Tobias A H, Slinker B K, Kirkpatrick R D, Campbell K B
Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman 99164-6520, USA.
Am J Physiol. 1996 Jul;271(1 Pt 2):H51-8. doi: 10.1152/ajpheart.1996.271.1.H51.
The results of isolated myocyte and cardiac muscle experiments indicate that inotropic agents that increase responsiveness of myofilaments to Ca2+ (so-called Ca2+ sensitizers) may prolong myocardial contraction and increase diastolic tone, but the importance of these effects in the whole heart is unclear. Therefore, we studied the effects of the Ca2+ sensitizer EMD-57033 (EMD) on left ventricular (LV) contractile events and passive properties in isovolumically beating isolated rabbit hearts that were buffer perfused at 30 degrees C. Several LV pressure and timing variables were evaluated, including the passive pressure-volume relationship, the Frank-Starling relationship, and the wall stress dependence of the duration of relaxation during perfusion with 0, 2, and 4 microM EMD. EMD (2 microM) increased average peak developed pressure of the Frank-Starling relationship by approximately 18%. In contrast, the peak developed pressure of the Frank-Starling relationship decreased toward control with 4 microM EMD, and therefore all the results presented pertain to 2 microM EMD. The maximum developed pressure at baseline volume was increased by approximately 19% by 2 microM EMD, and this was accompanied by an increase in contraction duration of approximately 13%, due exclusively to slowed relaxation. The relative contributions of maximal wall stress (sigma max) versus an independent negative lusitropic effect of EMD were determined at three LV volumes. At baseline volume, just less than one-half of the effect to slow relaxation was ascribable to an increase in sigma max, whereas the remainder was due to an independent EMD effect. LV passive properties were unchanged by perfusion with 2 microM EMD. We conclude that EMD is a potent inotrope in our isolated rabbit heart preparation, which has no effect on diastolic tone and causes a modest prolongation of contraction duration due to slowed relaxation. At baseline volume, approximately 50% of the slowed relaxation was ascribable to positive inotropy leading to increased sigma max, whereas the remaining approximately 50% was ascribable to a direct negative lusitropic effect of EMD. We discuss our results in terms of the current hypotheses regarding the mechanism of action of the Ca2+ sensitizers.
分离心肌细胞和心肌实验的结果表明，增加肌丝对Ca2+反应性的变力性药物（所谓的Ca2+增敏剂）可能会延长心肌收缩并增加舒张期张力，但这些效应在整个心脏中的重要性尚不清楚。因此，我们研究了Ca2+增敏剂EMD - 57033（EMD）对在30℃下缓冲灌注的等容跳动离体兔心脏左心室（LV）收缩事件和被动特性的影响。评估了几个左心室压力和时间变量，包括被动压力 - 容积关系、Frank - Starling关系以及在灌注0、2和4微摩尔EMD期间舒张持续时间的壁应力依赖性。EMD（2微摩尔）使Frank - Starling关系的平均峰值收缩压增加了约18%。相比之下，4微摩尔EMD使Frank - Starling关系的峰值收缩压降至对照水平，因此所有呈现的结果均与2微摩尔EMD有关。2微摩尔EMD使基线容积时的最大收缩压增加了约19%，并且这伴随着收缩持续时间增加了约13%，这完全是由于舒张减慢所致。在三个左心室容积下确定了最大壁应力（σmax）与EMD独立的负性变时性效应的相对贡献。在基线容积时，舒张减慢效应中略少于一半可归因于σmax的增加，而其余部分则是由于EMD的独立效应。灌注2微摩尔EMD对左心室被动特性无影响。我们得出结论，在我们的离体兔心脏标本中，EMD是一种有效的变力性药物，对舒张期张力无影响，并且由于舒张减慢导致收缩持续时间适度延长。在基线容积时，约50%的舒张减慢可归因于正性肌力作用导致σmax增加，而其余约50%可归因于EMD直接的负性变时性效应。我们根据当前关于Ca2+增敏剂作用机制的假说讨论了我们的结果。
