Blockade of thromboxane responses in the airway of the cat by SQ 29,548.
The effects of SQ 29,548, a thromboxane receptor antagonist, on airway responses were investigated in paralyzed, anesthetized, mechanically ventilated cats. Intravenous injections of the thromboxane and prostaglandin precursor, arachidonic acid (AA), and the thromboxane mimic, U 46619, produced dose-related increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance. After administration of SQ 29,548 (0.5 mg/kg iv), bronchoconstrictor responses to AA were reduced by approximately 50%, whereas responses to U 46619 were reduced by approximately 90%. The cyclooxygenase inhibitor, sodium meclofenamate (2.5 mg/kg iv), blocked the component of the airway response to AA remaining after treatment with SQ 29,548. The thromboxane receptor antagonist had no significant effect on bronchoconstrictor responses to prostaglandins F2 alpha, and D2, methacholine, 5-hydroxytryptamine, histamine, or BAY K 8644, an agent that promotes calcium entry. Reductions in systemic arterial pressure in response to AA were enhanced by the thromboxane receptor antagonist and abolished by meclofenamate. SQ 29,548 had no effect on terminal enzyme activity in microsomal fractions from cat lung. These data support the hypothesis that AA-induced bronchoconstriction in the cat is mediated in large part by the actions of thromboxane A2. These data also suggest that U 46619 and U 44069 stimulate the same airway receptor as thromboxane A2 and mimic the bronchomotor effects of this hormone, which has not yet been isolated as a pure substance. These data demonstrate that SQ 29,548 is a selective thromboxane receptor antagonist in the airways of the closed-chest cat and may be a useful probe for studying responses to thromboxane A2 in physiological and pathophysiological processes in the lung.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002415:Cats; D003577:Cytochrome P-450 Enzyme System; D015237:Dinoprost; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000096:biosynthesis / Q000378:metabolism; D005231:Fatty Acids, Unsaturated; D005260:Female; D006834:Hydrazines / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000378:metabolism; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D015230:Prostaglandin D2; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D011457:Prostaglandins D / Q000494:pharmacology; D011460:Prostaglandins F / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D013931:Thromboxanes / Q000378:metabolism*
D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D011457:Prostaglandins D; D011460:Prostaglandins F; D013931:Thromboxanes; D016718:Arachidonic Acid; D012701:Serotonin; D008469:Meclofenamic Acid; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D003577:Cytochrome P-450 Enzyme System; D015237:Dinoprost; D011464:Epoprostenol; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C022461:prostacyclin synthetase; D015230:Prostaglandin D2