Na(+) absorption by alteration of epithelial cell volume.