Influence and SK and F 95587 and BN 50730 on bronchoconstrictor responses in the cat

The effects of SK and F 95587 (4[2-(benzenesulfonamido)-ethyl]phenoxyacetic acid), a thromboxane (TX) receptor blocking agent, on bronchoconstrictor responses were investigated in paralyzed, anesthetized, mechanically ventilated cats. Intravenous injections of the TXA₂ receptor mimics, U-46619 [(15S)-hydroxy-11α,9α-(epoxymethano)prosta5Z,13E-dienoic acid] and U-44069 (9,11-dideoxy-11α,9α-epoxymethano PGF(2α)), produced dose-related increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance. After administration of SK and F 95587, 5 mg/kg i.v., bronchoconstrictor responses to U-46619 and U-44069 were reduced markedly, whereas airway responses to prostaglandin (PG)F(2α), serotonin, PGD₂ or the PGD₂ metabolite, 11β-PGF(2α), were not altered. The duration of action of SK and F 95587 was greater than 3 hr, and the blockade was overcome when 10-fold larger doses of the TXA₂ mimics were administered. Bronchoconstrictor responses to platelet-activating factor (PAF) were blocked by SK and F 95587 and by the novel PAF receptor antagonist, BN 50730. BN 50730 also blocked the fall in systemic arterial pressure in response to PAF. However, BN 50730 did not influence airway responses to U-46619, PGF(2α), PGD₂ or serotonin and had no effect on baseline bronchomotor tone or arterial pressure. The PAF receptor antagonism with BN 50730 was overcome when 10-fold larger doses of PAF were administered and the dose-response curves for changes in lung resistance and dynamic compliance were shifted to the right in a parallel manner. The present data suggest that SK and F 95587 has selective TX receptor blocking activity, and that BN 50730 has selective PAF receptor blocking properties in the airways of the cat. The present data also provide support for the hypothesis that bronchoconstrictor responses to PAF are mediated by specific receptors, which are coupled to a phospholipase and, when activated, result in the release of TXA₂ and contraction of airway smooth muscle.