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The effect of Ca2+ and calcimimetics on NaCl transport was investigated in the in vitro isolated microperfused mouse thin ascending limb of Henle’s loop. In the presence of a transmural NaCl gradient, the transepithelial diffusional potential was 13.7 ± 0.4 mV ( n = 17). When the Ca2+ in the bath was increased from 1.5 to 4.5 mM at 37°C, the relative permeability of Na+ to Cl− ( PNa /PCl) estimated from the diffusional voltage deflection due to the transepithelial NaCl gradient ( Vd) changed from 0.371 ± 0.017 to 0.341 ± 0.015 ( n = 10, P < 0.0001). When the Ca2+ in the lumen was increased from 1.5 to 4.5 mM, the PNa /PCl decreased from 0.349 ± 0.013 to 0.330 ± 0.013 ( n = 5, P < 0.002). The addition of 0.1 mM neomycin and 0.2 mM gentamicin to the bath or lumen also decreased the PNa /PCl. The same effect on PNa /PCl of Ca2+ and calcimimetics occurred in ClC-K1 (kidney-specific chloride channel) knockout mice. The addition of 300 μg/ml protamine to the bath strongly inhibited changes to PNa /PCl induced by basolateral Ca2+. These data indicate that ambient Ca2+ and calcimimetics inhibit Na+ transport in the thin ascending limb, which is known to occur via the paracellular shunt pathway. Our observations strongly suggest that Ca2+ is involved in the regulation of paracellular Na+ permeability in the thin ascending limbs. [ABSTRACT FROM AUTHOR]