Vleeming W, van Rooij H H, Wemer J, Porsius A J
Department of Pharmacotherapy, Faculty of Pharmacy, University Utrecht, The Netherlands.
J Cardiovasc Pharmacol. 1990 Oct;16(4):584-93. doi: 10.1097/00005344-199010000-00009.
After a 16-h in vivo infusion period of isoproterenol (400 micrograms/kg/h) from a minipump implanted subcutaneously (s.c.) in rats, we observed an increase in heart weight due to tissue edema. In isolated perfused heart preparations, the EC50s of isoproterenol to induce positive inotropy and increase in coronary flow were increased approximately 7 and 4 times, respectively. Isoproterenol dose-response curves performed in trachea preparations, were shifted to the right by about fivefold as compared with the control group. In the presence of phentolamine, the isoproterenol induced maximal relaxation in the isolated aorta from isoproterenol-pretreated animals was reduced from 46.5 to 9.2% as compared with saline-pretreated rats. In the absence of phentolamine, the epinephrine (EPI) and norepinephrine (NE) cumulative dose-response curves in this preparation were not affected by isoproterenol pretreatment with respect to EC50 and maximal effect. However, in the presence of phentolamine, the contractile response to a supramaximal dose of NE (10 microM) amounted to 30 and 70% in the saline- and isoproterenol-pretreated rats, respectively. In the presence of both phentolamine and propranolol, a similar response of 70% was observed by this supramaximal dose of agonist in the saline-pretreated rats as well. In anesthetized rats, 120 min after removal of the minipumps, sodium nitroprusside induced increase in heart rate (HR) was reduced after isoproterenol pretreatment, whereas for salbutamol the decrease in diastolic blood pressure (DBP) was also reduced. As compared with salbutamol, a marked increase was observed in the ratio of mean arterial blood pressure (MAP) to HR for SNP after isoproterenol pretreatment. The phenylephrine-induced increase in MAP was increased after isoproterenol pretreatment. We conclude that in the pathogenesis of heart failure the beta-adrenoceptor-mediated effects of catecholamines are attenuated and alpha-adrenoceptor-mediated effects become progressively important.
在通过皮下植入微型泵对大鼠进行16小时异丙肾上腺素（400微克/千克/小时）体内输注后，我们观察到由于组织水肿导致心脏重量增加。在离体灌注心脏标本中，异丙肾上腺素诱导正性肌力作用和增加冠脉流量的半数有效浓度（EC50）分别增加了约7倍和4倍。在气管标本中进行的异丙肾上腺素剂量-反应曲线与对照组相比右移了约5倍。在酚妥拉明存在的情况下，与生理盐水预处理的大鼠相比，异丙肾上腺素预处理动物的离体主动脉中异丙肾上腺素诱导的最大舒张率从46.5%降至9.2%。在不存在酚妥拉明的情况下，该标本中肾上腺素（EPI）和去甲肾上腺素（NE）的累积剂量-反应曲线在EC50和最大效应方面不受异丙肾上腺素预处理的影响。然而，在酚妥拉明存在的情况下，生理盐水预处理和异丙肾上腺素预处理的大鼠对超最大剂量NE（10微摩尔）的收缩反应分别为30%和70%。在同时存在酚妥拉明和普萘洛尔的情况下，生理盐水预处理的大鼠对该超最大剂量激动剂也观察到了70%的类似反应。在麻醉大鼠中，移除微型泵120分钟后，异丙肾上腺素预处理后硝普钠诱导的心率（HR）增加减少，而沙丁胺醇导致的舒张压（DBP）降低也减少。与沙丁胺醇相比，异丙肾上腺素预处理后硝普钠的平均动脉血压（MAP）与HR之比显著增加。异丙肾上腺素预处理后去氧肾上腺素诱导的MAP增加。我们得出结论，在心力衰竭的发病机制中，儿茶酚胺的β-肾上腺素能受体介导的效应减弱，α-肾上腺素能受体介导的效应变得越来越重要。
