Calcium receptors located in fibrotic septa: a new target to reduce portal pressure in liver cirrhosis

2013 ◽  
Vol 125 (2) ◽  
pp. 67-75 ◽  
Author(s):  
Giovanni Sansoè ◽  
Manuela Aragno ◽  
Raffaella Mastrocola ◽  
Claudia Paternostro ◽  
Maurizio Parola
Keyword(s):  
Liver Cirrhosis ◽  
Arterial Pressure ◽  
Portal Pressure ◽  
Hormonal Status ◽  
Experimental Cirrhosis ◽  
Indirect Immunofluorescence Staining ◽  
Carbon Tetrachloride Administration ◽  
Specific Stimulation ◽  
And Function ◽  
Calcium Receptors

In rats with experimental liver cirrhosis, the kidney contains reduced amounts of membrane-bound CaRs (calcium-sensing receptors), and the specific stimulation of CaRs causes the generation of PGE2 (prostaglandin E2), renal vasodilation and increased natriuresis. CaR content and function in the liver of cirrhotic rats are unknown. To assess the activity of this Ca2+-dependent vasomotor system, we evaluated the effects of intravenous administration of PolyAg (poly-L-arginine), a selective CaR agonist, on hormonal status, portal haemodynamics, MAP (mean arterial pressure) in rats with liver cirrhosis induced by chronic CCl4 (carbon tetrachloride) administration. Two groups of eight control rats received intravenously 1 ml of 5% (w/v) glucose solution alone or containing 0.5 mg of PolyAg; two groups of ten cirrhotic rats were administered vehicle or PolyAg. Compared with controls, at baseline cirrhotic rats showed higher portal pressure (P<0.01), lower estimated functional liver plasma flow, measured as CICG (Indocyanine Green clearance) (P<0.03) and reduced hepatic protein content of CaRs (P<0.03), which were located mainly in sub-endothelial layers of portal venules and in myofibroblasts of fibrotic septa (immunohistochemistry and indirect immunofluorescence staining of liver sections). In cirrhotic animals, 0.5 mg of PolyAg decreased portal pressure (P<0.01) and increased CICG (P<0.05), without effects on arterial pressure and hormonal status. In conclusion, the present study provides evidence that in experimental cirrhosis agonists of liver CaRs elicit beneficial portal hypotensive effects by reducing intrahepatic resistance to portal flow. Moreover, these drugs are devoid of effects on systemic haemodynamics.

Overexpression of kidney neutral endopeptidase (EC 3.4.24.11) and renal function in experimental cirrhosis

2006 ◽  
Vol 290 (6) ◽  
pp. F1337-F1343 ◽  
Author(s):  
G. Sansoè ◽  
M. Aragno ◽  
R. Mastrocola ◽  
J. C. Cutrin ◽  
S. Silvano ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Specific Inhibitor ◽  
Free Water ◽  
Plasma Renin ◽  
Neutral Endopeptidase ◽  
Experimental Cirrhosis ◽  
Proximal Tubule Cells ◽  
Advanced Cirrhosis ◽  
Normal Humans ◽  
Renal Proximal Tubule Cells

Neutral endopeptidase degrades atrial natriuretic peptide (ANP) and bradykinin and may generate endothelin-1 from big-endothelin. In advanced cirrhosis, sodium retention is accompanied by elevated plasma ANP levels, and infusion of ANP causes hypotension, but in normal humans increasing the concentration of ANP through the inhibition of neutral endopeptidase, localized in renal proximal tubule cells, causes natriuresis without any arterial pressure drop. The purpose of this study was the assessment of kidney neutral endopeptidase expression and responses to candoxatrilat (a specific inhibitor of this enzyme) in rats with CCl4-induced cirrhosis. Two groups of control rats ( n = 5) were injected with vehicle or 3 mg/kg candoxatrilat. Three groups of cirrhotic rats with ascites ( n = 10) received vehicle alone or 3 or 10 mg/kg candoxatrilat. In cirrhotic rats, Western blot analysis revealed a 170% increase in renal neutral endopeptidase protein content ( P < 0.03), mainly in the proximal nephron and macula densa, and both candoxatrilat dosages increased plasma ANP levels, urinary volume, and urinary excretion of sodium, ANP, and cGMP compared with vehicle alone (all P < 0.03). Candoxatrilat (10 mg/kg) also reduced tubular solute-free water reabsorption ( P < 0.03) in cirrhotic rats, but renal blood flow, arterial pressure, and plasma renin activity were unaffected. Neutral endopeptidase inhibition has natriuretic and aquaretic actions in cirrhosis without any effect on blood pressure and kidney perfusion due to a significant overexpression of this enzyme in renal cortex.

