Inhibition of furosemide-sensitive cation transport and activation of sodium-lithium exchange by endogenous circulating factor(s) in Bartter's and Gitelman's syndromes

Background The nature of the cellular abnormality causing hypokalemia, hypotension, and hypovolemia in Bartter's and Gitelman's syndromes is still being debated. In fact, despite the recent descriptions of an array of nonconservative missense or point mutations in some ion transporters and in K+ channel, the lack of detectable defects in some patients suggests that other abnormalities of cell ion homeostasis may be involved in the pathophysiology of these syndromes. The study of the activity of cell ion transporters in patients with these syndromes using red blood cells (RBC) as a cellular model never investigated the role of plasma factor(s) affecting ion transport. Objective To evaluate the effect of plasma from patients with these syndromes on furosemide-sensitive lithium efflux (FSLE) from lithium (Li+)-loaded RBC of healthy subjects in vitro. Methods RBC of healthy controls were loaded with Li+ in the presence of nystatin and FSLE was evaluated in the presence of various concentrations of plasma from controls and patients with the two syndromes. Results Plasma from controls did not affect FSLE (0.08 +/- 0.02 mmol/l cells per h with 1 : 4 vol : vol and 0.07 +/- 0.02 mmol/l cells per h with 1 : 2 vol : vol plasma dilution). In contrast, doubling concentrations of plasma from patients with either syndrome in the efflux solution halved FSLE (from 0.10 +/- 0.0 mmol/l cells per h with 1 : 4 vol : vol to 0.05 +/- 0.01 mmol/l cells per h with 1 : 2 vol : vol plasma dilution, P < 0.05). Na+/Li+ exchange was significantly greater for RBC from patients with either syndrome than it was for RBC from controls (0.373 +/- 0.06 versus 0.257 +/- 0.01 mmol/l cells per h, P < 0.01), but the kinetic properties of furosemide-sensitive Na+-K+-2Cl(-) cotransport were similar. Conclusion These data provide evidence for the hypothesis that plasma factor(s) affect ion transport in patients with these two syndromes. Since FSLE estimates Na+-K+-2Cl(-) cotransport the data suggest that plasma factor( s) contribute( s) to K+ wasting, hypokalemia, and hypotension by inhibiting cotransport in patients with these syndromes. The increase of Na+/Li+ exchange is most likely a secondary phenomenon associated with the hypermineralocorticoid state.