The cyclic AMP system in sensitized and desensitized guinea-pig tracheal smooth muscle.

Egg albumin decreased the cyclic AMP content and the protein kinase ratio of sensitized guinea-pig tracheal smooth muscle. The effect preceded the contraction of the tracheal preparation. Antigen challenge increased cyclic AMP phosphodiesterase activity without changing the Km value. In tracheal preparations of desensitized guinea-pigs, the mechanical and metabolic effects of egg albumin were markedly reduced. These results suggest that the effects on the cyclic AMP system in response to immunological challenge might represent an important mechanism modulating the contractile response of guinea-pig tracheal smooth muscle.

Effects of SRS (slow reacting substance) on cyclic nucleotides in guinea pig tracheal muscle.

Leukotriene (SRS) appears to contribute to the prolonged phase of the tracheal contraction induced by egg albumin, indomethacin and tartrazine as this response was effectively antagonised by FPL 55712. Egg albumin, indomethacin and tartrazine reduced the cAMP level of guinea pig trachea pretreated with adrenergic, cholinergic, histaminergic and 5-hydroxytryptaminergic antagonists. Egg albumin, but not the other agents, caused a transient increase of the cGMP content. The metabolic and contractile effects were blocked by FPL 55712. It is suggested that the cAMP reduction caused by egg albumin, indomethacin and tartrazine might promote contractions ot the tracheal muscle.

Decreased Schultz-Dale reaction in airways from sensitized guinea pigs treated with threshold concentrations of egg albumin in vivo.

Treatment of egg albumin sensitized guinea pigs with repeated concentrations of egg albumin changed the Schultz-Dale response. The dose-response curve of egg albumin on the trachea was shifted to the right. Both the amount of SRS-A and histamine released by antigen exposure from sensitized or desensitized guinea pig lungs were almost similar. Regarding the number of H1-receptors in an isolated membrane fraction from the lungs of sensitized and desensitized guinea pigs, no significant difference was observed. on the contrary, the receptor-response to SRS-A was found to be decreased in desensitized trachea in comparison with sensitized trachea. The treatment of guinea pigs with repeated threshold concentrations of histamine did not change the contractile response neither to histamine nor to egg albumin. The decreased Schultz-Dale response after repeated egg albumin treatment in vivo might depend on desensitization of a hypothetical SRS-A receptor.

Potent bronchodilating effects of enprofylline and theophylline on contractions induced by egg albumin or by slow reacting substance (SRS).

Isolated sensitized guinea pig tracheal smooth muscle tone was induced by use of egg albumin or SRS-A (slow reacting substance of anaphylaxis). The dose-response relationships of theophylline and enprofylline were studied on these preparations. Enprofylline was more potent than theophylline in relaxing the egg albumin- or SRS-A-induced tracheal muscle tone. The theophylline relaxation-curve was significantly shifted to the left after addition of adenosine-deaminase to the egg albumin-contracted trachea, but this was not observed with the enprofylline relaxation-curve. In SRS-A-contracted tracheas, the addition of adenosine-deaminase did not significantly alter the relaxation curves of theophylline or enprofylline. It is therefore suggested that the relaxing effects of theophylline and enprofylline on SRS-A-induced contractions, at the therapeutically relevant concentrations demonstrated in this study, might be of importance for the anti-asthmatic effects of xanthines.

Studies of the contracting mechanism induced by slow reacting substance of anaphylaxis (SRS-A): interaction with calcium.

The present study demonstrates the Ca2+ dependency of the contractions elicited by egg albumin and SRS-A in isolated tracheal preparations from sensitized guniea-pigs. The egg albumin contraction consisted of a rapid, initial and a long lasting, tonic phase; the first phase independent and the latter dependent of extracellular Ca2+. The SRS-A contraction was completely dependent of extracellular Ca2+ ions. On the other hand, the egg albumin contraction of the parenchymal strips was not influenced by extracellular Ca2+. SRS-A released Ca2+ from a microsomal fraction of sensitized lung tissue. This effect was, however, absent in microsomes from desensitized lung tissue. It is suggested that the Ca2+ -mobilizing effect of SRS-A is of utmost importance for the initiation of contraction of the tracheal smooth muscle.

Effects of tartrazine of different contractile stimuli in guinea pig tracheal muscle.

Tracheal smooth muscle obtained from ovalbumin-sensitized guinea pigs contracted with micromolar concentrations of tartrazine and indomethacin. The contractions were slightly reduced by clemastine, but were completely blocked by the SRS-A antagonist FPL 55712. Arylsulfatase B, which is an enzyme that inactivates SRS-A, also abolished the contractions induced by tartrazine. Contractions induced by carbacholine, histamine, egg albumin and arachidonic acid were slightly reduced by indomethacin and tartrazine. Tartrazine like indomethacin inhibited the generation of thromboxanes from human platelets. We suggest that SRS-A plays an important role in the immediate hypersensitivity reactions of tartrazine and indomethacin in guinea pig trachea.