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α 2 ‐Adrenoceptor blocking profile of SK&F 104078: further evidence for receptor subtypes
Author(s) -
Akers I.,
Coates J.,
Drew G.M.,
Sullivan A.T.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12281.x
Subject(s) - yohimbine , vas deferens , xylazine , endocrinology , medicine , prazosin , stimulation , agonist , chemistry , ileum , antagonist , receptor , biology , anesthesia , ketamine
1 The ability of the putative, selective post‐junctional α 2 ‐adrenoceptor antagonist, SK&F 104078 to antagonize the effects of structurally‐diverse agonists at pre‐junctional α 2 ‐adrenoceptors in the guinea‐pig ileum and rat vas deferens in vitro and in the rat heart in vivo , and at post‐junctional α 2 ‐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 (pA 2 = 6.45). Yohimbine competitively antagonized both agonists in each tissue (pA 2 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 (pA 2 values ranged between 6.63 and 6.72). Yohimbine also competitively antagonized each of the agonists in this preparation (pA 2 values ranged between 7.81 and 8.07). 5 SK&F 104078 was also a competitive antagonist (pA 2 = 6.20) against noradrenaline at post‐junctional α 1 ‐adrenoceptors in the rabbit aorta. 6 These data show that SK&F 104078 is a competitive antagonist at post‐junctional α 1 ‐ and α 2 ‐adrenoceptors. Its antagonist potency at pre‐junctional α 2 ‐adrenoceptors is agonist‐ and tissue‐dependent. Yohimbine does not discriminate between pre‐ and post‐junctional α 2 ‐adrenoceptors. The findings are discussed in terms of the possible existence of subclasses of α 2 ‐adrenoceptors.