Effects of Vasopressin (AVP) Deficiency and Conivaptan (an AVP Receptors Antagonist) on Liver Physiology and Fibrosis in Rats with Protracted Portacaval Anastomosis

Abstract

Liver fibrosis is due to the over deposition of collagens on the extracellular matrix, causing fibrotic septa and liver failure. Portocaval anastomosis (PCA) is a model of liver disease. Fibrogenesis is stimulated by AVP. We have described the healthy effect of the AVP deficiency, induced by neurointermediate pituitary lobectomy (NIL), on liver functions and cirrhosis. We hypothesize that blocking the AVP receptors with the V1a-V2 AVP receptor antagonist conivaptan (CV) will induce the same healthy effects of NIL on liver fibrosis. Male Wistar rats were divided in 6 groups (8-10 each): Sham surgery (SHAM), PCA, NIL, PCA+NIL, CV and PCA+CV. SHAM, NIL and the 4 groups with PCA were operated at week 0, whereas NIL surgery in the PCA+NIL group was done at week 8. CV treatments (30 mg/day/im/8 weeks) in the CV group started at week 0, whereas in the PCA+CV group started at week 8. NIL and CV groups were sacrificed at week 8, whereas SHAM, PCA, PCA+NIL and PCA+CV groups were sacrificed at week 16. At sacrifice, serum levels of ALT, AST, bilirubin, NH4, urea, albumin and glucose were assessed. Livers were weighed and samples were processed for glycogen content and the other processed for light microscopy analysis (slide tissues stained with H-E, Masson and Sirius red). Results are summarized in Table 1. Table 1. Comparative effects of sham surgery (SHAM), portocaval anastomosis (PCA), neurointermediate pituitary lobectomy (NIL), PCA+NIL, conivaptan (CV) and PCA+CV on body weight, liver weight, glycogen liver content and serum biochemical parameters of liver functions GROUPS SHAM PCA NIL PCA+NIL CV PCA+CV (Basal values) Body weight = ↓ (-29%) ↓ (-22%) (- ↓(-29%) = ↓ (23%) (g) NS vs SHAM NS vs SHAM NS vs SHAM NS vs SHAM Liver weight = ↓ (-54%) = = = ↓ (-22%) (g) p<0.05 vsSHAM NS vsSHAM ALT(U/L) = ↑↑↑ ↑↑↑ = = = AST(U/L) = ↑↑↑ ↑↑↑ ↑↑ = = Total bilirubin (mg/dL) = ↑↑↑ = = = = Unconjugated bilirubin (mg/dL) = ↑↑↑ = = = = Albumin(g/dL) = = = = = = Glucose (mg/dL) = = = = = ↓↓↓ NH4(µg/dL) = ↑↑↑ = = = ↑↑↑ Urea(mg/dL) = ↓↓↓ = = = = Liver glycogen(mg/gr of tissue) = ↓↓↓ = = = = Liver histopathology. In the PCA group, mainly in the periportal areas, small inflammatory infiltrates and big deposits of collagen were developed. Compared with the PCA, PCA+NIL and PCA+CV groups showed less inflammatory areas and much less collagen deposits. Conclusions, all results showed that: 1) AVP deficiency restores to normality the liver physiology and histology in the protracted liver disease, 2) Except the alterations in glycemia and NH4 metabolism, similar restored effects in liver histophysiology were induced by CV, suggesting that similar cellular mechanisms are involved, 3) Results strongly support that AVP is an important role in the pathophysiology of the liver fibrosis and possibly other fibrotic diseases.