Responses to Norepinephrine Resistant to Inhibition by Alpha and Beta Adrenoceptor Antagonists1

The mode of action of clonidine and norepinephnne (NE) has concentration-effect curve to NE remaining after treatment with been investigated in the isolated transmurally stimulated guinea- benextramine showed an ICsc of about 3 x 1 0 M and an pig ileum preparation using rauwolscine, idazoxan and benextra- intrinsic activity of 0.6. This curve was resistant to further inhi-mine as antagonists. Both donidine and NE produced concen- bftion by donidine (10 M), phentolamine (3 x 10 M), rauwol-tration-dependent inhibition of the cholinergically induced twitch sane (3 x 1 0 M), prazosin (1 0 M) and propranolol (1.2 x response and were antagonized by rauwoiscine and idazoxan, iO M). Thus, alpha and beta adrenergic receptors do not but only clonidine was antagonized in a truly competitive fashion. appear to be involved. It is postulated that NE-IndUCed inhibition Benextramine, an irreversible alpha adrenoceptor antagonist, in of the guinea-pig ileum twitch response is mediated by two a concentration of 1 0 M, inhibited the effect of clonidine corn- distinct sites: one is the classical a!pha-2 adrenoceptor (the site pletely but only partially antagonized the inhibitory action of NE. of action of clonidine and the alpha adrenoceptor antagonists) The antagonism of NE by rauwoiscane and benextramine was whereas the other is a site seemingly unrelated to the alpha and most pronounced after reserpine pretreatment and blockade of beta subtypes. neuronal and extraneuronal uptake. Under these conditions, the The receptor sites with which NE and other sympatho- of apha-2 agonists and antagonists. However, the results fro