Hayes J S, Wyss V L, Wilson H, Pollock G D
J Cardiovasc Pharmacol. 1985 Jan-Feb;7(1):182-9. doi: 10.1097/00005344-198501000-00029.
AR-L57 and AR-L115 have been of interest as inotropic agents for management of heart failure. Although their physiological effects are well documented, their mechanism(s) of action are unclear. Both AR-L57 and AR-L115 increased contractile force of cat papillary muscles in concentration-dependent manners; these effects were independent of either alpha- or beta-adrenoceptor stimulation. To determine if these effects occurred via a cAMP-dependent mechanism, cardiotonic actions were studied in the presence of carbachol. Muscarinic stimulation of papillary muscles attenuated contractile responses to AR-L115 thus implying a cAMP-mediated response. By contrast, carbachol did not alter the dose-response profile to AR-L57. In addition, AR-L115 potentiated the inotropic actions of isoproterenol whereas AR-L57 was ineffective. Both AR-L57 and ouabain increased diastolic resting tension in papillary muscles--a phenomenon associated with a state of Ca2+ overload; AR-L115 was without effect. In anesthetized dogs, i.v. AR-L57 and AR-L115 increased contractility and heart rate while reducing mean arterial blood pressure. Both agents had similar rates of onset (10-15 s) and durations of action (40-60 min). Although in vitro studies clearly indicate that AR-L57 and AR-L115 enhance inotropic state by distinct mechanisms, their in vivo cardiovascular profiles are comparable.
AR-L57和AR-L115作为治疗心力衰竭的变力性药物受到关注。尽管它们的生理效应已有充分记录，但其作用机制尚不清楚。AR-L57和AR-L115均以浓度依赖性方式增加猫乳头肌的收缩力；这些效应与α-或β-肾上腺素能受体刺激无关。为了确定这些效应是否通过cAMP依赖性机制发生，在卡巴胆碱存在的情况下研究了强心作用。毒蕈碱对乳头肌的刺激减弱了对AR-L115的收缩反应，因此提示存在cAMP介导的反应。相比之下，卡巴胆碱并未改变对AR-L57的剂量反应曲线。此外，AR-L115增强了异丙肾上腺素的变力作用，而AR-L57则无效。AR-L57和哇巴因均增加了乳头肌的舒张期静息张力——这一现象与Ca2+超载状态有关；AR-L115则无此作用。在麻醉犬中，静脉注射AR-L57和AR-L115可增加心肌收缩力和心率，同时降低平均动脉血压。两种药物的起效速度（10-15秒）和作用持续时间（40-60分钟）相似。尽管体外研究清楚地表明AR-L57和AR-L115通过不同机制增强心肌收缩状态，但它们在体内的心血管作用谱具有可比性。
