Arlt J, Wei W, Xie C, Homeyer A, Settmacher U, Dahmen U, Dirsch O
Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, Drackendorfer Str. 1, 07747, Jena, Germany.
Fraunhofer Institute for Medical Image Computing MEVIS, Universitätsallee 29, 28359, Bremen, Germany.
BMC Pharmacol Toxicol. 2017 Jun 26;18(1):50. doi: 10.1186/s40360-017-0155-4.
Focal hepatic venous outflow obstruction frequently occurs after extended liver resection and leads to a portal hypertension, arterial hypoperfusion and parenchymal necrosis. In this study, we investigated the pharmacological modulation of liver perfusion and hepatic damage in a surgical model of hepatic outflow obstruction after extended liver resection by administration of 5 different drugs in comparison to an operative intervention, splenectomy.
Male inbred Lewis rats (Lew/Crl) were subjected to right median hepatic vein ligation + 70% partial hepatectomy. Treatment consisted of a splenectomy or the application of saline, carvedilol or isosorbide-5-mononitrate (ISMN) (5 mg · kg respectively 7,2 mg · kg per gavage 12 h). The splenectomy was performed during operation. The effect of the treatments on hepatic hemodynamics were measured in non-operated animals, immediately after operation (n = 4/group) and 24 h after operation (n = 5/group). Assessment of hepatic damage (liver enzymes, histology) and liver cell proliferation (BrdU-immunohistochemistry) was performed 24 h after operation. Furthermore sildenafil (10 μg · kg i.p. 12h), terlipressin (0.05 mg · kg i.v. 12 h) and octreotide (10 μg · kg s.c. 12 h) were investigated regarding their effect on hepatic hemodynamics and hepatic damage 24 h after operation (n = 4/group).
Carvedilol and ISMN significantly decreased the portal pressure in normal non-operated rats from 11,1 ± 1,1 mmHg (normal rats) to 8,4 ± 0,3 mmHg (carvedilol) respectively 7,4 ± 1,8 mmHg (ISMN). ISMN substantially reduced surgery-induced portal hypertension from 15,4 ± 4,4 mmHg to 9,6 ± 2,3 mmHg. Only splenectomy reduced the portal flow immediately after operation by approximately 25%. No treatment had an immediate effect on the hepatic arterial perfusion. In all treatment groups, portal flow increased by approximately 3-fold within 24 h after operation, whereas hepatic arterial flow decreased substantially. Neither treatment reduced hepatic damage as assessed 24 h after operation. The distribution of proliferating cells appeared very similar in all drug treated groups and the splenectomy group.
Transient relative reduction of portal pressure did not result in a reduction of hepatic damage. This might be explained by the development of portal hyperperfusion which was accompanied by arterial hypoperfusion.
肝静脉流出道局部梗阻常见于扩大肝切除术后，可导致门静脉高压、动脉灌注不足及实质坏死。在本研究中，我们通过给予5种不同药物，并与手术干预脾切除术相比较，探讨了扩大肝切除术后肝静脉流出道梗阻手术模型中肝脏灌注和肝损伤的药物调节作用。
雄性近交系Lewis大鼠（Lew/Crl）接受右肝中静脉结扎+70%肝部分切除术。治疗方法包括脾切除术或给予生理盐水、卡维地洛或5-单硝酸异山梨酯（ISMN）（分别为5mg·kg或7.2mg·kg，每12小时灌胃一次）。脾切除术在手术过程中进行。在未手术动物、术后即刻（每组n = 4）和术后24小时（每组n = 5）测量治疗对肝脏血流动力学的影响。术后24小时进行肝损伤评估（肝酶、组织学）和肝细胞增殖评估（BrdU免疫组织化学）。此外，研究了西地那非（10μg·kg腹腔注射，12小时）、特利加压素（0.05mg·kg静脉注射，12小时）和奥曲肽（10μg·kg皮下注射，12小时）对术后24小时肝脏血流动力学和肝损伤的影响（每组n = 4）。
卡维地洛和ISMN可使正常未手术大鼠的门静脉压力从11.1±1.1mmHg（正常大鼠）显著降低至8.4±0.3mmHg（卡维地洛）和7.4±1.8mmHg（ISMN）。ISMN可使手术诱导的门静脉高压从15.4±4.4mmHg大幅降低至9.6±2.3mmHg。仅脾切除术可使术后即刻门静脉血流减少约25%。没有治疗方法对肝动脉灌注有即刻影响。在所有治疗组中，术后24小时内门静脉血流增加约3倍，而肝动脉血流则大幅减少。术后24小时评估发现，没有一种治疗方法可减轻肝损伤。在所有药物治疗组和脾切除组中，增殖细胞的分布看起来非常相似。
门静脉压力的短暂相对降低并未导致肝损伤减轻。这可能是由于门静脉高灌注伴动脉灌注不足所致。
