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Inhibition of neuronal apoptosis and axonal regression ameliorates sympathetic atrophy and hemodynamic alterations in portal hypertensive rats.

ABSTRACT: BACKGROUND AND AIM:A neuronal pathway participates in the development of portal hypertension: blockade of afferent sensory nerves in portal vein ligated (PVL) rats simultaneously prevents brain cardiovascular regularory nuclei activation, neuromodulator overexpression in superior mesenteric ganglia, sympathetic atrophy of mesenteric innervation and hemodynamic alterations. Here we investigated in PVL rats alterations in neuromodulators and signaling pathways leading to axonal regression or apoptosis in the superior mesenteric ganglia and tested the effects of the stimulation of neuronal proliferation/survival by using a tyrosine kinase receptor A agonist, gambogic amide. RESULTS:The neuronal pathway was confirmed by an increased neuronal afferent activity at the vagal nodose ganglia and the presence of semaphorin3A in sympathetic pre-ganglionic neurons at the intermediolateral nucleus of the spinal cord of PVL rats. Expression of the active form of tyrosine kinase receptor A (phosphorylated), leading to proliferation and survival signaling, showed a significant reduction in PVL comparing to sham rats. In contrast, the apoptotic and axonal retraction pathways were stimulated in PVL, demonstrated by a significant overexpression of semaphorin 3A and its receptor neuropilin1, together with increases of cleaved caspase7, inactive poly(ADP-ribose) polymerase and Rho kinase expression. Finally, the administration of gambogic amide in PVL rats showed an amelioration of hemodynamic alterations and sympathetic atrophy, through the activation of survival pathways together with the inhibition of apoptotic cascades and Rho kinase mediated axonal regression. CONCLUSION:The adrenergic alteration and sympathetic atrophy in mesenteric vessels during portal hypertension is caused by alterations on neuromodulation leading to post-ganglionic sympathetic regression and apoptosis and contributing to splanchnic vasodilation.

SUBMITTER: Ezkurdia N

PROVIDER: S-EPMC3882227 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Inhibition of neuronal apoptosis and axonal regression ameliorates sympathetic atrophy and hemodynamic alterations in portal hypertensive rats.

Ezkurdia Nahia N Raurell Imma I Rodríguez Sarai S González Antonio A Esteban Rafael R Genescà Joan J Martell María M

PloS one 20140106 1

<h4>Background and aim</h4>A neuronal pathway participates in the development of portal hypertension: blockade of afferent sensory nerves in portal vein ligated (PVL) rats simultaneously prevents brain cardiovascular regularory nuclei activation, neuromodulator overexpression in superior mesenteric ganglia, sympathetic atrophy of mesenteric innervation and hemodynamic alterations. Here we investigated in PVL rats alterations in neuromodulators and signaling pathways leading to axonal regression ...[more]

PMID: 24400086

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Project description:BackgroundThe mechanisms of intradialytic increases in blood pressure are not well defined. The present study was undertaken to assess the role of autonomic nervous system activation during intradialytic hypertensive episodes.Methodology/principal findingsContinuous interbeat intervals (IBI) and systolic blood pressure (SBP) were monitored during hemodialysis in 108 chronic patients. Intradialytic hypertensive episodes defined as a period of at least 10 mmHg increase in SBP between the beginning and the end of a dialysis session or hypertension resistant to ultrafiltration occurring during or immediately after the dialysis procedure, were detected in 62 out of 113 hemodialysis sessions. SBP variability, IBI variability and baroreceptor sensitivity (BRS) in the low (LF) and high (HF) frequency ranges were assessed using the complex demodulation technique (CDM). Intradialytic hypertensive episodes were associated with an increased (n = 45) or decreased (n = 17) heart rate. The maximal blood pressure was similar in both groups. In patients with increased heart rate the increase in blood pressure was associated with marked increases in SBP and IBI variability, with suppressed BRS indices and enhanced sympatho-vagal balance. In contrast, in those with decreased heart rate, there were no significant changes in the above parameters. End-of-dialysis blood pressure in all sessions associated with hypertensive episode was significantly higher than in those without such episodes. In logistic regression analysis, predialysis BRS in the low frequency range was found to be the main predictor of intradialytic hypertension.Conclusion/significanceOur data point to sympathetic overactivity with feed-forward blood pressure enhancement as an important mechanism of intradialytic hypertension in a significant proportion of patients. The triggers of increased sympathetic activity during hemodialysis remain to be determined. Intradialytic hypertensive episodes are associated with higher end-of-dialysis blood pressure, suggesting that intradialytic hypertension may play a role in generation of interdialytic hypertension.

Project description:Background:Portal hypertensive polyps in patients with portal hypertension are described. Aims:The most significant and serious complication in liver cirrhosis proves to be portal hypertension. Polypoid lesions, which can be seen in the stomach as endoscopic finding in patients with portal hypertension, have not quite been defined in the literature. The aim of this study, therefore, was to define polypoid lesion formation due to portal hypertension in the upper gastrointestinal system in patients with portal hypertension. Study Design. Cross-sectional study. Methods:The study covered a group of patients with liver cirrhosis and a healthy control group that did not have portal hypertension. All individuals covered by the study received upper GI endoscopy, while the endoscopic features and pathological characteristics of the identified polypoid lesions were defined. Standard histological criteria were used in polyp diagnosis. Results:A total of 400 individuals were included in the study. Upper GI endoscopy was performed for 200 patients with liver cirrhosis and another 200 healthy individuals with no portal hypertension in the control group. When the cases were gastroscopically assessed with regard to polypoid lesion presence, it was seen that a total of 87 (21.8%) individuals had polyps. While 67 (33.5%) cirrhotic patients were identified to have polyps, 20 (10%) individuals in the healthy control group had polyps. When the results of those with liver cirrhosis who received esophageal variceal endoscopic band ligation (EVL) and who did not were compared, it was observed that a higher number of individuals in the group with EVL had polypoid lesions. When the patient and control groups were compared as to Helicobacter pylori presence, the results showed that it was slightly higher in the dyspepsia group but the difference was not statistically significant (p > 0.05). Conclusion:Portal hypertension-associated polypoid lesions are common in advanced liver cirrhosis cases. The pathological analyses of these polyps pointed out that they were all benign and no malignant cases were detected. It was argued that these polypoid lesions, referred to as portal hypertensive polyps, were associated with elevated angiogenesis in the gastric mucosa.

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Inhibition of neuronal apoptosis and axonal regression ameliorates sympathetic atrophy and hemodynamic alterations in portal hypertensive rats.

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Inhibition of neuronal apoptosis and axonal regression ameliorates sympathetic atrophy and hemodynamic alterations in portal hypertensive rats.

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