sq-29548 and Bronchial-Diseases

Inhalation of cigarette smoke induces a biphasic bronchoconstriction in guinea pigs: the first phase is induced by a combination of cholinergic reflex and tachykinins, whereas the second phase involves cyclooxygenase metabolites (J.-L. Hong, I. W. Rodger, and L.-Y. Lee. J. Appl. Physiol. 78: 2260-2266, 1995). This study was carried out to further determine the causative agents in the smoke and the types of prostanoid receptors and endogenous prostanoids mediating the bronchoconstriction. Inhalation of 10 ml of high-nicotine cigarette smoke consistently elicited the biphasic bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Pretreatment with hexamethonium (10 mg/kg iv) significantly reduced the first-phase bronchoconstriction but did not have any measurable effect on the second-phase response. In sharp contrast, gas-phase smoke did not elicit any bronchoconstrictive effect. Furthermore, when the animals were challenged with low-nicotine cigarette smoke, only a single second-phase response was evoked, accompanied by increases in thromboxane (Tx) B2 (a stable metabolite of TxA2), prostaglandin (PG) D2, PGF2 alpha in the bronchoalveolar lavage fluid. The bronchoconstrictive response induced by low-nicotine smoke was completely prevented by pretreatment with SQ-29548 (0.3 mg/kg iv), a TxA2-receptor antagonist. These results indicate that 1) nicotine is the primary causative agent responsible for the first-phase bronchoconstriction and 2) nonnicotine smoke particulates evoke the release of TxA2, PGD2, and PGF2 alpha, which act on TxA2 receptors on airway smooth muscles and induce the second-phase response to cigarette smoke.

Topics: Air Pressure; Animals; Bridged Bicyclo Compounds, Heterocyclic; Bronchial Diseases; Bronchoalveolar Lavage Fluid; Cholinergic Antagonists; Constriction, Pathologic; Dinoprost; Fatty Acids, Unsaturated; Guinea Pigs; Hemodynamics; Hexamethonium; Hydrazines; Male; Nicotine; Nicotinic Agonists; Receptors, Thromboxane; Smoke; Smoking