EFFECT OF MOLSIDOMINE AND LINSIDOMINE ON THE HUMAN ISOLATED BRONCHUS AND THE GUINEA-PIG ISOLATED TRACHEA

The effects of molsidomine and its metabolite linsidomine were studied on the guinea-pig isolated trachea and on the human isolated bronchus . These effects were compared with those of nitrate derivatives (sodiu m nitroprusside, isosorbide dinitrate), theophylline, zardaverine and isoprenaline. Linsidomine exerted a relaxant effect similar to that of sodium nitroprusside on the two types of preparations precontracted w ith acetylcholine, histamine or potassium chloride. Molsidomine was ab out one-hundredth as potent as linsidomine, and less efficacious. The effects of the two substances were not modified by removal of the huma n bronchial epithelium. The concentration-response curves of linsidomi ne and sodium nitroprusside were significantly shifted to the right by methylene blue (3 x 10(-5) m) but the effects of isoprenaline were un modified. The effects of linsidomine and sodium nitroprusside were pot entiated specifically by zaprinast (10(-6)-10(-5) m), an inhibitor of type Ia or V phosphodiesterases, whereas the effects of isoprenaline w ere potentiated by zardaverine (10(-9)-10(-8) m), an inhibitor of clas s III and IV phosphodiesterases. The effects of all three substances ( linsidomine, isoprenaline and sodium nitroprusside) were potentiated e qually by theophylline (10(-5)-10(-4) M), a nonspecific inhibitor of p hosphodiesterases. It is concluded that linsidomine is a potent relaxa nt of the smooth muscle of the guinea-pig isolated trachea and human i solated bronchus. In terms of potency and efficacy, its effect is much superior to that of the parent compound molsidomine. It is suggested that linsidomine acts, like nitrate derivatives, through the guanylate cyclase-cGMP system.