Van Bortel L M, de Hoon J N, Kool M J, Wijnen J A, Vertommen C I, Van Nueten L G
Department of Pharmacology, University of Limburg, Cardiovascular Research Institute Maastricht, The Netherlands.
Eur J Clin Pharmacol. 1997;51(5):379-84. doi: 10.1007/s002280050217.
The aims of the present study were to determine (1) the beta 1-blocking potency and (2) the beta 1-adrenoceptor selectivity of nebivolol in man after repeated dosing (7 days) compared with that after a single oral intake and with that after atenolol for 7 days. In addition, it was investigated whether (3) nebivolol has alpha 1-blocking properties which might at least in part explain the vasodilating property of the compound.
Twelve healthy subjects were randomized in an open, two-way cross-over study. beta 1-Blocking potency and beta 1-adrenoceptor selectivity of nebivolol 5 mg once daily (o.d.) were compared with those of atenolol at three doses (25, 50 and 100 mg) o.d. Measurements were performed after 1 and 7 days of drug intake. beta 1-Adrenoceptor potency was assessed by the percentage decrease in exercise-induced tachycardia (delta EIT) during beta-blockade. beta 1-Selectivity of nebivolol and atenolol were investigated using the heart rate response to isoprenaline at equipotent beta 1-blocking dosages of both drugs. alpha 1-Blockade of nebivolol was measured using the phenylephrine dose-response test.
delta EIT after a single oral dose of nebivolol 5 mg (10%) was significantly smaller than after nebivolol 5 mg o.d. for 7 days (15%). After 1 week of treatment no difference was seen in delta EIT between nebivolol 5 mg o.d. and atenolol 25 mg o.d. (16%). At these dosages the suppression in isoprenaline-induced tachycardia by both drugs did not differ (CD20 ratio 1.7). In contrast to atenolol 25 mg, after 1 week of nebivolol 5 mg o.d., blood pressure decreased. This decrease averaged 10% and-like in a study with hypertensive patients-was similar with that after atenolol 100 mg o.d. None of the phenylephrine test parameters changed from pre-study values after nebivolol.
beta 1-Blockade of nebivolol 5 mg is larger after repeated dosing than after a single oral intake. After once daily repeated dosing nebivolol 5 mg and atenolol 25 mg are equipotent in beta 1-antagonism. No difference in beta 1-selectivity is observed between the two drugs. Nebivolol has no additional alpha 1-blocking property, which may at least in part explain its vasodilating effect.
本研究的目的是确定：（1）奈必洛尔在多次给药（7天）后与人单次口服给药后以及与阿替洛尔给药7天后相比的β1受体阻断效能；（2）奈必洛尔在多次给药（7天）后与人单次口服给药后以及与阿替洛尔给药7天后相比的β1肾上腺素能受体选择性。此外，还研究了（3）奈必洛尔是否具有α1受体阻断特性，这可能至少部分解释了该化合物的血管舒张特性。
12名健康受试者被随机纳入一项开放的双向交叉研究。将每日一次口服5mg奈必洛尔的β1受体阻断效能和β1肾上腺素能受体选择性与三种剂量（25mg、50mg和100mg）每日一次口服阿替洛尔的情况进行比较。在药物摄入1天和7天后进行测量。通过β受体阻滞剂治疗期间运动诱发心动过速（ΔEIT）的降低百分比来评估β1肾上腺素能受体效能。在两种药物等效的β1受体阻断剂量下，利用对异丙肾上腺素的心率反应来研究奈必洛尔和阿替洛尔的β1选择性。使用去氧肾上腺素剂量反应试验测量奈必洛尔的α1受体阻断情况。
单次口服5mg奈必洛尔后的ΔEIT（10%）显著小于每日一次口服5mg奈必洛尔7天后的ΔEIT（15%）。治疗1周后，每日一次口服5mg奈必洛尔与每日一次口服25mg阿替洛尔之间的ΔEIT无差异（16%）。在这些剂量下，两种药物对异丙肾上腺素诱发心动过速的抑制作用无差异（CD20比值为1.7）。与每日一次口服25mg阿替洛尔不同，每日一次口服5mg奈必洛尔1周后血压下降。这种下降平均为10%，并且——与一项针对高血压患者的研究一样——与每日一次口服100mg阿替洛尔后的情况相似。奈必洛尔治疗后，去氧肾上腺素试验的各项参数均未从研究前的值发生变化。
每日一次重复给药后，5mg奈必洛尔的β1受体阻断作用比单次口服给药后更强。每日一次重复给药后，5mg奈必洛尔和25mg阿替洛尔在β1拮抗作用方面等效。两种药物在β1选择性方面未观察到差异。奈必洛尔没有额外的α1受体阻断特性，这可能至少部分解释了其血管舒张作用。
