New concepts on alpha-adrenoceptors in pharmacology.

Alpha-adrenoceptors have been classified on a morphological basis as pre- and postsynaptic and on a pharmacological basis as alpha 1- and alpha 2-subtypes. Alpha 1 as well as alpha 2-receptors might be present at pre- as well as postsynaptic sites (fig. 1). The pressor effects after i.v. injection of alpha-adrenoceptor agonists in pithed rats are mediated by both, the alpha 1- and the alpha 2-subtype, as was shown by the different antagonistic potencies of yohimbine and prazosin respectively against the agonists methoxamine, clonidine and B-HT 920 (fig. 2). This method was extended to estimate the alpha 1/alpha 2 selectivity ratio of various agonists, by determination of the antagonistic potencies of rauwolscine ( D10R ) and prazosine ( D10P ), and calculating the ratio D10R / D10P (table I). The drugs with highest selectivity towards alpha 2 (B-HT 920) and towards alpha 1 (methoxamine) respectively were used to estimate the relative distribution of alpha 1/alpha 2 receptors ("receptor importance") in various peripheral target organs or systems by determination of the equipotent dose ratios B-HT 920/methoxamine (fig. 3, left). Later, the alpha 1-selective agonist St 587, which easily penetrates into the brain was used instead of methoxamine to estimate the ratio of alpha 1/alpha 2 "receptor importance" for several CNS activities (fig. 2, right). The presence of alpha 2-adrenoceptors in vitro was demonstrated in isolated perfused rat hindquarters after pretreatment with reserpine (fig. 4). The role of alpha-adrenoceptors in the CNS for a certain pattern of cardiovascular depression is reviewed. Stimulation of medullary alpha-adrenoceptors by e.g. clonidine mediates sympathoinhibition and facilitation of the vagally mediated baroreceptor reflex. The receptors concerned are postsynaptic as the effects were demonstrated following the depletion of brain noradrenaline by pretreatment with reserpine and alpha-methyl-p- tyrosin (table II). The receptors mediating central cardiovascular depression are of the alpha 2-type as the highly selective alpha 2-adrenoceptor agonists B-HT 920 and B-HT 933 were active whereas the alpha 1-agonist St 587 was ineffective.