Effect of Narcotic Agents and of Bleeding on Systemic and Renal Haemodynamics in Healthy and CCl4-treated Cirrhotic Rats

1997 ◽  
Vol 93 (6) ◽  
pp. 549-556 ◽  
Author(s):  
G. Van Roey ◽  
P. Lijnen ◽  
R. Verbesselt ◽  
A. Verbruggen ◽  
J. Fevery
Keyword(s):  
Arterial Pressure ◽  
Plasma Volume ◽  
Renal Plasma Flow ◽  
Portal Pressure ◽  
Plasma Renin ◽  
Repeated Measurements ◽  
Peripheral Vasodilatation ◽  
Profound Hypotension ◽  
Awake Rat ◽  
Related Mortality

1. The haemodynamic effects of different narcotic agents have been tested in healthy rats and in rats with cirrhosis. 2. Pentobarbital suppresses the sympathetic nervous system. Susceptibility to ketamine is unpredictable, leading to both insufficient pain relief and narcosis related mortality. The combination diazepam—fluanisone induces profound hypotension. After insertion of catheters, awake, freely moving rats are stable and not distressed. This allows repeated measurements after manipulation. Moreover, procedure-related mortality is low and rats have a better stress response. 3. In the awake animal, arterial pressure is 126 ± 10 for healthy animals, and 111 ± 16 and 102 ± 10 mmHg for cirrhotic animals without and with ascites, respectively (P = 0.018). The respective values for portal pressure are 6.9 ± 1.4, 11.6 ± 2.5 and 16.2 ± 2.9 mmHg (P = 0.0001). After a bleeding, arterial pressure is better preserved than portal pressure in the three groups (P < 0.0001). Plasma volume in cirrhotic rats exceeds that of healthy rats. Plasma renin activity, aldosterone and catecholamines do not differ between the groups studied. In cirrhotic rats with and without ascites, glomerular filtration rate tends to be higher (P = 0.12), renal plasma flow is elevated (P = 0.001) and nitration fraction is lower (P = 0.002) than in healthy rats. 4. In conclusion, haemodynamic experiments in the cirrhotic rat should be performed in the awake rat. Arterial hypotension, impaired filtration fraction, enlarged plasma volume and portal hypertension are present in cirrhosis before the development of ascites. This can as well be explained by splanchnic pooling of blood, as by peripheral vasodilatation. The decrease in portal pressure with preserved arterial pressure after a bleeding protects cirrhotic rats from ongoing variceal bleeding.

scholarly journals AN EXPERIMENTAL STUDY INTO THE CAUSE OF THE INCREASED PORTAL PRESSURE IN PORTAL CIRRHOSIS

1907 ◽  
Vol 9 (1) ◽  
pp. 93-104 ◽  
Author(s):  
Frederick C. Herrick
Keyword(s):  
Arterial Pressure ◽  
Portal Pressure ◽  
Normal Liver ◽  
Volume Flow ◽  
Cirrhotic Liver ◽  
Return Flow ◽  
Hepatic Veins ◽  
Portal Cirrhosis ◽  
Arterial Inflow ◽  
Flow Through

1. In the liver of portal cirrhosis there is a far freer communication between the arterial and portal currents than in the normal liver. 2. Factors contributing to the increased portal pressure in portal cirrhosis are (1) the direct communication of the arterial pressure to the portal vessels through dilated capillaries, (2) the larger volume-flow of the hepatic artery in proportion to the portal flow in cirrhosis as compared to that in the normal liver. 3. A portal cirrhotic liver gives passage to an amount of portal fluid proportionate to .its weight. There is no obstruction to the portal vessels from fibrosis in the large portal cirrhotic liver. 4. From an arterial inflow there is a free return flow through the portal as well as through the hepatic veins in both normal and cirrhotic livers. 5. From a portal inflow the return is through the hepatic vein only. The Gad's theory of valves and the arterial capillary network account for this fact. 6. The portal pressure has a decided influence on the arterial volume-flow and vice versa. This influence is more marked in the cirrhotic than in the normal liver. 7. The communication of the arterial pressure to the portal pressure is an important factor in an explanation of the increased portal pressure in portal cirrhosis.

