Tsugawa K, Hashizume M, Migou S, Kishihara F, Kawanaka H, Tomikawa M, Sugimachi K
Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
J Gastroenterol Hepatol. 1999 Jul;14(7):642-51. doi: 10.1046/j.1440-1746.1999.01930.x.
Prostacyclin has been shown to play a role in hyperdynamic circulation in portal hypertension. Recently, a new subtype of cyclo-oxygenase (COX), COX-2, which acts as an inducible synthase in response to various stimuli. The aim of this study was to investigate whether COX-2 contributes to portal hypertension and whether a COX-2 blockade induces the same sort of gastric mucosal injury as a COX-1 blockade.
Portal hypertension (PHT) in rats was induced by a two-step ligation of the portal vein. The mean arterial pressure (MAP), portal pressure (PP), visceral blood flow volume (BFV), serum levels of 6-keto-prostaglandin F1alpha (PGF1alpha), thromboxane B2 (TXB2) and gastric mucosal injury induced by pure ethanol were all measured in PHT rats receiving different inhibitors (indomethacin, a highly selective COX-1 inhibitor; NS-398, a highly selective COX-2 inhibitor). Control rats treated by a sham operation were also studied.
The NS-398 administration significantly decreased PP to the same extent as indomethacin at doses of 5 and 10 mg/kg in PHT rats after a 60 min administration, while neither inhibitor affected the control rats. Both inhibitors significantly increased PP after a 30 min administration in the PHT and control rats at a dose of 5 mg/kg while both inhibitors significantly decreased PP after 60 min administration only in the PHT rats. Portal vein ligation treatment induced a significant increase in PP and BFV of the portal vein, gastric mucosa, oesophageal mucosa and the serum levels of 6-keto-PGF1alpha and TXB2, while portal vein ligation treatment induced a significant decrease in BFV of the liver. Both blockades increased MAP and decreased PP and BFV in the splanchnic area and decreased the serum level of 6-keto-PGF1alpha and TXB2 in the PHT rats, while neither blockade modified any parameters in the control rats, except that indomethacin administration significantly decreased the BFV of the gastric mucosa. Indomethacin administration significantly increased the ulcer index (UI). The NS-398 had no effect on UI in either the PHT or control rats. Only indomethacin significantly increased the number of rats demonstrating gastric mucosal long lesions (> 2 cm) in the PHT rats.
In the PHT rats, prostaglandin seemed to contribute to portal hypertension. Both COX blockades reduced PP and BFV of the portal vein and gastric mucosa. NS-398, a selective COX-2 inhibitor, may, therefore, improve portal hypertension without inducing gastric mucosal injury.
前列环素已被证明在门静脉高压的高动力循环中起作用。最近，一种新的环氧化酶（COX）亚型，即COX-2，作为一种诱导型合酶，可对各种刺激作出反应。本研究的目的是调查COX-2是否与门静脉高压有关，以及COX-2阻断是否会像COX-1阻断那样引起相同类型的胃黏膜损伤。
通过门静脉两步结扎诱导大鼠门静脉高压（PHT）。在接受不同抑制剂（吲哚美辛，一种高度选择性的COX-1抑制剂；NS-398，一种高度选择性的COX-2抑制剂）的PHT大鼠中，测量平均动脉压（MAP）、门静脉压力（PP）、内脏血流量（BFV）、6-酮-前列腺素F1α（PGF1α）、血栓素B2（TXB2）的血清水平以及纯乙醇诱导的胃黏膜损伤。还研究了接受假手术治疗的对照大鼠。
在PHT大鼠中，给予NS-398 60分钟后，5毫克/千克和10毫克/千克剂量的NS-398可使PP显著降低至与吲哚美辛相同的程度，而两种抑制剂对对照大鼠均无影响。在PHT大鼠和对照大鼠中，5毫克/千克剂量的两种抑制剂给药30分钟后均显著增加PP，而仅在PHT大鼠中，60分钟给药后两种抑制剂均显著降低PP。门静脉结扎治疗导致门静脉、胃黏膜、食管黏膜的PP和BFV以及6-酮-PGF1α和TXB2的血清水平显著升高，而门静脉结扎治疗导致肝脏BFV显著降低。两种阻断均增加了PHT大鼠的MAP，降低了内脏区域的PP和BFV，并降低了6-酮-PGF1α和TXB2的血清水平，而两种阻断对对照大鼠的任何参数均无影响，除了给予吲哚美辛显著降低了胃黏膜的BFV。给予吲哚美辛显著增加了溃疡指数（UI）。NS-398对PHT大鼠或对照大鼠的UI均无影响。仅吲哚美辛显著增加了PHT大鼠中出现胃黏膜长病变（>2厘米）的大鼠数量。
在PHT大鼠中，前列腺素似乎与门静脉高压有关。两种COX阻断均降低了门静脉和胃黏膜的PP和BFV。因此，选择性COX-2抑制剂NS-398可能改善门静脉高压而不引起胃黏膜损伤。
