Gastroenterology Unit, Gradenigo Hospital, Torino, Italy.
Clin Sci (Lond). 2013 Jul 1;125(2):67-75. doi: 10.1042/CS20120476.
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.
在实验性肝硬化大鼠中，肾脏中膜结合型 CaR（钙敏感受体）的含量减少，CaR 的特异性刺激会导致 PGE2（前列腺素 E2）的产生、肾血管舒张和钠排泄增加。肝硬化大鼠肝中 CaR 的含量和功能尚不清楚。为了评估该 Ca2+依赖性血管运动系统的活性，我们评估了静脉内给予 PolyAg（聚精氨酸），一种选择性 CaR 激动剂，对激素状态、门脉血液动力学、MAP（平均动脉压）的影响在慢性 CCl4（四氯化碳）给药诱导的肝硬化大鼠中。两组 8 只对照大鼠分别静脉内给予 1ml 5%（w/v）葡萄糖溶液单独或含有 0.5mg PolyAg；两组 10 只肝硬化大鼠给予载体或 PolyAg。与对照组相比，基线时肝硬化大鼠的门脉压更高（P<0.01），估计功能性肝血浆流量更低，以 CICG（吲哚菁绿清除率）表示（P<0.03），并且 CaR 的肝蛋白含量降低（P<0.03），主要位于门脉小静脉的内皮下层和纤维间隔的肌成纤维细胞中（肝脏切片的免疫组织化学和间接免疫荧光染色）。在肝硬化动物中，0.5mg PolyAg 降低门脉压（P<0.01）并增加 CICG（P<0.05），对动脉压和激素状态没有影响。总之，本研究提供的证据表明，在实验性肝硬化中，肝 CaR 的激动剂通过降低肝内对门脉血流的阻力产生有益的门脉降压作用。此外，这些药物对全身血液动力学没有影响。
