Partial restoration of defective chloride conductance in Delta F508 CF mice by trimethylamine oxide

This study was designed to test the in vivo efficacy of the chemical chaper one trimethylamine oxide (TMAO) in correcting the Cl- transport defect in a mouse model of cystic fibrosis (CF). Rectal potential difference (RPD) mea surements were done in matched wild-type and Delta F508 CF mice. Mice were treated by subcutaneous injections of TMAO. Wild-type mice demonstrated a f orskolin-stimulated, Cl--dependent hyperpolarization of -6.4 +/- 0.8 mV (n = 11), which was significantly increased to -13.1 +/- 1.4 mV after treatmen t with TMAO. Delta F508 CF mice showed no significant responses to forskoli n. Treatment with TMAO recovered a forskolin-activated RPD in Delta F508 CF mice (-1.1 +/- 0.2 mV; n = 17) but not in CFTR null mice. The effects of T MAO were dose dependent, resulting in a slope of -0.4 +/- 0.1 mV . g(-1) . kg(-1) in Delta F508 CF mice. The forskolin-stimulated RPD in TMAO-treated Delta F508 CF mice was partially blocked by glibenclamide and further stimu lated by apigenin. The total response to forskolin plus apigenin was -2.5 /- 0.45 mV(n = 6 mice), corresponding to 39% of the response evoked by fors kolin only in wild-type mice.