Intracerebroventricular losartan infusion modulates angiotensin II type 1 receptor expression in the subfornical organ and drinking behaviour in bile-duct-ligated rats

New Findings: • What is the central question of this study? Dilutional hyponatraemia increases morbidity and mortality associated with heart or liver failure. Vasopressin release and increased fluid intake contribute to hyposmolality, but the underlying mechanisms are poorly understood. Our study tests the role of the central renin-angiotensin system in hyposmolality in a rat model of liver failure. • What is the main finding and its importance? Hepatic cirrhosis produced hyposmolality, with increased water intake and increased angiotensin receptors in the subfornical organ, a forebrain circumventricular organ. Central infusions of the angiotensin receptor blocker losartan normalized both water intake and the increase in angiotensin receptors. However, the rats remained hyposmotic, suggesting a selective role for the central renin-angiotensin system. Bile duct ligation (BDL) causes congestive liver failure that initiates haemodynamic changes, including peripheral vasodilatation and generalized oedema. Peripheral vasodilatation is hypothesized to activate compensatory mechanisms, including increased drinking behaviour and neurohumoral activation. This study tested the hypothesis that changes in the expression of angiotensin II type 1 receptor (AT₁R) mRNA and protein in the lamina terminalis are associated with BDL-induced hyposmolality in the rat. All rats received either BDL or sham-ligation surgery. The rats were housed in metabolic chambers for measurement of fluid and food intake and urine output. Expression of AT₁R in the lamina terminalis was assessed by Western blot and quantitative real-time PCR (RT-qPCR). Average baseline water intake increased significantly in BDL rats compared with sham-operated rats, and upregulation of AT₁R protein and AT_1aR mRNA were observed in the subfornical organ of BDL rats. Separate groups of BDL and sham-ligated rats were instrumented with minipumps filled with either losartan (2.0 μg μl^-1) or 0.9% saline for chronic intracerebroventricular or chronic subcutaneous infusion. Chronic intracerebroventricular losartan infusion attenuated the increased drinking behaviour and prevented the increased abundance of AT₁R protein in the subfornical organ in BDL rats. Chronic subcutaneous infusion did not affect water intake or AT₁R abundance in the subfornical organ. The data presented here indicate a possible role of increased central AT₁R expression in the regulation of drinking behaviour during congestive cirrhosis.