The pharmacological activities of the enantiomers of
amosulalol (YM-09538), a combined alpha- and
beta-adrenoceptor antagonist, and the corresponding desoxy derivative (YM-11133) were investigated in the cardiovascular system of rats. The optical isomers of
amosulalol and YM-11133 antagonized the vasopressor effect of
phenylephrine and the positive chronotropic effect of
isoproterenol in normotensive pithed rats. Based on DR2 values (micrograms/kg, i.v.) obtained from Schild plots, (+)-
amosulalol and YM-11133 (DR2 = 30) were approximately 10 times more potent than (-)-
amosulalol (DR2 = 324) in blocking alpha 1-adrenoceptors. For beta 1-adrenoceptors, in contrast, (-)-
amosulalol (DR2 = 107) was approximately 60 times more potent than (+)-
amosulalol (DR2 = 6460), which was almost equipotent with YM-11133 (DR2 = 3250). The results indicate that the optical isomers of
amosulalol interact differently with alpha 1- and beta 1-adrenoceptors. The effects of these
phenethylamines on blood pressure and heart rate were studied in
urethane-anesthetized rats (i.v.). The rank order of hypotensive potency in anesthetized rats [+)- = desoxy greater than (-)-form) was consistent with the rank order of alpha 1-
adrenoceptor antagonism in pithed rats. In contrast, (-)-
amosulalol having a more potent beta 1-
adrenoceptor antagonist activity than (+)-
amosulalol and
YM-11133 only produced dose-dependent
bradycardia at the hypotensive doses. The results indicate that the vascular alpha 1- and cardiac beta 1-
adrenoceptor blocking activities of the optical isomers of
amosulalol contribute to their hypotensive and
bradycardia, respectively. Thus, the racemate of
amosulalol appears to exert an overall activity reflecting the activities of the individual isomers.