COMBINED α‐ AND β‐ADRENOCEPTOR BLOCKING DRUG AH 5158: FURTHER STUDIES ON α‐ADRENOCEPTOR BLOCKADE IN ANAESTHETIZED ANIMALS

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Abstract
1 AH 5158, 5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]salicylamide, competitively antagonised phenylephrine-induced vasopressor responses in anaesthetized dogs, thus confirming that the drug possesses α-adrenoceptor blocking activity. 2 In contrast, AH 5158 was a relatively ineffective antagonist of vasopressor responses to noradrenaline in anaesthetized dogs. Thus, at the lowest dose-level tested (1 mg/kg) AH 5158 abolished the increase in pulse width caused by noradrenaline, but otherwise had little or no blocking effect in doses as high as 10 mg/kg. Propranolol (0.1 mg/kg) also abolished the increase in pulse width caused by noradrenaline. With both drugs this effect is thought to be a consequence of blockade of the β-adrenoceptor-mediated cardiac stimulant action of noradrenaline. 3 The interaction between AH 5158 and noradrenaline in spinal dogs, anaesthetized cats and pithed rats was very similar to that seen in anaesthetized dogs. 4 Noradrenaline pressor responses were effectively antagonized by AH 5158 in anaesthetized dogs pretreated with cocaine. The degree of block was similar to that obtained when phenylephrine was the agonist in untreated dogs. 5 These results are consistent with the hypothesis that AH 5158 blocks a cocaine-sensitive inactivation process for noradrenaline in addition to blocking α- and β-adrenoceptors. The resultant increase in the level of circulating noradrenaline would tend to counteract the adrenoceptor blocking action of the drug. 6 The implications of these findings are discussed.