Endogenous inhibitor of the Na-K-Cl cotransport system in inbred Dahl rats

The primary defect of salt-sensitive Dahl rats is increased NaCl reabsorption in the thick ascending limb of Henleʹs loop (TAHL). We suspected a possible role for CIF (“cotransport inhibitory factor”) a new neurohumoral natriuretic compound inhibiting the luminal Na-K-Cl cotransport system in TAHL. Therefore, we investigated plasmatic levels and urinary CIF excretion in salt-sensitive (SS/JR) and salt-resistant (SR/JR) Dahl rats. SS (n=7) and SR (n=6) rats were put in metabolic cages and were given 2% NaCl to drink. After 10 days of salt-loading, mean blood pressure values were 161.6 ± 3.1 mmHg vs. 118.3 ± 3.4 mmHg in SS/JR rats and SR/JR rats respectively (p < 0.0001). Plasmatic CIF activity, measured as the % plasma dilution required to inhibit 50% of cotransport fluxes (IC50), was 6.4 ± 1.5 % vs. 24.2 ± 5.4 % in SS/JR and SR/JR rats respectively (p < 0.0001). In urines, CIF activity was constantly increased in SS/JR before and all during the whole salt-loading period (after 8 days of salt-loading IC50 was 3.64 ± 0.11 % and 24.2 ± 1.1 % in SS/JR and SR/JR rats respectively, p < 0.0001). Freshly drawn erythrocytes from SS/JR rats loose membrane-bound CIF by repeated washings. Washed SS/JR erythrocytes showed increased cotransport activity (kc = 156.8 ± 12.9 vs. 107.9 ± 7.9 h−1 × 103 in SR/JR, P=0.01). Such increased cotransport activity was strongly correlated with increased urinary CIF excretion, even in the SS/JR group alone (r=0.92, P=0.0014). In conclusion, Dahl salt-sensitive rats exhibit increased plasmatic and urinary CIF levels. These changes may reflect the triggering of a long-term natriuretic mechanism to compensate the increased NaCl reabsorption in the thick ascending limb of Henleʹs loop.