?-Adrenergic agonists, potent nonspecific inhibitors of circulatory shock in rats

The activity of a series of nine β-adrenergic agonists was studied in the potassium cyanide (KCN; 5.00 mg/kg i.v.) and the compound 48/80 (0.50 mg/kg i.v.) lethality tests in rats. All compounds were found active in both tests. The ED50 values in mg/kg for protection against KCN-induced lethality were as follows: clenbuterol (0.0047), zinterol (0.0055), hexoprenaline (0.0093), fenoterol (0.012), isoproterenol (0.014), colterol (0.019), salbutamol (0.028), terbutaline (0.14), and metaproterenol (0.33). The obtained results illustrate that KCN antagonism in rats is a general property of β-adrenergic agonists and that their potency is in agreement with previously reported data for β-adrenergic stimulation. By increasing the dose levels, the protective activity of some of the compounds disappeared and LD50s at which lethality to KCN was restored could be calculated. The protective dose range, which is defined as the ratio of the LD50 and the ED50, greatly varies among the test compounds. Protection from compound 48/80 induced lethality was also obtained with all compounds. This protection occurred at higher dose levels than in the KCN test, but persisted at agonist doses that had lost protective effect against KCN. Protection from KCN-induced lethality seems to be due to an increased tissue perfusion and to occur as long as myocardial activity is not markedly changed from normal by the test compound.