Gastric mucosal protection by new aryl sulfhydryl drugs

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Abstract
Alkyl sulfhydryl drugs protect against acute gastric hemorrhagic mucosal lesions. We tested the protective effect of cyclic drugs containing oxidized (KT1-32, KT1-39, KT1-94), or reduced (KT1-66, KT1-109, KT1-293, KT1-720, KT1-756) sulfhydryls. The most potent protective agents (KT1-32, KT1-109, KT1-720, KT1-756) were investigated in detail. Drugs were administered intragastrically to fasted rats 30 min before 100% ethanol (1 ml) or acidified aspirin (10 mg/100 g), and mucosal lesions were measured planimetrically 1 hr later. Control rats receiving only ethanol had lesions involving 14.5% of the glandular mucosa. KT1-32, KT1-109, KT1-720, or KT1-756 (10 mg/100 g) reduced lesions to 0.7, 2.7, 1.8, or 0.7% of glandular stomach respectively. Aspirin-induced lesions involved 1.52% of the glandular mucosa and 10 mg/100 g of KT1-32, KT1-109, or KT1-720, or 2 mg/100 g of KT1-756 diminished the damage to 0.13, 0.02, or 0.04, or 0.00%, respectively. Indomethacin interfered with protection against ethanol by KT1-109, while the sulfhydryl alkylator N-ethylmaleimide abolished protection by both KT1-32 and KT1-109. Among the drugs investigated in detail, KT1-756 increased gastric acid output, while KT1-720 and KT1-756 significantly enhanced pepsin secretion. All four compounds studied in detail (ie, KT1-32, KT1-109, KT1-720, KT1-756) decreased the extent of vascular lesions in the gastric mucosa as revealed by monastral blue 1 min after ethanol. Thus, the mechanism of gastric mucosal protection by these novel aryl sulfhydryl compounds cannot be ascribed to an antisecretory effect, but may be related to prevention of vascular injury.