CAMP-REGULATED BUT NOT CA2-REGULATED CL- CONDUCTANCE IN THE OVIDUCT IS DEFECTIVE IN MOUSE MODEL OF CYSTIC-FIBROSIS()

Defective adenosine 3',5'-cyclic monophosphate (cAMP)-mediated Cl- tra nsport in cystic fibrosis (CF) reflects defects in the cystic fibrosis transmembrane conductance regulator (CFTR). A moderate level of CFTR mRNA expression has been found in rodent and human oviductal epitheliu m, but unlike other CFTR-expressing tissues, the oviduct in CF patient s is apparently normal. The present study was carried out to investiga te the relative magnitude of the cAMP- and intracellular Ca2+ (Ca-i(2))-regulated Cl- secretion in primary cultures of the oviduct from nor mal and CF mice generated by targeted disruption of the murine CF gene . Normal oviductal epithelium exhibited a basal equivalent short-circu it current (I-eq) of 20.3 +/- 1.7 mu A/cm(2). CF oviduct exhibited a l ower basal I-eq of 4.5 +/- 1.9 mu A/cm(2). In normal mice, forskolin ( 10(-5) M, apical) elicited a slowly developing sustained rise in I-eq, whereas ionomycin (5 x 10(-6) M, apical) and ATP (10(-4) M, apical) i nduced larger increases in I-eq consisting of a prompt, transient resp onse followed by a slowly decreasing component. The I-eq response to f orskolin was totally abolished in CF mouse oviducts, but the magnitude s of the peak I-eq responses to ionomycin and ATP were not different f rom normal. The time courses of the ionomycin- and ATP-evoked response s, however, mere significantly more transient in CF than in normal ovi ducts. These results demonstrate that CF mouse oviduct exhibits defect ive cAMP- but not Ca-i(2+)-mediated Cl- secretion. The relatively high level of functional expression of the alternative Ca-i(2+)-activated Cl- secretory pathway in the mouse oviduct may contribute to the absen ce of major pathology in the CF oviduct.