Jakubetz J, Schmuck S, Poller U, Fuchs B, Gorf A, Radke J, Pönicke K, Brodde O E
Department of Anesthesiology, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany.
J Cardiovasc Pharmacol. 1999 Mar;33(3):461-72. doi: 10.1097/00005344-199903000-00017.
The aim of this study was to find out whether cardiac responses to the beta-adrenoceptor antagonists with intrinsic sympathomimetic activity (ISA) xamoterol and celiprolol are mediated by cardiac beta1- or beta2-adrenoceptors or both. For this purpose we assessed, in six healthy male volunteers, the effects of xamoterol (100 and 200 mg, p.o.) and celiprolol (200, 600, and 1,200 mg, p.o.) on blood pressure, heart rate, and heart rate-corrected duration of the electromechanical systole (QS2c, as a measure of inotropism). Xamoterol, in both doses, increased systolic blood pressure and heart rate, transiently decreased diastolic blood pressure, and shortened QS2c; all these effects were attenuated after pretreatment of the volunteers with the beta1-adrenoceptor antagonist bisoprolol. Celiprolol, in all three doses, increased heart rate, decreased diastolic blood pressure, and shortened QS2c but only marginally increased systolic blood pressure. Bisoprolol did not attenuate these celiprolol effects but rather enhanced celiprolol effects on systolic blood pressure and heart rate. In a further set of experiments, we studied cardiovascular effects of celiprolol in six healthy volunteers whose beta2-adrenoceptors had been desensitized by a 2-week treatment with 3x5 mg/day terbutaline. Under these conditions, celiprolol failed to increase heart rate or to shorten QS2c. We conclude that, under resting conditions, in healthy volunteers, beta-adrenoceptor antagonists with ISA can exert increases in heart rate and contractility that are mediated by either cardiac beta1-adrenoceptor (xamoterol) or cardiac beta2-adrenoceptor (celiprolol) stimulation. Thus in the human heart, the ISA of beta-adrenoceptor antagonists can be a beta1- or beta2-adrenoceptor agonistic component.
本研究的目的是查明对具有内在拟交感活性（ISA）的β-肾上腺素能拮抗剂昔莫特罗和塞利洛尔的心脏反应是由心脏β1-还是β2-肾上腺素能受体介导，或是由两者共同介导。为此，我们评估了6名健康男性志愿者口服昔莫特罗（100和200毫克）和塞利洛尔（200、600和1200毫克）对血压、心率以及经心率校正的机电收缩期持续时间（QS2c，作为心肌收缩力的指标）的影响。昔莫特罗的两种剂量均使收缩压和心率升高，舒张压短暂降低，QS2c缩短；在用β1-肾上腺素能拮抗剂比索洛尔对志愿者进行预处理后，所有这些效应均减弱。塞利洛尔的三种剂量均使心率升高，舒张压降低，QS2c缩短，但仅轻微升高收缩压。比索洛尔并未减弱塞利洛尔的这些效应，反而增强了塞利洛尔对收缩压和心率的作用。在另一组实验中，我们研究了塞利洛尔对6名健康志愿者的心血管效应，这些志愿者的β2-肾上腺素能受体已通过每日3×5毫克特布他林治疗2周而脱敏。在这些条件下，塞利洛尔未能使心率升高或使QS2c缩短。我们得出结论，在静息状态下，在健康志愿者中，具有ISA的β-肾上腺素能拮抗剂可通过心脏β1-肾上腺素能受体（昔莫特罗）或心脏β2-肾上腺素能受体（塞利洛尔）刺激发挥心率和收缩力增加的作用。因此，在人类心脏中，β-肾上腺素能拮抗剂的ISA可以是β1-或β2-肾上腺素能受体激动成分。
