BOURA A L, GREEN A F
Br J Pharmacol Chemother. 1962 Aug;19(1):13-41. doi: 10.1111/j.1476-5381.1962.tb01424.x.
Bretylium depresses the slope of regression lines relating frequency of sympathetic nerve stimulation to magnitude of contractions of the cat nictitating membrane. In contrast, guanethidine and reserpine preferentially abolish responses to low rates of nerve stimulation and cause a roughly parallel shift of the regression lines. The hypersensitivity of the nictitating membranes of cats to intravenous adrenaline or noradrenaline is far greater after a series of small daily doses of bretylium or guanethidine than after single large doses. The maximal sensitivity produced was similar to that after postganglionic sympathetic nerve section and exceeded that produced by ganglion blockade. The development of hypersensitivity to catechol amines is accompanied by some return of responses of the nictitating membranes to sympathetic nerve stimulation despite continued daily administration of bretylium or guanethidine. In cats given bretylium daily, responses to low rates of nerve stimulation become greater than in controls unless the dose of bretylium given subcutaneously is 50 mg/kg or more. When marked hypersensitivity to catechol amines has been produced by giving bretylium or guanethidine daily for 7 or 14 days, the sympathomimetic effects of these compounds are greater. Responses to intravenous dimethylphenylpiperazinium are also increased and the results suggest that even large daily doses of adrenergic neurone blocking agents do not appreciably impair the functioning of the adrenal medulla. The pressor effects of intravenous adrenaline, noradrenaline and dimethylphenylpiperazinium iodide increase less than the corresponding nictitating membrane responses. These results are discussed in relation to tolerance to adrenergic neurone blockade, and differences between the effects of bretylium and guanethidine found in man. Bretylium and guanethidine depress the slopes of the dose-response curves for the pressor and nictitating membrane contracting effects of tyramine. When single doses or a short series of daily doses were given, guanethidine caused more depression of the slopes than did bretylium, but nevertheless large depressions of slope were found after giving bretylium daily for several weeks. The magnitude of the responses can be greater or less than in controls depending on the dose of the sympathomimetic amine, the dose of the adrenergic neurone blocking agent and the duration of its administration. The results suggest that injection of tyramine produces a progressively smaller release of adrenaline or noradrenaline during the daily administration of bretylium (or guanethidine) but that in some test situations this is more than compensated for by the development of hypersensitivity to the catechol amine released. Some corresponding changes in responses to amphetamine and ephedrine are also described.
溴苄铵可降低猫瞬膜收缩幅度与交感神经刺激频率之间的回归线斜率。相比之下，胍乙啶和利血平优先消除对低频率神经刺激的反应，并使回归线大致平行移动。在每日给予小剂量溴苄铵或胍乙啶连续数天后，猫瞬膜对静脉注射肾上腺素或去甲肾上腺素的超敏反应比单次给予大剂量时要大得多。产生的最大敏感性与节后交感神经切断后的情况相似，且超过了神经节阻断所产生的敏感性。对儿茶酚胺的超敏反应发展过程中，尽管持续每日给予溴苄铵或胍乙啶，但瞬膜对交感神经刺激的反应仍会有一定程度的恢复。在每日给予溴苄铵的猫中，除非皮下注射溴苄铵的剂量为50mg/kg或更高，否则对低频率神经刺激的反应会比对照组更大。当通过每日给予溴苄铵或胍乙啶7天或14天产生明显的儿茶酚胺超敏反应时，这些化合物的拟交感神经作用会更强。对静脉注射二甲基苯基哌嗪鎓的反应也会增强，结果表明，即使每日给予大剂量的肾上腺素能神经元阻断剂，也不会明显损害肾上腺髓质的功能。静脉注射肾上腺素、去甲肾上腺素和二甲基苯基哌嗪鎓碘化物的升压作用增加幅度小于相应的瞬膜反应。结合对肾上腺素能神经元阻断的耐受性以及在人体中发现的溴苄铵和胍乙啶作用差异对这些结果进行了讨论。溴苄铵和胍乙啶可降低酪胺升压和使瞬膜收缩作用的剂量 - 反应曲线斜率。当给予单次剂量或短疗程的每日剂量时，胍乙啶比溴苄铵更能降低曲线斜率，但在连续数周每日给予溴苄铵后，也会出现斜率的大幅降低。根据拟交感神经胺的剂量、肾上腺素能神经元阻断剂的剂量及其给药持续时间，反应幅度可能大于或小于对照组。结果表明，在每日给予溴苄铵（或胍乙啶）期间，注射酪胺引起的肾上腺素或去甲肾上腺素释放逐渐减少，但在某些测试情况下，对释放的儿茶酚胺产生的超敏反应可对此进行更多补偿。还描述了对苯丙胺和麻黄碱反应的一些相应变化。
