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Abstract: FR-PO625

Drug-Induced Hyponatremia: Vasopressin-2 Receptor-Dependent and -Independent Pathway

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Kim, Gheun-Ho, Hanyang University College of Medicine, Seoul, Korea (the Republic of)
  • Jo, Chor ho, Hanyang University, Seoul, Korea (the Republic of)
  • Kim, Sua, Hanyang University, Seoul, Korea (the Republic of)
Background

Drugs associated with hyponatremia were traditionally classified into those enhancing vasopressin release and those potentiating the renal action of vasopressin. For the latter mechanism to act, vasopressin-2 receptor would have the pivotal role in activating aquaporin-2 in the collecting duct. However, vasopressin-2 receptor-independent pathways might be activated as well by drugs that induce renal water retention. This preliminary study was undertaken to find antidiuretic drugs acting through vasopressin-2 receptor-independent pathways.

Methods

Five drugs or active metabolites were treated in inner medullary collecting duct suspensions prepared from male Sprague-Dawley rats. The intracellular cAMP levels were determined using a competitive enzyme immunoassay kit to compare the responses with and without tolvaptan (100 nM) cotreatment. Also, dDAVP (10 nM) was used as positive control.

Results

As expected, dDAVP induced an increase in cAMP production (20.7 ± 2.0 vs. 11.4 ± 0.6 pmol/mg protein, P<0.05) Similarly, haloperidol (14.7 ± 0.9 pmol/mg protein, P<0.05), sertraline (18.7 ± 0.9 pmol/mg protein, P<0.05), and carbamazepine (17.3 ± 0.7 pmol/mg protein, P<0.05) had higher levels of cAMP. These responses were almost completely blocked by tolvaptan cotreatment (haloperidol, 8.5 ± 0.5 pmol/mg protein; sertraline, 12.6 ± 1.2 pmol/mg protein; carbamazepine 12.5 ± 0.7 pmol/mg protein, all P<0.05). Notably, the cAMP level was increased by vincristine treatment (16.7 ± 1.6 pmol/mg protein, P<0.05), but not reversed by tolvaptan cotreatment. On the other hand, chlorpropamide did not induce any change in cAMP with and without tolvaptan cotreatment.

Conclusion

As known before, chlorpropamide appears to enhance vasopressin release. Contrary to a previous notion, vincristine may induce water retention via vasopressin-2 receptor-independent pathways. Activation of vasopressin-2 receptor has a role in hyponatremia induced by haloperidol, sertraline, and carbamazepine.

Funding

  • Government Support - Non-U.S.