pituitrin and Liver-Failure

Hyponatremia due to elevated arginine vasopressin (AVP) secretion increases mortality in liver failure patients. The mechanisms causing dysregulation of AVP secretion are unknown. Our hypothesis is that inappropriate AVP release associated with liver failure is due to increased brain-derived neurotrophic factor (BDNF) in the supraoptic nucleus (SON). BDNF diminishes GABAA inhibition in SON AVP neurons by increasing intracellular chloride through tyrosine receptor kinase B (TrkB) activation and downregulation of K+/Cl- cotransporter 2 (KCC2). This loss of inhibition could increase AVP secretion. This hypothesis was tested using shRNA against BDNF (shBDNF) in the SON in bile duct ligated (BDL) male rats. All BDL rats had significantly increased liver weight (p < 0.05; 6-9) compared to shams. BDL rats with control -shRNA injections (BDL scrambled [SCR]) developed hyponatremia with increased plasma AVP and copeptin (CPP; all p < 0.05; 6-9) compared to sham groups. This is the first study to show that phosphorylation of TrkB is significantly increased along with significant decrease in phosphorylation of KCC2 in BDL SCR rats compared to the sham rats (p < 0.05;6-8). Knockdown of BDNF in the SON of BDL rats (BDL shBDNF) significantly increased plasma osmolality and hematocrit compared to BDL SCR rats (p < 0.05; 6-9). The BDL shBDNF rats had significant (p < 0.05; 6-9) decreases in plasma AVP and CPP concentration compared to BDL SCR rats. The BDNF knockdown also significantly blocked the increase in TrkB phosphorylation and decrease in KCC2 phosphorylation (p < 0.05; 6-8). The results indicate that BDNF produced in the SON contributes to increased AVP secretion and hyponatremia during liver failure.

Topics: Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Hyponatremia; Liver Failure; Male; Neurons; Rats; Supraoptic Nucleus; Vasopressins

Bile duct ligation (BDL) causes congestive liver failure that initiates hemodynamic changes, resulting in dilutional hyponatremia due to increased water intake and vasopressin release. This project tested the hypothesis that angiotensin signaling at the subfornical organ (SFO) augments drinking behavior in BDL rats. A genetically modified adeno-associated virus containing short hairpin RNA (shRNA) for ANG II receptor subtype 1a (AT1aR) gene was microinjected into the SFO of rats to knock down expression. Two weeks later, BDL or sham surgery was performed. Rats were housed in metabolic chambers for measurement of fluid and food intake and urine output. The rats were euthanized 28 days after BDL surgery for analysis. A group of rats was perfused for immunohistochemistry, and a second group was used for laser-capture microdissection for analysis of SFO AT1aR gene expression. BDL rats showed increased water intake that was attenuated in rats that received SFO microinjection of AT1aR shRNA. Among BDL rats treated with scrambled (control) and AT1aR shRNA, we observed an increased number of vasopressin-positive cells in the supraoptic nucleus that colocalized with ΔFosB staining, suggesting increased vasopressin release in both groups. These results indicate that angiotensin signaling through the SFO contributes to increased water intake, but not dilutional hyponatremia, during congestive liver failure.

Topics: Animals; Behavior, Animal; Bile Ducts; Dependovirus; Disease Models, Animal; Down-Regulation; Drinking Behavior; Gene Knockdown Techniques; Genetic Vectors; Hyponatremia; Ligation; Liver Failure; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; RNA Interference; RNA, Small Interfering; Signal Transduction; Sodium; Subfornical Organ; Transduction, Genetic; Vasopressins

Hepatorenal syndrome (HRS) is a serious complication of end-stage liver disease that was associated with a fatal prognosis in the past. A clear definition of HRS and increased understanding of the pathogenesis have led to considerable progress in therapy outcome.. The major pathogenetic factor is vasodilation of the mesenteric circulation with arterial underfilling and consecutive renal vasoconstriction.. Restoration of an effective arterial blood volume can be achieved by the combination of vasopressor therapy (terlipressin, norepinephrine), in combination with volume expansion (albumin) with a success rate of up to 75%. Restoration of the effective arterial blood volume may also be achieved by implantation of a transjugular intrahepatic portosystemic stent (TIPS). This has also been successful in up to 50% of patients in selected cohorts. Finally, extracorporeal liver support systems based on exchange or detoxification of albumin have been successfully employed in a number of patients. Liver transplantation remains the only principal therapy of HRS as this is the single measure with a curative intent. All other forms of therapy are palliative but may serve as a bridge to liver transplantation.

Topics: Adrenergic alpha-Agonists; Fluid Therapy; Hepatorenal Syndrome; Humans; Kidney; Liver Failure; Liver Transplantation; Mesenteric Arteries; Prognosis; Renal Dialysis; Serum Albumin; Survival Rate; Vasoconstriction; Vasodilation; Vasopressins

Pretransplant renal function is the major determinant of survival after liver transplantation (LTx). Patients with hepatorenal syndrome (HRS) have a poor outcome after LTx compared with patients transplanted without HRS.. To analyze the impact of treatment of HRS before LTx on outcome after transplantation.. The outcome of patients with HRS (n=9) treated with vasopressin analogues before LTx was compared with that of a contemporary control group of patients without HRS (n=27) matched by age, severity of liver failure, and type of immunosuppression.. Cases and controls were similar with respect to pretransplantation characteristics. Three-year survival probability was similar between the two groups (HRS-treated: 100% vs control: 83%, P=0.15). No significant differences were found between the two groups with respect to the incidence of impairment of renal function after LTx (HRS-treated: 22% vs control: 30%), severe infections (22 vs 33%), acute rejection (33 vs 41%), days in Intensive Care Unit (6+/-1 vs 8+/-1), days in hospital (27+/-4 vs 31+/-4), and transfusion requirements (11+/-3 vs 10+/-2 units).. Patients with HRS treated with vasopressin analogues before LTx have a posttransplantation outcome similar to that of patients transplanted with normal renal function. These results suggest that HRS should be treated before LTx.

Topics: Case-Control Studies; Female; Hepatorenal Syndrome; Humans; Kidney; Liver Failure; Liver Transplantation; Lypressin; Male; Middle Aged; Ornipressin; Postoperative Complications; Postoperative Period; Prognosis; Survival Analysis; Terlipressin; Treatment Outcome; Vasoconstrictor Agents; Vasopressins