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 liver disease. Plasma AVP remains elevated leading to 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 increased plasma AVP and dilutional hyponatremia. Method We used the Bile duct ligation (BDL) rat model of liver failure for our experiments. 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 plasma AVP using ELISA. Plasma osmolality and hematocrit measurements were also taken. Immunohistochemistry for delta fosB and dopamine beta-hydroxylase (DβH) was performed on brain tissue slices. The slices were viewed using an Olympus microscope (BX41) equipped for epifluorescence and images were taken using Olympus DP70 digital camera with DP manager software (version 2.2.1). The number of immunoreactive cells to ΔFosB and DβH were counted using Image J. Results We found that lesioning of the A1/A2 neurons in the Saporin/BDL group (n=9) caused a decrease in the plasma AVP concentration versus the Vehicle/BDL control group (n=6), p<0.05. However, the number of delta fosB immunoreactive A1/A2 cells was not significantly different. Lesioning of the A1/A2 neurons seemed to normalize osmolality and hematocrit in the BDL group. Although the difference was not statistically significant. Conclusion Our experiments suggests that A1/A2 neurons could be involved in the increased plasma AVP seen in male BDL rats as well as the decreased plasma osmolality.