15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Bronchial-Spasm

A novel chemical compound, DT-TX 30 SE (E-6-(4-2-(4-chlorobenzenesulphonylamino)-ethyl)phenyl)-6-(3-pyrid yl)- hex-5-enoic acid), was studied in various models of guinea pig pulmonary function. The compound was a potent inhibitor (ED50 0.019 mg/kg, i.v.) of bronchospasm induced by the thromboxane receptor agonist U-46619, indicating thromboxane receptor antagonism. At even lower doses (ED50 0.0036 mg/kg, i.v.), it blocked arachidonic acid-induced bronchospasm. Interpretation of the latter results as evidence for additional thromboxane synthetase inhibitory activity was supported by the inhibition of arachidonic acid- or bradykinin-induced thromboxane B2 production in an isolated lung preparation, although prostaglandin E2 and prostaglandin 6-oxo-F(1 alpha) production measured at the same time were not inhibited. The potency of DT-TX 30 SE was compared with thromboxane receptor antagonists and synthetase inhibitors described in the literature. As a receptor antagonist, DT-TX 30 SE was significantly more potent than BM 13505 and BM 13177 (assessed by antagonism of U-46619-induced bronchospasm), but less potent than SQ 29548, while as a thromboxane synthetase inhibitor, it was significantly more potent than OKY 046 and UK 37248 as assessed by antagonism of arachidonic acid-induced bronchospasm or (OKY 046) inhibition of thromboxane production in isolated lung. The compound was active by the oral route as shown by its ability, at 10 mg/kg, p.o., to significantly reduce the immediate allergic response of sensitized guinea pigs to an ovalbumin aerosol.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arachidonic Acid; Bronchial Spasm; Dinoprostone; Enzyme Inhibitors; Fatty Acids, Unsaturated; Guinea Pigs; Lung; Male; Prostaglandin Endoperoxides, Synthetic; Pyridines; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

1. The aim of this study was to determine whether an inhalation of ovalbumin (OA, 10 or 20 mg ml-1) by conscious OA-sensitized guinea-pigs leads to airway hyperreactivity to spasmogens 24 h later. In contrast to most previous studies, the spasmogens (5-HT, methacholine (MCh), U-46619 and adenosine) were administered by inhalation and airway function was measured in conscious guinea-pigs. 2. Guinea-pigs were sensitized by i.p. injection of 10 micrograms OA and 100 mg aluminium hydroxide in 1 ml normal saline; 14-21 days later they were exposed to an inhalation of 5-HT, MCh, U-46619 or adenosine. Specific airway conductance (sGaw) was measured in conscious animals by whole body plethysmography. The spasmogens caused bronchoconstriction, measured as a reduction in sGaw from the pre-inhalation basal values. Dose-related bronchoconstrictions were observed with 5-HT, MCh and U-46619. 3. The effect of an ovalbumin macroshock challenge upon the responses to each spasmogen were examined by giving an inhalation of aerosolized OA at 24 h (or 7 days in the cause of adenosine) after an initial spasmogen challenge. Eighteen to twenty-four hours after the OA macroshock, the same guinea-pigs were exposed to a repeated inhalation of 5-HT, MCh, U-46619 or adenosine. 4. U-46619 was the only spasmogen to demonstrate hyperresponsiveness, the peak change in sGaw being increased from -12.3 +/- 9.9 to -38.8 +/- 5.0% by 10 mg ml-1 OA challenge. In contrast, the ovalbumin challenge (20 mg ml-1) inhibited the bronchoconstrictions to 5-HT (50 micrograms ml-1) and MCh (100 micrograms ml-1). Adenosine demonstrated bronchoconstriction in sensitized guinea-pigs but no significant change in the response was observed after an OA challenge. 5. All results were compared with a control group of sensitized guinea-pigs receiving a NaCl challenge. The bronchoconstrictor responses to 5-HT, MCh, U-46619 or adenosine did not differ significantly before and after the saline challenge, indicating reproducibility of the responses. 6. In further experiments, guinea-pigs were exposed to inhalation of 5-HT (50 micrograms ml-1) or MCh (300 micrograms ml-1) 24 h before atropine (10 micrograms, 100 micrograms or 1 mg ml-1) and again at 0.5 to 1.5 h afterwards. Atropine, antagonized the 5-HT- and MCh-induced bronchoconstrictions over the same antagonist dose-range. This suggests that the bronchoconstriction induced in the conscious guinea-pig by 5-HT is mediated primarily via muscarinic receptors, possibly

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine; Administration, Inhalation; Airway Resistance; Animals; Asthma; Atropine; Bronchial Spasm; Bronchoconstrictor Agents; Bronchodilator Agents; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Male; Methacholine Chloride; Ovalbumin; Plethysmography, Whole Body; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bronchial Spasm; Dogs; In Vitro Techniques; Leukotriene B4; Muscle, Smooth; Ozone; Platelet Activating Factor; Prostaglandin Endoperoxides, Synthetic; SRS-A; Synaptic Transmission; Thromboxane A2; Trachea