Poller U, Fuchs B, Gorf A, Jakubetz J, Radke J, Pönicke K, Brodde O E
Institute of Pharmacology and Toxicology, Martin-Luther-University of Halle-Wittenberg, Germany.
Cardiovasc Res. 1998 Oct;40(1):211-22. doi: 10.1016/s0008-6363(98)00101-1.
In patients with chronic heart failure cardiac beta 1-adrenoceptors are desensitized whereas beta 2-adrenoceptors are only marginally affected. The mechanism underlying this differential regulation is not known.
To find out whether or not human cardiac beta 2-adrenoceptors might be 'resistant' to agonist-induced desensitization and whether or not the antiallergic drug ketotifen might attenuate possible desensitization.
We investigated, in a single blinded, randomised, placebo-controlled, cross-over study of ten healthy male volunteers (mean age, 25.3 +/- 0.7 years), the effects of two weeks treatment with the beta 2-adrenoceptor agonist terbutaline (3x5 mg/day p.o.) with and without simultaneous treatment with ketotifen (2x1 mg/day p.o. for three weeks) or placebo on beta-adrenoceptor-mediated cardiovascular effects. Cardiovascular effects were assessed as isoprenaline (3.5-35 ng/kg/min)- and terbutaline (25-150 ng/kg/min)-infusion-induced increases in heart rate and systolic blood pressure, decreases in diastolic blood pressure and shortening of the systolic time intervals (STIs), heart rate corrected duration of electromechanical systole (QS2c) and pre-ejection period (PEP; as a measure of inotropism).
Ketotifen did not significantly affect basal haemodynamics in the volunteers. Isoprenaline- and terbutaline-infusion caused dose-dependent increases in systolic blood pressure and heart rate, decreases in diastolic blood pressure and shortening of QS2c and PEP, whereby isoprenaline effects were more pronounced. After two weeks of treatment with terbutaline p.o., isoprenaline- and terbutaline-infusion-induced increases in heart rate, shortening of QS2c and PEP were significantly reduced whereby terbutaline-infusion effects were markedly more attenuated than isoprenaline-infusion effects. Ketotifen significantly reduced terbutaline p.o. treatment-induced attenuation of all terbutaline-infusion effects (largely beta 2-adrenoceptor-mediated) and the isoprenaline-infusion-induced increase in heart rate (beta 1- and beta 2-adrenoceptor-mediated), but did not (or only marginally) affect reduction in isoprenaline-induced shortening of QS2c and PEP (largely beta 1-adrenoceptor-mediated).
Human cardiac beta 2-adrenoceptors are not 'resistant' to agonist-induced desensitization: Ketotifen might prevent such beta 2-adrenoceptor-agonist-evoked desensitization.
在慢性心力衰竭患者中，心脏β1肾上腺素能受体脱敏，而β2肾上腺素能受体仅受到轻微影响。这种差异调节的潜在机制尚不清楚。
研究人类心脏β2肾上腺素能受体是否可能对激动剂诱导的脱敏“有抗性”，以及抗过敏药物酮替芬是否可能减轻可能的脱敏。
在一项单盲、随机、安慰剂对照、交叉研究中，我们纳入了10名健康男性志愿者（平均年龄25.3±0.7岁），研究了β2肾上腺素能受体激动剂特布他林（口服，3×5mg/天，共两周）在有或无同时使用酮替芬（口服，2×1mg/天，共三周）或安慰剂治疗的情况下，对β肾上腺素能受体介导的心血管效应的影响。心血管效应通过异丙肾上腺素（3.5 - 35ng/kg/min）和特布他林（25 - 150ng/kg/min）输注诱导的心率增加、收缩压升高、舒张压降低以及收缩时间间期（STIs）缩短、心率校正的机电收缩期持续时间（QS2c）和射血前期（PEP；作为心肌收缩力的指标）来评估。
酮替芬对志愿者的基础血流动力学没有显著影响。异丙肾上腺素和特布他林输注导致收缩压和心率呈剂量依赖性增加，舒张压降低，QS2c和PEP缩短，其中异丙肾上腺素的作用更明显。口服特布他林两周后，异丙肾上腺素和特布他林输注诱导的心率增加、QS2c和PEP缩短显著降低，其中特布他林输注的作用比异丙肾上腺素输注的作用明显更减弱。酮替芬显著减少了口服特布他林治疗引起的所有特布他林输注效应（主要由β2肾上腺素能受体介导）的减弱以及异丙肾上腺素输注诱导的心率增加（由β1和β2肾上腺素能受体介导），但对异丙肾上腺素诱导的QS2c和PEP缩短的减少（主要由β1肾上腺素能受体介导）没有（或仅有轻微）影响。
人类心脏β2肾上腺素能受体对激动剂诱导的脱敏并非 “有抗性”：酮替芬可能预防此类β2肾上腺素能受体激动剂诱发的脱敏。
