Endothelin induces vascular and mucosal lesions, enhances the injury by HCl/ethanol, and the antibody exerts gastroprotection.
Vascular factors play an important role in the pathogenesis and prevention of acute gastric mucosal lesions. Endothelin-3 (ET-3), a potent vasoactive peptide, was infused intra-arterially to induce gastric microvascular and hemorrhagic mucosal lesions, and to enhance the damaging effects of dilute HCl and ethanol. ET-3 antibody was injected intravenously to decrease hemorrhagic mucosal lesions induced by ethanol. Locally infused ET (0.01, 0.1, and 1.0 nmol.100 g-1.min-1 for up to 15 min) was followed in some cases by intragastric dilute ethanol or HCl, which alone caused no or only mild vascular and mucosal lesions. Monastral blue was used to visualize and quantify vascular injury. ET-3 produced dose-dependent vascular lesions that affected the walls of mucosal capillaries and venules and induced mucosal congestion and focal endothelial labeling in vessels of the gastric muscular layers. The highest dose of ET induced hemorrhagic gastric mucosal lesions, mortality, and periods of hyper- and hypotension in the rat. Medium and low doses of ET-3 caused vascular injury, and dose-dependently potentiated the vascular and hemorrhagic mucosal lesions caused by dilute HCl and ethanol. Indomethacin slightly enhanced damage induced by ET and 50% ethanol, suggesting a limited mediatory role of prostaglandins in the ET-induced mucosal lesions. Anti-ET-3 serum dose-dependently decreased but did not abolish the hemorrhagic gastric mucosal lesions induced by 75% ethanol. Thus, ET-3 causes endothelial damage in capillaries and venules of rat stomach and predisposes to mucosal damage even after exposure to dilute ethanol or HCl. ET is more potent than leukotrienes and histamine and thus may play an important role in the mechanisms of acute gastric mucosal injury and protection where the vascular network appears to be a major target.
Morales
R E
RE
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Johnson
B R
BR
Szabo
S
S
D000818:Animals; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000276:immunology / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D006851:Hydrochloric Acid / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology; D051381:Rats; D013270:Stomach / Q000098:blood supply
D016232:Endothelins; D000431:Ethanol; D006851:Hydrochloric Acid; D007213:Indomethacin