Left and right ventricular morphology and function in athletes with elevated pulmonary systolic arterial pressure

2018 ◽  
Vol 35 (6) ◽  
pp. 769-776 ◽  
Author(s):  
Oana Mirea ◽  
Oana M. Corîci ◽  
Octavian Istrătoaie ◽  
Ionuț Donoiu ◽  
Maria Iancău ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Right Ventricular ◽  
Systolic Arterial Pressure ◽  
Left And Right ◽  
And Function

scholarly journals Serum levels of bone sialoprotein correlate with portal pressure in patients with liver cirrhosis

PLoS ONE ◽  
2020 ◽  
Vol 15 (4) ◽  
pp. e0231701 ◽  
Author(s):  
Fabian Benz ◽  
Andreas Bogen ◽  
Michael Praktiknjo ◽  
Christian Jansen ◽  
Carsten Meyer ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Pressure ◽  
Serum Levels ◽  
Bone Sialoprotein

Splanchnic blood flow in the monkey during hemorrhagic shock

1965 ◽  
Vol 208 (2) ◽  
pp. 265-269 ◽  
Author(s):  
Francis L. Abel ◽  
John A. Waldhausen ◽  
Ewald E. Selkurt
Keyword(s):  
Blood Flow ◽  
Arterial Pressure ◽  
Portal Vein ◽  
Hemorrhagic Shock ◽  
Hepatic Vein ◽  
Venous Pressure ◽  
Portal Pressure ◽  
Mesenteric Arteries ◽  
Splanchnic Blood Flow

Blood flow in the celiac and superior mesenteric arteries was measured in nine Macaca monkeys during a standardized hemorrhagic shock procedure. Simultaneous pressures were obtained from the hepatic vein, portal vein, and aorta. Each animal was bled rapidly to an arterial pressure of 40 mm Hg and maintained at this level until 30% of the bled volume had spontaneously reinfused. The remaining blood was then rapidly reinfused and the animal observed until death. The results show a lack of overshoot of venous pressure on reinfusion, grossly pale intestines with some microscopic congestive changes, and a decrease in splanchnic conductance throughout the postinfusion period. Hepatic venous pressure exceeded portal pressure in six of the nine animals during the period of hemorrhage. The results are interpreted as indicative of insignificant splanchnic pooling during hemorrhagic shock in this animal.

scholarly journals HEMOPOIEITC SPLEEN COLONY STUDIES

1967 ◽  
Vol 125 (4) ◽  
pp. 703-720 ◽  
Author(s):  
J. L. Curry ◽  
J, J. Trentin ◽  
N. Wolf
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Morphological Differentiation ◽  
Erythroid Differentiation ◽  
Colony Growth ◽  
The Other ◽  
Colony Development ◽  
Undifferentiated Cells ◽  
Specific Stimulation ◽  
And Function

