STIMULATION OF THE ANTIGEN‐INDUCED CONTRACTION OF GUINEA‐PIG TRACHEA AND IMMUNOLOGICAL RELEASE OF HISTAMINE AND SRS‐A FROM SENSITIZED GUINEA‐PIG LUNG BY (2‐ISOPROPYL‐3‐INDOLYL)‐3 PYRIDYL KETONE (L8027) AND INDOMETHACIN

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Abstract
(2‐Isopropyl‐3‐indolyl)‐3 pyridyl ketone (L8027) and indomethacin reduced basal tension and enhanced the antigen‐ and histamine‐induced contractions of tracheal spirals obtained from actively sensitized guinea‐pigs. The stimulating effect of L8027 required the presence of the drug, while that of indomethacin persisted after its removal from the organ bath. L8027 and indomethacin stimulated the immunological release of histamine and slow reacting substance of anaphylaxis (SRS‐A) and inhibited the de novo synthesis and release of malondialdehyde from actively sensitized guinea‐pig lung fragments. L8027 was 2,800 times more potent than indomethacin in both in vitro models of anaphylaxis. A selective antagonist of SRS‐A (FPL 55712) inhibited contractions produced by antigen, but had no effect on contractions produced by histamine. Prostaglandins E and F2α were continuously released into the organ bath fluid by the resting trachea. Contractions induced by antigen or histamine increased the rate of prostaglandin efflux. L8027 had no effect on the efflux of prostaglandins E and F2α at rest and during contraction. Indomethacin inhibited prostaglandin efflux at rest and during contraction while present in the organ bath. Prostaglandin efflux was restored to 80% of control after removal of indomethacin. The results suggest that prostaglandins E and F2α have no role in the stimulation by L8027 and indomethacin of the contractile responses of guinea‐pig trachea. The possible mechanism for the effects of these drugs is discussed.