α2‐Adrenoceptor blocking profile of SK&F 104078: further evidence for receptor subtypes

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Abstract
1 The ability of the putative, selective post-junctional α2-adrenoceptor antagonist, SK&F 104078 to antagonize the effects of structurally-diverse agonists at pre-junctional α2-adrenoceptors in the guinea-pig ileum and rat vas deferens in vitro and in the rat heart in vivo, and at post-junctional α2-adrenoceptors in the rabbit ear vein in vitro, was examined. Results obtained with SK&F 104078 were compared with those obtained with yohimbine. 2 Xylazine and B-HT933 each caused a concentration-dependent inhibition of the field-stimulation-evoked twitch responses of the guinea-pig ileum and rat vas deferens. SK&F 104078 did not antagonize either agonist in the guinea-pig ileum and exerted only minimal blocking activity against xylazine in the rat vas deferens. In contrast, SK&F 104078 competitively antagonized B-HT933 in the rat vas deferens (pA2 = 6.45). Yohimbine competitively antagonized both agonists in each tissue (pA2 values ranged between 7.46 and 7.88). 3 In the pithed rat xylazine and B-HT933, injected intravenously, caused a dose-dependent reduction in the tachycardia elicited by stimulation of the cardiac preganglionic sympathetic nerves. SK&F 104078 (10 mg kg−1, i.v.) caused a 20–30 fold rightward displacement of the dose-response curve to xylazine, but did not affect responses to B-HT933. Yohimbine (1 mg kg−1, i.v.) antagonized both agonists to a similar degree. 4 In the rabbit ear vein xylazine, B-HT933, noradrenaline and UK14304 elicted vasoconstrictor responses. Prazosin was without effect, but in contrast, SK&F 104078 was a competitive antagonist of each of the agonists (pA2 values ranged between 6.63 and 6.72). Yohimbine also competitively antagonized each of the agonists in this preparation (pA2 values ranged between 7.81 and 8.07). 5 SK&F 104078 was also a competitive antagonist (pA2 = 6.20) against noradrenaline at post-junctional α1-adrenoceptors in the rabbit aorta. 6 These data show that SK&F 104078 is a competitive antagonist at post-junctional α1- and α2-adrenoceptors. Its antagonist potency at pre-junctional α2-adrenoceptors is agonist- and tissue-dependent. Yohimbine does not discriminate between pre- and post-junctional α2-adrenoceptors. The findings are discussed in terms of the possible existence of subclasses of α2-adrenoceptors.