Portal Hypotensive Action Of Calcimimetic Agents In Rats With Ccl4-Induced Ascitic Liver Cirrhosis
Sansoè G Gastroenterology Unit, Gradenigo Hospital, Torino, Italy. *Department of Experimental Medicine and Oncology, **Department of Gastroenterology, University of Torino, Italy.
Abstract:
Calcium causes vasoconstriction through L-type voltage-operated Ca++ channels (L-VOCCs), and vasodilatation through stimulation of membrane-bound calcium-sensing receptors (CaRs), which mediate generation of PGE2. In activated hepatic stellate cells (HSCs) of cirrhotic liver, L-VOCCs are over-expressed and responsible for HSC contraction. CaRs content and function in cirrhotic liver and mesenteric arterioles are unknown. To assess the activity of this Ca++-dependent vasodilator system we evaluated the effects of intravenous poly-L-arginine (PolyAg), a selective CaRs-agonist, on hormonal status, portal hemodynamics, mean arterial pressure in rats with ascitic liver cirrhosis induced by CCl4 intoxication. Two groups of control rats received intravenously 1 ml 5% glucose solution alone or containing 0.5 mg PolyAg; two groups of cirrhotic rats were administered vehicle or PolyAg. Compared to controls, at baseline cirrhotic rats showed higher portal pressure (P<0.01) and lower estimated functional liver plasma flow, measured as steady-state indocyanine green clearance (P<0.03). In cirrhotic rats, liver and mesenteric intestine showed reduced CaRs protein content, compared to controls (all P<0.03). In cirrhotic animals, CaRs were located in sub-endothelial layers of intrahepatic portal venules, and in the bowel CaRs were only found in the wall of mesenteric arterioles at the tip of the villi. In cirrhotic animals 0.5 mg i.v. PolyAg decreased portal pressure from 10.6 ± 0.7 mmHg to 7.45 ± 0.83 mmHg (P<0.01), without effects on arterial pressure, and increased indocyanine green clearance (P<0.05) and PGE2 urinary excretion (P<0.01). Pharmacological agonists of cirrhotic liver CaRs elicit beneficial portal hemodynamic effects by reducing intrahepatic resistance to portal flow.
