Control of renal endothelin release by medullary osmolarity

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Exposure of renal tubular epithelial cells to high Na+ concentrations or hyperosmotic solutions enhances endothelin-1 (ET-1) production and release in vitro. Whilst providing a plausible mechanism for the increased urinary ET-1 excretion observed during high salt intake, it is not known whether infusion of hyperosmotic saline into the renal medulla would produce a similar effect in vivo. Therefore we tested the hypothesis that acute renal medullary interstitial infusion of a hyperosmotic NaCl solution will enhance urinary excretion of ET-1 in anesthetized rats. Isosmotic saline (NaCl at 284 mOsmol/kg H2O; 0.5 ml/h) was infused into the medullary interstitium of the left kidney during a 1 h equilibration period and 30 min baseline period, followed by either isosmotic or hyperosmotic NaCl (1714 mOsmol/kg H2O) for two further 30 min periods. Compared to isosmotic NaCl, infusion of hyperosmotic NaCl into the renal medulla significantly increased the rate of ET-1 excretion in the urine (P<0.05; from 0.30±0.02 to 0.49±0.03 fmol/min), increased urine flow (P<0.05) and increased the rate of Na+ excretion (P<0.05) without affecting mean arterial pressure. To determine whether the stimulus for ET-1 release was osmolarity per se or NaCl specifically, the experiment was repeated in separate groups of rats using mannitol rather than NaCl. Compared to an isosmotic mannitol solution (300 mOsmol/kg H2O), infusion of hyperosmotic mannitol (1820 mOsmol/kg H2O) significantly increased the rate of ET-1 excretion (P<0.05; from 0.54±0.03 to 0.94±0.12 fmol/min). Thus exposure of the renal medulla to hyperosmotic concentrations of NaCl stimulates renal ET-1 release in vivo. High osmolarity, rather than NaCl concentration per se, appears to act as the stimulus for this effect, consistent with the hypothesis that medullary osmolarity is an important regulator of renal medullary endothelin synthesis.