In a complementary neonatal piglet model, some of us have likewise shown the F508del mutation reduces aortic smooth muscle cell agonist-induced calcium release and aortic tone. In order to further assess the cardiovascular effects of the F508del mutation, we have turned to a mouse model. Unlike CF piglets, CF mice do not develop co-morbid lung disease and arterial pressures can be measured while the mice are housed in their home environment, thereby clarifying the direct effect of CFTR on blood pressures. With human data suggesting a correlation between reduced chloride gating and decreased blood pressure and cell culture data suggesting the F508del mutation interferes with agonist-induced calcium mobilization,, we hypothesized that the F508del mutation reduces arterial tone and lowers arterial pressures in the absence of hypovolemia. While the effects of CFTR expression on epithelial tissue are well described,, the effects of CFTR on muscle tissue are Evodiamine relatively undefined. Both human and murine studies have shown skeletal muscle dysfunction may be intimately linked with the respiratory insufficiency and exercise intolerance that contribute to the morbidity of patients with F508del mutations. Likewise, both human and murine studies suggest CFTR mutations directly interfere with cardiac myocyte function. Utilizing a neonatal piglet CF model, we recently replicated human data showing decreased calcium transients in F508del expressing smooth muscle cells and further correlated this with impaired aortic constriction. In that study, F508del heterozygous aortic smooth muscle cells had a phenotype intermediate between that of the WT and CF cells. The present studies investigated whether a Tubeimoside-I single copy of the F508del mutation is sufficient to reduce arterial pressure and arterial contractility. As reported in human carriers, F508del heterozygous mice had significantly decreased baseline arterial pressures. In both cases, the phenotype is stronger in females than males. In the human studies, women with the lowest blood pressures tended to have the lowest level of CFTR activity, as measured by sweat chloride levels. Similarly, the hypotensive effect of the mutation in mice was most pronounced during the transition between dark and light cycles, a time of heightened arousal associated with increased sympathetic tone and potentially increased CFTR activation. In F508del male mice, a hypotensive phenotype was elicited during the administration of beta-adrenergic receptor agonists, compounds that increase cAMP levels and, at least theoretically, WT CFTR activity, thereby magnifying the phenotypic effect of endogenous CFTR expression. Among the intracellular processes that may contribute to the CFTR modulation of b-adrenergic signaling, there is experimental support for CFTR-mediated membrane depolarization leading to enhanced flux through voltage-dependent calcium channels. To begin testing the hypothesis that cAMP-mediated WT CFTR co-activation facilitates myocyte contraction as a buffer against b-adrenergic receptor-mediated vasodilation, the reactivity of isolated aortic segments was assessed. There were no significant differences between WT and F508del aortic reactivity to depolarizing concentrations of KCl, possibly reflecting a low level of basal CFTR activation.