MacNaughton W K, Keenan C M, McKnight G W, Wallace J L
Department of Physiology, Queen's University, Kingston, Ontario, Canada.
J Cardiovasc Pharmacol. 1989;13 Suppl 5:S118-22; discussion S123. doi: 10.1097/00005344-198900135-00029.
The interaction of the vasoconstrictor peptide, endothelin-1 (ET-1), and the endothelium-derived vasodilator eicosanoid, prostacyclin, was examined as it pertains to the modulation of gastric mucosal integrity. Using an ex vivo chamber preparation of the rat stomach, the effects of intravenous ET-1 on the susceptibility of the mucosa to damage induced by topical application of an irritant, 20% ethanol, were examined. ET-1 significantly augmented gastric hemorrhagic damage induced by the irritant when administered at concentrations in the 10(-7) to 10(-6) M range. Pretreatment with indomethacin at a dose that inhibited gastric prostacyclin synthesis by over 85% resulted in significant augmentation of the ulcerogenic actions of ET-1. The damaging actions of ET-1 could be significantly reduced by topical pretreatment of the gastric mucosa with prostacyclin (5-50 micrograms/ml). This pretreatment also significantly reduced the hypertension and hemoconcentration observed following ET-1 administration. ET-1 also significantly augmented the susceptibility of the gastric mucosa to injury induced by hydrochloric acid. Oral administration of 150 mM HCl produced little or no gastric damage in control rats. However, a 5-min intravenous infusion of ET-1 produced significant increases in the severity of acid-induced gastric damage in a concentration-dependent manner (10(-7) to 10(-6) M). These results demonstrate that ET-1 is a potent ulcerogenic agent in the rat stomach. The ulcerogenic actions of ET-1 can be significantly reduced by prostacyclin, suggesting that the balance between endothelial cell release of ET-1 and prostacyclin may be an important factor in modulating gastric mucosal integrity.
研究了血管收缩肽内皮素-1（ET-1）与内皮源性血管舒张类花生酸前列环素之间的相互作用，及其与胃黏膜完整性调节的关系。利用大鼠胃的离体腔室制备方法，研究了静脉注射ET-1对局部应用刺激性物质20%乙醇所致黏膜损伤易感性的影响。当以10^(-7)至10^(-6) M范围内的浓度给药时，ET-1显著增强了刺激性物质所致的胃出血性损伤。用吲哚美辛预处理，剂量能抑制胃前列环素合成超过85%，导致ET-1的致溃疡作用显著增强。用前列环素（5 - 50微克/毫升）局部预处理胃黏膜可显著降低ET-1的损伤作用。这种预处理还显著降低了ET-1给药后观察到的高血压和血液浓缩。ET-1还显著增强了胃黏膜对盐酸所致损伤的易感性。口服150 mM HCl在对照大鼠中几乎不产生或不产生胃损伤。然而，5分钟静脉输注ET-1以浓度依赖方式（10^(-7)至10^(-6) M）显著增加了酸诱导的胃损伤严重程度。这些结果表明，ET-1是大鼠胃中的一种强效致溃疡剂。前列环素可显著降低ET-1的致溃疡作用，提示内皮细胞释放ET-1与前列环素之间的平衡可能是调节胃黏膜完整性的一个重要因素。
