Pharmacological characterization using selected antagonists of the leukotriene receptors mediating contraction of guinea-pig trachea.

The effects of six leukotriene (LT) antagonists on LTC4-, D4- and E4-induced contraction of isolated guinea-pig tracheal spirals were examined. Concentration-response effects of the leukotrienes were determined by cumulative addition in the presence of indomethacin (5 microM) alone for LTE4, or with 10 mM of either glutathione or L-cysteine to inhibit metabolism of LTC4 or LTD4, respectively. Concentration-response curves to the LTs were obtained in the absence and presence of Wy-45,911, Wy-44,329, FPL-55,712, Ly-171,883, Wy-48,252 and ICI-198,615 representing three structurally different chemical groups of LT antagonists. At 30 microM, the antagonists produced little or no antagonism of LTC4-induced contractions. Analysis of the Schild plots for antagonism of LTD4 and E4 suggested two receptors for the agonist effects of LTD4 and a single receptor for the agonist effects of LTE4. Comparison of pA2 values for Wy-45,911, FPL-55,712, LY-171,883 and Wy-48,252 provided evidence that LTE4 is acting at the antagonist high affinity LTD4 receptor to produce contractile effects. From the data, we conclude that there are three LT receptors (one for LTC4 and two LTD4 subtypes) through which exogenously applied LTs evoke contraction of the isolated guinea-pig trachea.

Prevention and reversal of aerosol LTD4-induced changes in guinea pig pulmonary mechanics by Wy-48252, an orally active LTD4/E4 receptor antagonist.

Anesthetized male albino guinea pigs were prepared for recording changes in the pulmonary mechanics parameters, dynamic compliance (Cdyn) and airway conductance (Gaw). Two aerosol leukotriene D4 (LTD4) challenges (0.125 microgram/ml, 3-7 breaths, 1 h apart) were administered via an ultrasonic nebulizer to each animal and, produced reductions in Cdyn that were approximately 60% of those of Gaw. Intraduodenal administration of the LTD4/E4 receptor antagonists Wy-48252 (30 min), Wy-45911 and Ly-171883 (15 min) produced dose-related inhibition of the second LTD4 challenge. From the data, ID50 values were calculated and, Wy-48252 was 8- to 17-fold more potent (mg/kg) than Wy-45911 or Ly-171883. Responses to histamine were not altered by the antagonists. In separate experiments, Wy-48252 (0.3 and 1 mg/kg i.v.) rapidly reversed aerosol LTD4-induced decreases of Cdyn and Gaw, but did not reverse pulmonary mechanics decreases produced by prostaglandin F2 alpha. The results indicate that systemically administered LTD4 receptor antagonists can both prevent and reverse bronchoconstriction produced by aerosol LTD4 in the guinea pig.

Bronchoprotective and bronchodilator activity of anaritide (human atrial natriuretic factor [102-126]) infusion in the anesthetized guinea pig.

The present study examined the bronchoprotective and bronchodilator efficacy of infused human atrial natriuretic factor [102-126] (Anaritide) in the guinea pig. Anesthetized and paralyzed male guinea pigs, ventilated via a tracheal cannula, were placed in a plethysmograph for measurement of agonist-induced changes in pulmonary mechanics. Reductions in dynamic compliance of the lung and airway conductance were produced either by 3 to 7 tidal volume breaths of leukotriene D4 (0.125 micrograms/ml) delivered through an ultrasonic nebulizer or by intravenous histamine (2.8 +/- 0.2 micrograms/kg). Infusion of Anaritide (1 microgram/kg/min), before evoking bronchoconstriction with either LTD4 or histamine, produced a significant protection against bronchoconstriction produced by aerosol LTD4, but not against histamine-induced bronchoconstriction of similar magnitude. In other experiments, Anaritide infusion (0.5-2 micrograms/kg/min) also rapidly reversed a stable LTD4-induced decrease in airway conductance, but did not produce a similar reversal of the decrease in dynamic compliance. The data provide evidence that intravenous Anaritide exerts both bronchoprotective and bronchodilator effects against LTD4-induced bronchospasm.