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

Abstract

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.

Comparative portal hypotensive effects as propranolol of vitamin D3 treatment by decreasing intrahepatic resistance in cirrhotic rats

“…Considering the persistent systemic hypotension in cirrhotic animals, the portal hypotensive agents should be chosen carefully to avoid further decrease blood pressure of cirrhotic patients. Fortunately, our and previous studies reported that acute and chronic1,25(OH) 2 D 3 administration spare the systemic hypotensive effects . These results strengthen the potential of using 1,25(OH) 2 D 3 to treat cirrhotic portal hypotensive animals.…”

“…Fortunately, our and previous studies reported that acute and chronic1,25(OH)2D3 administration spare the systemic hypotensive effects. 13 These results strengthen the potential of using 1,25(OH)2D3 to treat cirrhotic portal hypotensive animals.…”

“…This study displayed that 1,25(OH) 2 D 3 ‐regulated hepatic VDR and CaSR expressions were significantly decreased in cirrhotic human livers. Different from previous studies focusing on the management of PH and hepatic fibrosis, our study aimed to explore the chronic effects of 1,25(OH) 2 D 3 on the systemic, splanchnic, and hepatic circulation in two cirrhotic models. Remarkably, acute and chronic 1,25(OH) 2 D 3 administration inhibited the RAS, hepatic oxidative stress, inflammation, fibrosis, and ANGII production in our cirrhotic rats.…”

“…Actually, VDR activation increases CaSR expression and vice versa . The reduced CaSR expression had been reported in cirrhotic rat kidney and hepatic fibrotic septa; nevertheless, acute CaSR agonist administration could decrease portal pressure in cirrhotic rats without systemic adverse effects . On the other hand, activation of VDR had been declared to improve inflammation‐related endothelial dysfunction .…”

Roles of the calcium sensing receptor in digestive physiology and pathophysiology (Review)

“…In the hepatic ischemia/reperfusion (I/R) injury model, CaSR activation induced cell apoptosis by promoting the p38 MAPK and ERK-1/2 signal pathway phosphorylation and regulating the downstream Bcl-2, Cyt-c, caspase-3 and Bax gene expression (39). More importantly, in the cirrhotic animal model which was induced by carbon tetrachloride (CCl 4 ), CaSR has been reported to reduce the intrahepatic resistance to portal flow (40). Thus, the regulation of CaSR might serve as a new pharmacological target for the prevention and treatment of drug-or alcohol-induced liver disease.…”