The polycythemic repression of erythropoiesis and the restoration of erythropoiesis by specific stimulation were studied in the spleen colony system in irradiated mice. 1. A 5 day period of erythropoietin stimulation (exogenous erythropoietin) or repression (polycythemia) of the bone marrow donor only, does not significantly alter the number or type of colonies formed by the transplanted marrow cells. 2. Erythropoietin stimulation did not alter the number or type of endogenous colonies formed in mice receiving 580 R. Erythropoietin repression (polycythemia) markedly reduced the growth but not the number of erythroid colonies, while not affecting the other types of colonies formed endogenously. 3. Erythropoietin stimulation of the irradiated recipient during colony growth did not alter the number or type of spleen colonies formed by transplanted marrow. Erythropoietin repression by polycythemia during colony growth completely suppressed the appearance of morphologically erythroid colonies without significantly altering the incidence of the other colony types. This effect of polycythemia was completely prevented by exogenous erythropoietin. Irradiated mice are therefore presumed to be secreting sufficient erythropoietin for maximal erythroid colony development. 4. The erythroid colonies suppressed by polycythemia were recognizable as microscopic foci of undifferentiated cells. Exposure of these foci to erythropoietin stimulation at different periods in their development was manifested by different degrees of growth and differentiation, from which it is apparent that erythropoietin stimulates not only morphological differentiation but also rapid mitosis. Retransplantation of either erythroid or of neutrophilic primary spleen colonies gave rise to both erythroid and neutrophilic secondary spleen colonies. The percentage of erythroid secondary colonies was slightly but significantly higher among the progeny of transplanted erythroid primary colonies than among the progeny of transplanted neutrophilic primary colonies. On the basis of these and other results, a working hypothesis is proposed for factors controlling the growth and differentiation of spleen colonies from transplanted bone marrow. It is postulated that most but perhaps not all spleen colony-forming units are pluripotent hemopoietic stem cells. It is further postulated that hemopoietic-inductive microenvironments (HIM) of different kinds exist in both the spleen and the bone marrow, and that these determine the differentiation of pluripotent stem cells into each of the lines of hemopoietic differentiation. Erythropoietin therefore may "induce" erythroid differentiation of only those stem cells under the influence of an erythroid HIM. Alternatively erythropoietin may act only as a growth and function stimulant of those stem cells that have been "induced" by an erythroid HIM into a state of erythropoietin responsiveness. In the latter case morphological differentiation presumably results from the functional activity stimulated by ESF.

scholarly journals Mesenchymal Stem Cells with Enhanced Bcl-2 Expression Promote Liver Recovery in a Rat Model of Hepatic Cirrhosis

2016 ◽  
Vol 40 (5) ◽  
pp. 1117-1128 ◽  
Author(s):  
Shizhu Jin ◽  
Hulun Li ◽  
Mingzi Han ◽  
Mengting Ruan ◽  
Zishuai Liu ◽  
...  
Keyword(s):  
Liver Function ◽  
Hepatic Cirrhosis ◽  
Post Transplantation ◽  
Experimental Cirrhosis ◽  
Adeno Associated Virus ◽  
Protein Levels ◽  
Histological Sign ◽  
And Function

Background/Aims: Mesenchymal stem cell (MSC) transplantation has emerged as an option for the treatment of chronic hepatic cirrhosis, while its therapeutic efficacy could be improved. The bcl-2 gene is anti-apoptotic and can help cell survival and proliferation. Therefore, we explored whether transplanted MSCs with enhanced bcl-2 expression may be beneficial in the treatment of experimental cirrhosis in rats. Methods: MSCs were isolated from rat bone marrow, expanded in vitro and transfected with adeno-associated virus (AAV) engineered the bcl-2 gene (AAV-bcl-2). Rats with cirrhosis induced by carbon tetrachloride (CCl4) were treated with AAV-bcl-2 infected BMSCs-AAV-bcl-2, with the cells traced in vivo post transplantation. Liver pathology and function were evaluated 7, 14, 21, and 28 days post transplantation, respectively. Results: On day 7 post transplantation, the infused AAV-bcl-2 had integrated into the hepatocyte-like cells (HLCs) that expressed albumin (ALB), Cytokeratin 18 (CK18), and hepatocytes nuclear factor 4a (HNF4a). On day 28 post transplantation, rats in the cirrhosis + BMSCs-AAV-bcl-2 group showed the most dense HLCs, highest mRNA and protein levels of ALB, CK18, and HNF4a, compared to the other groups. Their liver function recovered most rapidly in 4 week observation, while histological sign of cirrhosis remained at the end of this period. Conclusion: BMSCs over expressing bcl-2 gene showed better survival, and enhanced the differentiation into hepatocytes-like cells, and appeared to promote the recovery of liver function in rats with experimental cirrhosis.

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