安托美汀胍基酯的胃保护作用：一种可激活诱导型胃一氧化氮合酶的新型非甾体抗炎药。

Coruzzi G, Coppelli G, Spaggiari S, Cavestro G M, Okolicsanyi L, Lo Giudice P, Pisano C, Tepperman B L

Institute of Pharmacology, School of Medicine, University of Parma, Italy.

Dig Liver Dis. 2002 Jun;34(6):403-10. doi: 10.1016/s1590-8658(02)80037-8.

BACKGROUND

The novel non-steroidal anti-inflammatory drug amtolmetin guacyl has been shown to possess markedly reduced ulcerogenic effects and nitric oxide-mediated gastroprotective activity against the damage induced by ethanol in the rat.

AIMS

To investigate, in the rat, the role of nitric oxide and of inducible nitric oxide synthase isoform in the protective effect of amtolmetin guacyl against the gastric damage induced by ethanol.

METHODS

The effects of amtolmetin guacyl on gastric transmucosal potential difference and on gastric mucosal blood flow were investigated in the anaesthetised rat; myeloperoxidase activity, inducible and endothelial nitric oxide synthase protein content were determined in rat gastric mucosal homogenates. The anti-inflammatory drug tolmetin and the bacterial lipopolysaccharide from Escherichia coli were studied for comparison.

RESULTS

In the anaesthetised rat, amtolmetin guacyl, but not tolmetin, reduced by approximately 50% the fall in gastric potential difference and, to a lesser extent, the macroscopic damage induced by ethanol. The effect of amtolmetin guacyl on transmucosal potential difference was prevented by the selective inducible nitric oxide synthase inhibitor 1400W. In amtolmetin guacyl-treated rats, 1400W decreased gastric mucosal blood flow, whereas it was inactive in vehicle- and tolmetin-treated animals. In gastric mucosal homogenates, both amtolmetin guacyl and lipopolysaccharide, but not tolmetin, increased inducible, but not endothelial, nitric oxide synthase protein content, as revealed by Western immunoblotting.

CONCLUSIONS

These data confirm that amtolmetin guacyl is a non-steroidal anti-inflammatory agent devoid of gastrolesive properties, that can actually reduce the damaging effects of ethanol through the increase in nitric oxide production, via the inducible isoform of nitric oxide synthase.

背景

新型非甾体抗炎药阿明洛芬胍已被证明具有显著降低的致溃疡作用，以及对大鼠乙醇诱导损伤的一氧化氮介导的胃保护活性。

目的

在大鼠中研究一氧化氮和诱导型一氧化氮合酶同工型在阿明洛芬胍对乙醇诱导的胃损伤保护作用中的作用。

方法

在麻醉大鼠中研究阿明洛芬胍对胃跨粘膜电位差和胃粘膜血流量的影响；测定大鼠胃粘膜匀浆中的髓过氧化物酶活性、诱导型和内皮型一氧化氮合酶蛋白含量。研究了抗炎药托美汀和大肠杆菌的细菌脂多糖作为对照。

结果

在麻醉大鼠中，阿明洛芬胍而非托美汀使胃电位差下降约50%，并在较小程度上减轻了乙醇诱导的宏观损伤。选择性诱导型一氧化氮合酶抑制剂1400W可阻止阿明洛芬胍对跨粘膜电位差的作用。在阿明洛芬胍治疗的大鼠中，1400W降低了胃粘膜血流量，而在给予赋形剂和托美汀治疗的动物中则无此作用。通过蛋白质免疫印迹法显示，在胃粘膜匀浆中，阿明洛芬胍和脂多糖均可增加诱导型而非内皮型一氧化氮合酶蛋白含量，而托美汀则无此作用。