Among the many side actions of antihistamine drugs which have been reported, the only direct action on smooth muscle which is well known is that on the uterus; most antihistamines have some oxytocic activity. It is generally believed that these drugs have no action of their own on the bronchial musculature, but a few exceptions have been reported. Bovet (1934) found that the early precursor thymoxyethyldiethylamine (929F) contracted guinea-pig bronchi, and Staub (1939) observed a similar action with N-phenyl-N-ethyl-N'-diethylethylenediamine (1571F). Castillo and de Beer (1947) show a tracing which illustrates that diphenhydramine (10-5) contracts the guineapig tracheal chain, but do not comment thereon. Herxheimer (1953) found that inhalations of aerosols of 3 % promethazine or 5% chlorcyclizine caused dyspnoea in guinea-pigs. On the other hand, De Schaepdrijver (1948) found that large doses of antazoline relaxed the bronchi of perfused guinea-pig lungs.Antihistamines are usually tested against histamine, using only low concentrations of the antagonist. In order to antagonize the anaphylactic contraction of bronchial muscle, much higher concentrations are required. In the course of some work in this field it was observed that all the antihistamines used caused contractions of the guinea-pig tracheal chain in concentrations between 10-6 and 10-4, and above these concentrations they caused relaxation. Because these were the very concentrations required to antagonize the anaphylactic contraction of isolated guineapig trachea or the allergic contraction of isolated human bronchus (Schild, Hawkins, Mongar and Herxheimer, 1951), the bronchoconstrictor action of antihistamine drugs was investigated further. The present work consists of a study of the direct action on the bronchial musculature of a series of twelve well-known antihistamine drugs.
METHODSGuinea-pig Tracheal Chains.-Tracheal chains (Epstein, 1932;Castillo and de Beer, 1947) were made using 6 to 8 rings, tied tightly with cotton thread, and orientated alternately so that the muscle strips were aligned. Guinea-pigs of all sizes were used, but it was found that chains were easiest to prepare from the tracheas of animals weighing between 500 and 600 g. The preparations were maintained at 370 C. in KrebsHenseleit solution (NaCl 6.87; KCI 0.43; CaCl2 0.28; MgSO4,7H20 0.29; NaH2P]O,2H20 0.18; NaHCO3 2.10; glucose 1.00 g./l.) aerated with 02 + 5% C02, or in a similar solution containing one-tenth as much NaHCO3 aerated with 02 alone. The tonus level of the preparations was continuously recorded with a light balsa-wood frontal writing lever giving a magnification of about x20, tension about 200 mg., writing on a lightly smoked kymograph drum. The preparations were left for 1 to 2 hours before any drugs were given. During this period a marked rise of tonus level invariably occurred, the preparation then relaxing to a steady tonus level. Similar "post-mortem contractures" of isolated bronchial muscle were observed by Macht and Ting (1921).In general, two or thre...