Bosentan, a novel synthetic mixed-type endothelin receptor antagonist, attenuates acute gastric mucosal lesions induced by indomethacin and HCl in the rat: role of endogenous endothelin-1.
Endothelin-1 has been reported to be responsible for gastric mucosal damage in various experimental models. We evaluated the role of endogenous endothelin-1 in the pathogenesis of gastric mucosal damage induced by indomethacin and HCl in the rat. Rats were given indomethacin (25 mg/kg) subcutaneously, and 15 min later, 0.2N HCl intragastrically. Gastric mucosal damage, gastric endogenous endothelin-1, and gastric mucosal hemodynamics were measured. The effects of bosentan, a mixed endothelin receptor antagonist, on gastric mucosal integrity and hemodynamics were assessed. Gastric endogenous endothelin-1 was significantly elevated at 20 min, gastric mucosal blood flow began to decrease significantly at 25 min, and gastric damage occupied 52.2% of the total glandular mucosa at 135 min after injection of indomethacin. Intragastric pretreatment with bosentan (5, 10, 30, and 60 mg/kg) significantly attenuated gastric damage, to 26.1%, 7.7%, 3.6%, and 1.6%, respectively, of the total glandular mucosa. Bosentan (60 mg/kg) prevented the initial decrease of blood flow and, even at 135 min, improved blood flow and hemoglobin oxygen saturation significantly. We suggest that indomethacin-induced endogenous endothelin-1 diminishes gastric mucosal blood flow and tissue oxygenation and ultimately causes gastric damage. Endogenous endothelin-1 may play an important role in the pathogenesis of the acute gastric mucosal lesions induced by indomethacin and HCl.
Matsumaru
K
K
Department of Internal Medicine, University of Tsukuba, Ibaraki, Japan.
Kashimura
H
H
Hassan
M
M
Nakahara
A
A
Hayashi
T
T
Iwata
R
R
Goto
K
K
Muto
H
H
Tanaka
N
N
Fukutomi
H
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects*; D006851:Hydrochloric Acid / Q000009:adverse effects; D007213:Indomethacin / Q000009:adverse effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D013449:Sulfonamides; D000077300:Bosentan; D006851:Hydrochloric Acid; D007213:Indomethacin