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

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 C_ICG (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 C_ICG (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.