Role of A1/A2 Neurons in the Dysregulation of Vasopressin Release and Dilutional Hyponatremia in Liver Disease

Abstract Purpose: Inappropriate release of arginine vasopressin (AVP) has been linked to dilutional hyponatremia in patients with cirrhosis. Elevated Plasma AVP causes water retention, hypoosmolality, ascites formation, and a perceived decrease in plasma volume. The perceived decrease in plasma volume is sensed by the A1/A2 norepinephrine neurons in the caudal ventrolateral medulla (CVLM) and the nucleus tractus solitarius (NTS) respectively. We propose that these neurons provide the initial stimuli that activates AVP-secreting neurons in the supraoptic nucleus (SON) leading to inappropriate AVP release and dilutional hyponatremia. Method: Adult male rats were bile duct ligated (BDL) to model cirrhosis. Selective lesioning of the SON-projecting A1/A2 norepinephrine neurons was achieved using anti-DβH-Saporin [IT-03] (Advanced Targeting Systems). Plasma copeptin concentration was measured as a surrogate marker for AVP using ELISA. Plasma osmolality and hematocrit measurements were also taken. Immunohistochemistry for delta FosB and dopamine beta-hydroxylase (DβH) was performed on brain slices. Results: Lesions of the A1/A2 neurons projecting to SON (Saporin/BDL n=9) was associated with decreased copeptin as compared to BDL controls (Vehicle/BDL, n=6, p< 0.05). However, the number of delta FosB immunoreactive A1/A2 cells was not significantly different. While A1/A2 lesions seemed to normalize osmolality and hematocrit in the BDL rats, the trends were not statistically significant. Conclusion: The result suggests that A1/A2 neurons could contribute to increased plasma AVP seen in male BDL rats, but there could be other contributing factors preventing a recovery of plasma osmolality.