Evaluation of the selectivity of alpha-adrenoreceptor blocking drugs for postsynaptic alpha 1- and alpha 2-adrenoreceptors in a simple animal model.

1 The increase of diastolic pressure of pithed, normotensive rats was determined after i.v. administration of the alpha-adrenoreceptor agonists L-phenylephrine and B-HT 933. 2 alpha-Adrenoreceptor antagonists varied widely in their relative inhibitory effects towards either L-phenylephrine- or B-HT 933-induced vasoconstrictor responses. Prazosin displayed the highest affinity for the postsynaptic alpha-adrenoreceptor triggered by L-phenylephrine. The rank order of potency was further: phenotlamine greater than dihydroergotamine greater than clozapine greater than corynanthine greater than azapetine greater than yohimbine greater than piperoxan greater than tolazoline greater than mainserin greater than rauwolscine. On the other hand, the rank order of potency towards B-HT 933 was: dihydroergotamine greater than rauwolscine greater than yohimbine greater than phentolamine greater than piperoxan greater than prazosin greater than tolazoline greater than mainserin greater than corynanthine greater than azapetine greater than clozapine. These data are in general agreement with the classification of alpha 1-(triggered by L-phenylephrine) and alpha 2-(triggered by B-HT 933) adrenoreceptors. Both populations are present postsynaptically in vascular smooth muscle of the pithed rat and are involved in vasoconstriction. 3 The ratio of KB post alpha 2/KB post alpha 1 was calculated as a measure of selectivity for either alpha-adrenoreceptor site. The alpha-adrenoreceptor antagonists used cover a 20,000-fold range of activity ratios. The antagonists most selective for either type were prazosin (alpha 1) and rauwolscine (alpha 2). The selectivity of the alpha-adrenoreceptor antagonists for postsynaptic alpha 1- and alpha 2-adrenoreceptors in the intact circulatory system of the pithed rat is comparable with the reported selectivity of these blocking agents for alpha 1 (postsynaptic)- and alpha 2(presynaptic)-adrenoreceptors in the rabbit isolated pulmonary artery. 4 It is concluded that two distinct types of postsynaptic alpha-adrenoreceptors participate in vasoconstriction in the pithed rat. Apart from the classical alpha 1-adrenoreceptor, vascular smooth muscle of the pithed rat contains postsynaptic alpha 2-adrenoreceptors resembling those previously found mainly presynaptically. The presence of separate classes of postsynaptic alpha 1- and alpha 2-adrenoreceptors in the intact circulatory system of the pithed rat offers the possibility to use this relatively simple animal model as an in vivo test system for the pharmacological characterization of alpha-adrenoreceptors agonists and antagonists.