| Asthma is a disease characterized by chronic airway inflammation, airway hyper-responsiveness to a variety of stimuli and airway obstruction. Although the exact reason of asthma remains unclear, several factors would influence the disease, for example genetic factors, environmental factors and life style factors. In recent years, the morbidity and mortality of asthma are increasing.There are three kinds of drugs commonly used in the treatment of asthma: (1) The bronchodilators such asβ2-agonist, anti-cholinergic bronchodilators and extended-release theophyllamine; (2)Anti-inflammatory therapy such as glucocorticoids and leukotriene receptor antagonists; (3)Anti-allergic drugs such as disodium cromoglycate. Asthma is such a serious and common condition that rarely can be fully resolved. Although these drugs can alleviate both the symptom and the local inflammation effectively, the patients would develop tolerance to these drugs when used for a relative long period. Besides, these drugs have less efficiency to the severe asthma. Thus, there still need to develop new treatment to asthma as complement of these treatments.At present, immunotherapy aimed at the abnormal immunity of asthma such as cytokine antagonist developed rapidly. Researchers also focus on the drugs such as matrix metalloproteinases antagonist, adenosine receptor modulator, NF-κB antagonist, intercellular adhesion molecule-1 antagonist, endothelium-1 receptor antagonist. On the other hand, several studies showed that traditional Chinese herbal medicine such as radix astragali, radix salviae miltiorrhiae, herba ephedrae, et al, used alone or in combination, may improve the immune system of patient with asthma and alleviate the local inflammation of bronchia. However, the effect of Chinese herb is relatively weak and the components in it are very complex which may cause unexpected side-effects.Based on the pharmacological efficiency of traditional Chinese herb in the treatment of asthma and the results of our previous work on cholic acid and its analogs, the aim of our present study is to evaluate the effects of Ephedrine isomers and cholic acid analogs, which are the main components of Danmapian, used alone or in combination, against histamine induced constriction of guinea pig tracheal in vitro and to provide experimental evidences for developing a new composite preparation, which is expected to increase the curative effect and decrease the side-effect in the treatment of asthma. There were three steps in our study. Firstly, determination on the potency of the four Ephedrine isomers was conducted; Secondly the potency of cholic acid analogs was evaluated; Thirdly the concentration-response curves for the most potent Ephedrine isomer and cholic acid analog, alone or in combination, were ploted. The ED50 of both components, either alone or in combination, were calculated to judge synergic effect between the components.Med-lab-u/4cs system was used to record the changes of the tension of the isolated guinea pig tracheal after different drugs exposure. The statistical method in determination the potency of the four ephedrine isomers and cholic acid analogs was anova analysis,α=0.05. OriginPro 7.0 was used in curve fitting. Mapping analysis was used to evaluate the interaction of the combination of 1S, 2R-(+) Ephedrine hydrochloride and Deoxycholic acid.The result of the first step showed that 1S, 2R-(+) Ephedrine hydrochloride is the most potent antagonist as compared to the other isomers. Both Deoxycholic acid and Chendehydroxycholic acid are more effective than the other analogs, as showed in the second step. The combination of 1S, 2R -(+) Ephedrine hydrochloride and Deoxycholic acid, at ratio of 4:1 corresponding to the ED50 of them, exhibit more effective than the two components alone in that the dose-effect curve of the combination was shifted to the left compared to that of the component alone. The ED50 of the combination is smaller than the two components. The interaction between them is synergism according the mapping analysis. The results indicated that the combination of 1S, 2R-(+) Ephedrine hydrochloride and Deoxycholic acid might more effective than the two components alone in the treatment of asthma. The lower dose of the combination allowed for a decrease in the incidence of adverse effects.Danmapian is a traditional method to treat asthma which mainly consists of cholic acid analogs and Ephedrine isomers. Cholic acid and its analogs have extensive effects such as sedation, cholagogue, antiinflammation, defervesce and so on. Our previous work showed that the rank order of potency against pulmonary edema was deoxycholic acid > sodium chenodeoxycholate > hyodeoxycholic acid > ursodeoxycholic acid > cholic acid, which is consistent to the result of this study. It seemed clearly to us that the more the surfactant effects are, the more the pharmacological potency is.Alkaloids such as ephedrine, are the other main components of Danmapian. They are nonselectiveαandβreceptor agonist and used for the treatment of asthma because of their dilation effect to the bronchia. Both Ephedrine and pseudoephedrine may cause the side-effects of cardiovascular and neural system which maybe due to the nonselectivity effects on bothα- andβ-adrenergic receptors. Ephedrine, with two chiral centers, exists as four isomers that exhibit direct and indirect effects on bothα- andβ-adrenergic receptors (AR). The four isomers of ephedrine are 1R, 2S-(-) ephedrine, 1S, 2R-(+) ephedrine, 1R, 2R-(-) pseudoephedrine, and 1S, 2S-(+) pseudoephedrine. The result of our study showed that 1S, 2R-(+) Ephedrine hydrochloride was the most potent antagonist as compared to the others. Previous work showed that On humanβ1-AR, the rank order of potency was 1R, 2S-ephedrine > 1S, 2R-ephedrine > 1S, 2S-pseudoephedrine = 1R, 2R-pseudoephedrine. On humanβ2-AR, the rank order of potency was 1R, 2S-ephedrine > 1R, 2R-pseudoephedrine≥1S, 2S-pseudoephedrine > 1S, 2R-ephedrine. The rank order of potency on humanα-AR remained unknown. The result of our study is different from the reports. The reason may be due to the different method used in the study.According to our study, we found that 1S, 2R-(+) Ephedrine hydrochloride and Deoxycholic acid were the most potent antagonists as compared to the others and that the combination of 1S, 2R - (+) Ephedrine hydrochloride and Deoxycholic acid was more effective than the two components used alone. The interaction between them is synergism according the mapping analysis. Furthermore, the lower dose of the combination allowed for a decrease in the incidence of adverse effects. We found some evidences for a new combination of 1S, 2R-(+) Ephedrine hydrochloride and Deoxycholic acid in the treatment of asthma. In addition, our study might be of some value for the modernization of Chinese herb.
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