Norepinephrine innervation of the supraoptic nucleus contributes to increased copeptin and dilutional hyponatremia in male rats

Abstract

Dilutional hyponatremia associated with liver cirrhosis is due to inappropriate release of arginine vasopressin (AVP). Elevated plasma AVP causes water retention resulting in a decrease in plasma osmolality. Cirrhosis, in this study caused by ligation of the common bile duct (BDL), leads to a decrease in central vascular blood volume and hypotension, stimuli for non-osmotic AVP release. The A1/A2 neurons stimulate the release of AVP from the supraoptic nucleus (SON) in response to non-osmotic stimuli. We hypothesize that the A1/A2 noradrenergic neurons support chronic release of AVP in cirrhosis leading to dilutional hyponatremia. Adult, male rats were anesthetized with 2-3% isoflurane (mixed with 95% O2/5% CO2) and injected in the SON with anti-DBH saporin (DSAP) or vehicle followed by either BDL or sham surgery. Plasma copeptin, osmolality, and hematocrit were measured. Brains were processed for delta FosB, dopamine β-hydroxylase (DBH) and AVP immunohistochemistry. DSAP injection: i) significantly reduced the number of DBH immunoreactive A1/A2 neurons (A1, P<0.0001; A2, P=0.0014), ii) significantly reduced the number of A1/A2 neurons immunoreactive to both DBH and delta FosB positive neurons (A1, P=0.0015; A2, P<0.0001), iii) reduced the number of SON neurons immunoreactive to both AVP and delta FosB (P<0.0001), iv) prevented the increase in plasma copeptin observed in vehicle injected BDL rats (P=0.0011) and v) normalized plasma osmolality and hematocrit (plasma osmolality, P =0.0475; hematocrit, P = 0.0051) as compared to vehicle injection. Our data suggest that A1/A2 neurons contribute to increased plasma copeptin and hypoosmolality in male BDL rats.

Effects of bile duct ligation on the inhibitory control of supraoptic vasopressin neurons

“…Our results show that liver cirrhosis was successfully induced in the BDL rats due to their relatively higher liver weight to bodyweight ratio as compared to the sham rats. This was consistent with our previous studies 17,18,39,41 . Also, plasma osmolality and hematocrit values in the BDL rats were significantly lower than those from sham rats.…”

“…[15][16][17] A recent publication from our laboratory has suggested that the increased plasma AVP concentration associated with these disorders could be caused in part by increased stimulation of SON AVP neurons by noradrenergic A1 and A2 neurons due to a decreased central blood volume. 18 This is consistent with the traditional view that inappropriate AVP release in cirrhosis is due to a change in non-osmotic regulatory pathways. 19 However, since patients with liver failure are hypoosmotic, a stimulus that inhibits the release of AVP, it suggests a possible failure of inhibitory mechanisms could play a role in the increased plasma AVP and dilutional hyponatremia observed.…”

“…Previous studies have shown that similar changes occur in animal models of portal hypertension and cirrhosis 15–17 . A recent publication from our laboratory has suggested that the increased plasma AVP concentration associated with these disorders could be caused in part by increased stimulation of SON AVP neurons by noradrenergic A1 and A2 neurons due to a decreased central blood volume 18 . This is consistent with the traditional view that inappropriate AVP release in cirrhosis is due to a change in non‐osmotic regulatory pathways 19 .…”

“…This mechanism partly explains the impaired inhibition of AVP neurons during a state of hypoosmolality as occurs in liver cirrhosis. Additionally, the increased cell firing rate in response to GABA A receptor activation could contribute to the increased plasma AVP observed in this model from previous studies 18,39 . Increases in hippocampal and cortical BDNF and norepinephrine are observed in male rats after vagal nerve stimulation 57 .…”

“…Additionally, the increased cell firing rate in response to GABA A receptor activation could contribute to the increased plasma AVP observed in this model from previous studies. 18,39 Increases in hippocampal and cortical BDNF and norepinephrine are observed in male rats after vagal nerve stimulation. 57 We propose a similar mechanism via A1/A2 neurons that would increase BDNF and change the activity of cation chloride cotransporters leading to impaired GABA inhibition.…”