Inhibiton of platelet aggregation by 1-alkylimidazole derivatives, thromboxane a synthethase inhibitors

Kayama, N; Sakaguchi, Kimiko; Kaneko, Shuji; Kubota, Tetsuaki; Fukuzawa, Taira; Kawamura, Sumio; Yohimoto, Tanihiro; Yamamoto, Shozo

doi:10.1016/0090-6980(81)90003-4

Cited by 15 publications

(2 citation statements)

References 21 publications

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“…Since the cyclooxygenase, thromboxane synthetase, and PGI2 synthetase steps are apparently calcium independent (32)(33)(34), it remains the release of the precursor arachidonic acid that must be inhibited by extracellular calcium depletion and by the application of TMB 8. Phospholipase (A2/C)-dependent release of arachidonic acid from cell membranes appears to be the general ratelimiting step in arachidonic acid metabolism (35,36).…”

Section: Methodsmentioning

confidence: 99%

Staphylococcal alpha-toxin elicits hypertension in isolated rabbit lungs. Evidence for thromboxane formation and the role of extracellular calcium.

Seeger¹,

Bauer²,

Bhakdi³

1984

J. Clin. Invest.

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Astract. Staphylococcal a-toxin is known to damage mammalian cell membranes. Studies of erythrocytes indicate that the native toxin generates a discrete transmembrane channel with an effective diameter of 2-3 nm. (Fiissle, R., S. Bhakdi, A. Szeigoleit, J. TranumJensen, T. Kranz, and H. J. Wellensiek. 1981. J. Cell BioL 91:83-94.) In isolated rabbit lungs, perfused with recirculating blood-and plasma-free perfusion fluid, the mediation of a toxin-provoked vascular pressor response by the triggering of the arachidonic acid cascade and its dependence on extracellular calcium were investigated. Dose-dependent pulmonary artery pressor responses were elicited by the injection of 0.5-5 jg staphylococcal a-toxin into the pulmonary artery. The pressor responses were completely abolished by preincubation of the toxin with neutralizing antibodies or by preformation of atoxin hexamers in vitro. They were accompanied by the release of the arachidonic acid metabolites thromboxane B2 and 6-keto-prostaglandin Fl, ( release of potassium, but not lactatedehydrogenase into the medium. Calcium depletion of the intravascular space did not suppress the toxin-dependent potassium release but did abrogate the pressor response and the release of the arachidonic acid metabolites. When calcium was reintroduced into the circulation without the application of a second toxin stimulus, marked pressor responses paralleled by the release of arachidonic acid metabolites occurred.The conclusion drawn from these studies is that staphylococcal a-toxin provokes pulmonary vascular hypertension which is apparently mediated by thromboxane A2 formation, which surpasses the biological effect of the simultaneously formed prostaglandin 12. The triggering of the arachidonic acid cascade is strictly dependent on extracellular calcium and may be mediated by a nonphysiological calcium bypass through transmembrane toxin channels with subsequent stimulation of phospholipase activity.

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Section: Methodsmentioning

confidence: 99%

Staphylococcal alpha-toxin elicits hypertension in isolated rabbit lungs. Evidence for thromboxane formation and the role of extracellular calcium.

Seeger¹,

Bauer²,

Bhakdi³

1984

J. Clin. Invest.

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“…It is also possible that inhibition of the enzyme has lead to enhanced formation of other cyclooxygenase products, e.g. PGDl and PGF,, (Kayama et al 1981), which could contribute to the constriction seen after hydrogen peroxide in the presence of carboxyheptylimidazole. Indeed, perfusion of the guinea pig lung with concentrations of carboxyheptylimidazole higher than 100 pM did not further reduce the constricting effects of hydrogen peroxide (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Peroxide‐Induced Broncho‐ and Vasoconstriction in the Isolated Perfused and Ventilated Guinea Pig Lung

Bannenberg¹,

Kimland²,

Ryrfeldt³

et al. 1993

Pharmacology & Toxicology

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The effect of hydrogen peroxide on perfusion flow, airway conductance (Gaw) and dynamic compliance (Cdyn of isolated perfused and ventilated guinea pig lungs was investigated. Hydrogen peroxide (50 microM in the perfusion buffer) induced a decrease in Gaw and Cdyn and perfusion flow during 5 min. of exposure. Hydrogen peroxide also caused an increase in the levels of thromboxane in the perfusate of the lung. The constrictor effects as well as the formation of thromboxane were inhibited by the cyclooxygenase inhibitor ibuprofen (50 microM). The thromboxane/prostaglandin endoperoxide receptor antagonist L-670,596 (1 microM) abolished the effects of hydrogen peroxide on perfusion flow, Gaw and Cdyn, but did not affect the formation of thromboxane. The thromboxane-synthetase inhibitor carboxyheptylimidazole (100 microM) reduced both the hydrogen peroxide-induced formation of thromboxane and vaso- and bronchoconstriction, suggesting a predominant role for thromboxane A2 versus prostaglandin H2 in these effects. A role for platelet-activating factor in mediating the effect of hydrogen peroxide could not be supported, as the platelet-activating factor receptor antagonist WEB 2086 (10 microM) did not affect hydrogen peroxide induced vaso- and brochoconstriction. The results of this study show that hydrogen peroxide induces thromboxane A2 mediated vaso- and bronchoconstriction in the isolated perfused and ventilated guinea pig lung. Platelet-activating factor does not appear to play a significant role in the hydrogen peroxide-induced vaso- and bronchoconstriction. Our results also suggest that the perfused guinea pig lung is more sensitive to hydrogen peroxide than the perfused rat lung.

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Prostaglandin H2 Causes Calcium Mobilization in Intact Human Platelets

Brace

Breton

Venton

1985

Prostaglandins, Leukotrienes, and Lipoxins

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Inhibiton of platelet aggregation by 1-alkylimidazole derivatives, thromboxane a synthethase inhibitors

Cited by 15 publications

References 21 publications

Staphylococcal alpha-toxin elicits hypertension in isolated rabbit lungs. Evidence for thromboxane formation and the role of extracellular calcium.

Staphylococcal alpha-toxin elicits hypertension in isolated rabbit lungs. Evidence for thromboxane formation and the role of extracellular calcium.

Hydrogen Peroxide‐Induced Broncho‐ and Vasoconstriction in the Isolated Perfused and Ventilated Guinea Pig Lung

Prostaglandin H2 Causes Calcium Mobilization in Intact Human Platelets

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