Osmotic regulation during acute and chronic osmotic challenges in rats with prolonged TRPV4 blockade

The transient receptor potential vanilloid 4 (TRPV4) is an osmotically activated cation channel that is expressed in osmotic sensing sites in the brain and in renal tubules. Previous studies suggest that osmoregulation is abnormal in TRPV4−/− mice although the results are conflicting. We tested the hypothesis that TRPV4 mediates osmoregulation during acute and chronic hypoosmotic or hyperosmotic challenges. Sprague Dawley rats were administered the selective TRPV4 antagonist GSK2193874A (30 mg/kg/d) or vehicle for at least four days and then challenged with acute water load (30 ml/kg), acute 2.0% NaCl load (30 ml/kg), chronic 2.0% NaCl drinking water (7 days), or chronic dDAVP (5ng/hr, s.c. for 7 days). TRPV4 blockade in rats had no effect on urine flow, electrolyte or osmolar excretions and plasma electrolyte concentrations or osmolality during normal conditions, acute hypoosmotic challenge or chronic hypoosmotic challenge. Acute hyperosmotic challenge transiently increased urine flow, electrolyte and osmolar excretions and plasma AVP, which were attenuated by GSK2193874A. In contrast, TRPV4 blockade had no effect on the renal excretory response or plasma AVP and osmolality responses to chronic hyperosmotic challenge. These data suggest that TRPV4 may help facilitate the acute response to hyperosmotic challenge but has no major role in long-term osmotic regulation.