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Abstract-The tracheal smooth muscle dissected free from connective tissues was used as a test preparation, since isoprenaline caused a decrease in cyclic GMP in the muscle while it caused an increase in cyclic GMP in the remaining tracheal tissue. Acetylcholine, histamine and papaverine increased both cyclic AMP and cyclic GMP levels in the tracheal muscle. Isoprenaline increased the cyclic AMP level but decreased the cyclic GMP level. However, when tracheal muscle was incubated with isoprenaline in the presence of acetylcholine, isoprenaline did not cause a decrease in cyclic GMP but rather a significant increase in cyclic AMP after only 1 min incubation. These results indicate that the relaxation of the tracheal muscle by isoprenaline is initiated by the increase in cyclic AMP but is not associated with the change in cyclic GMP.Several authors have reported that elevation of the intracellular cyclic AMP level is associated with relaxation of smooth muscle induced by isoprenaline or papaverine (1, 2, 3, 4, 5, 6). It has also been reported that acetylcholine and other muscarinic receptor stimulants increase the intracellular level of cyclic GMP in mammalian heart muscle, brain, lung slices and intestinal smooth muscle (2,7,8,9,10,11). Recently, Murad and Kimura (12) tested the effects of several drugs on cyclic AMP and cyclic GMP levels in incubations of guinea pig tracheal ring preparations and concluded that drugs which can relax the tracheal muscle increased the cyclic AMP level and drugs which can contract the muscle increased the cyclic GMP level. It is, however, well known that the tracheal smooth muscle contracted by acetylcholine is relaxed by beta-adrenomimetics. Therefore, the aim of the present work was to test changes in cyclic AMP and cyclic GMP levels involved in antagonism between acetylcholine and isoprenaline. MATERIALS AND METHODSFemale Hartley guinea pigs (250-350 g in body weight) were sacrificed by a blow on the head and then bled from the femoral artery. The trachea was isolated and placed in a Locke-

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Abstract-The mode of action of a novel compound, 3-isobutyryl-2-isopropylpyrazolo [1,5-a]pyridine (KC-404), as a potential anti-allergic agent has been investigated. KC 404 was shown to have a direct bronchodilator activity in guinea pig trachea in vitro and in anesthetized guinea pig in vivo. In addition, KC-404 had a fairly selective antago nistic action against slow reacting substance of anaphylaxis (SRS-A) on guinea pig ileum in vitro. In anesthetized guinea pigs, ED50 values for intravenously and intraduodenally injected KC-404 to inhibit SRS-A-induced bronchoconstriction were 0.0014 and 0.0065 mg/kg, respectively. Much higher doses were required to inhibit bronchospasms produced by histamine or particularly by acetylcholine. Orally administered KC-404 , 0.001 to 0.1 mg/kg, also showed a selective inhibitory effect on increased vascular permeability by intradermal SRS-A in guinea pigs and rats. KC-404 inhibited the immunological release of mediators, notably SRS-A from sensitized guinea pig chopped lung in vitro at 10-8 to 10-4 g/ml. In vivo, the release of SRS-A, but not of histamine , mediated by a nonreaginic antibody in the peritoneal cavity of sensitized rats was inhibited by KC-404 at oral doses above 3 mg/kg. In a similar anaphylactic reaction but mediated by a reaginic antibody, KC-404 also inhibited SRS-A release at intraperitoneal doses of 2 .5 to 10 mg/kg. The inhibitory activity on histamine release was less than half of that on SRS-A release . These results indicate that KC-404 is an orally active compound with a unique mode of action to inhibit preferentially both the effects and immunological release of SRS-A.