Heller J, Shiozawa T, Trebicka J, Hennenberg M, Schepke M, Neef M, Sauerbruch T
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Eur J Clin Invest. 2003 Nov;33(11):1006-12. doi: 10.1046/j.1365-2362.2003.01251.x.
Portal hypertension in cirrhosis is the result of increased intrahepatic vascular resistance to portal outflow as well as increased portal tributary blood flow. The angiotensin II type 1 receptor antagonist losartan has been suggested as a portal pressure-lowering drug in patients with cirrhosis.
To investigate the systemic and splanchnic haemodynamic effects of different doses of losartan.
In 35 anaesthetized rats with secondary biliary cirrhosis, 3, 10 or 30 mg of losartan kg(-1) or solvent were administered intravenously. Ten sham-operated rats served as controls. Mean arterial pressure and portal pressure were measured by catheters in the femoral artery or portal vein. Systemic and splanchnic haemodynamics and mesenterico-systemic shunt rate were determined by the coloured microsphere method.
Losartan reduced portal pressure (sham: 9.1 +/- 0.4. cirrhosis: 19.3 +/- 1.1, after 3 mg kg(-1) of losartan 16.4 +/- 0.4, after 10 mg kg(-1) of losartan 15.6 +/- 0.6, after 30 mg kg(-1) of losartan 14.9 +/- 0.6 mmHg) without reducing portal sinusoidal resistance. However, in cirrhotic rats it reduced portal tributary blood flow (sham: 4.3 +/- 0.6. cirrhosis: 8.6 +/- 1.4, after 3 mg kg(-1) of losartan 3.8 +/- 0.7, after 10 mg kg(-1) of losartan 4.7 +/- 0.5, after 30 mg kg(-1) of losartan 5.9 +/- 0.9 mmHg). This was owing either to an increase in splanchnic vascular resistance at the 3 mg kg(-1) dose or to a reduction in the splanchnic perfusion-pressure gradient secondary to a reduction in mean arterial pressure at the 10 and 30 mg kg(-1) doses (mean arterial pressure: sham: 109.7 +/- 4.8. cirrhosis: 109.4 +/- 2.8, after 3 mg kg(-1) of losartan 99.7 +/- 2.9, after 10 mg kg(-1) of losartan 89.9 +/- 3.4, after 30 mg kg(-1) of losartan 81.0 +/- 2.9 mmHg).
Low doses of losartan reduce portal hypertension by an increase in splanchnic vascular resistance without hypotensive side-effects on arterial pressure.
肝硬化门静脉高压是肝内血管对门静脉血流阻力增加以及门静脉分支血流增加的结果。血管紧张素II 1型受体拮抗剂氯沙坦已被提议作为肝硬化患者降低门静脉压力的药物。
研究不同剂量氯沙坦对全身和内脏血流动力学的影响。
对35只麻醉的继发性胆汁性肝硬化大鼠静脉注射3、10或30mg/kg氯沙坦或溶剂。10只假手术大鼠作为对照。通过股动脉或门静脉导管测量平均动脉压和门静脉压力。采用彩色微球法测定全身和内脏血流动力学以及肠系膜-全身分流率。
氯沙坦降低了门静脉压力（假手术组：9.1±0.4，肝硬化组：19.3±1.1，3mg/kg氯沙坦后为16.4±0.4，10mg/kg氯沙坦后为15.6±0.6，30mg/kg氯沙坦后为14.9±0.6mmHg），但未降低门静脉窦阻力。然而，在肝硬化大鼠中，它降低了门静脉分支血流（假手术组：4.3±0.6，肝硬化组：8.6±1.4，3mg/kg氯沙坦后为3.8±0.7，10mg/kg氯沙坦后为4.7±0.5，30mg/kg氯沙坦后为5.9±0.9mmHg）。这要么是由于3mg/kg剂量时内脏血管阻力增加，要么是由于10mg/kg和30mg/kg剂量时平均动脉压降低导致内脏灌注压梯度降低（平均动脉压：假手术组：109.7±4.8，肝硬化组：109.4±2.8，3mg/kg氯沙坦后为99.7±2.9，10mg/kg氯沙坦后为89.9±3.4，30mg/kg氯沙坦后为81.0±2.9mmHg）。
低剂量氯沙坦通过增加内脏血管阻力降低门静脉高压，且对动脉压无降压副作用。
