Libonati J R, Eberli F R, Sesselberg H W, Apstein C S
Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, MA 02118, USA.
Cardiovasc Res. 1997 Jan;33(1):71-81. doi: 10.1016/s0008-6363(96)00185-x.
Angiotensin II (ANG II) has recently been reported to increase inotropy in adult rabbit myocytes by a mechanism of alkalinization and consequent increased myofilament sensitivity to calcium. Accordingly, we tested the hypothesis that ANG II would have a greater inotropic effect during ischemic conditions than it would during normoxia, since ischemia-induced intracellular acidosis contributes to ischemic contractile depression by decreasing myofilament calcium sensitivity.
We studied the effects of ANG II in isolated, red-blood-cell-perfused, isovolumic rat and rabbit hearts during normoxic perfusion conditions and at graded reductions in coronary perfusion pressure (CPP). At each level of perfusion, ANG II was infused at progressively increasing concentrations ranging from 10(-11) to 10(-5) M. The maximal effective ANG II concentration was 10(-7) M.
Our studies show that ANG II caused comparable absolute increases in isovolumic LV developed pressure in normoperfused and hypoperfused rabbit hearts. However, since contractile function was markedly depressed in ischemic hearts prior to ANG II administration, the relative inotropic response to ANG II was significantly greater during ischemia than normoxia. Similarly, ANG II had no positive inotropic effect in the rat during normoxia, but increased contractility during ischemia. To assess specifically the potential of ANG II to reverse the negative inotropy of acidosis, normoxic non-ischemic rat hearts were perfused with a hypercarbic acidotic perfusate (pH = 7.1). During the hypercarbic perfusion when contraction was depressed by acidosis, ANG II [10(-7)]M increased LV developed pressure by 19% and +dP/dt by 27% (P < 0.05), in contrast to its lack of intropic effect at a normal pH. The positive inotropic effect observed in rat hearts with ANG II during ischemia was significantly attenuated (P < 0.001) by concomitant infusion with amiloride, 5-(N-ethyl-N-isopropyl) (EIPA), a Na+/H+ exchange inhibitor.
We conclude that during normoxia, ANG II has a different inotropic potency in rabbits from that in rats. In both species, the relative inotropic responsiveness of ANG II is potentiated during low-flow ischemia. These results are consistent with a relative intracellular alkalinization that occurs secondary to ANG II's action to stimulate Na+/H+ exchange.
最近有报道称，血管紧张素II（ANG II）通过碱化机制增加成年兔心肌细胞的收缩力，进而增加肌丝对钙的敏感性。因此，我们检验了以下假设：由于缺血诱导的细胞内酸中毒通过降低肌丝钙敏感性导致缺血性收缩功能障碍，ANG II在缺血状态下比在正常氧合状态下具有更大的正性肌力作用。
我们研究了在正常氧合灌注条件下以及冠状动脉灌注压（CPP）逐步降低时，ANG II对离体的、红细胞灌注的等容大鼠和兔心脏的影响。在每个灌注水平，以浓度范围从10⁻¹¹至10⁻⁵ M逐步增加的方式输注ANG II。ANG II的最大有效浓度为10⁻⁷ M。
我们的研究表明，ANG II在正常灌注和低灌注兔心脏中引起的等容左心室舒张末压绝对增加值相当。然而，由于在给予ANG II之前缺血心脏的收缩功能明显降低，因此在缺血期间ANG II的相对正性肌力反应比正常氧合时显著更大。同样，ANG II在正常氧合时对大鼠没有正性肌力作用，但在缺血期间增加了收缩力。为了具体评估ANG II逆转酸中毒负性肌力作用的潜力，用高碳酸血症性酸中毒灌注液（pH = 7.1）灌注正常氧合的非缺血大鼠心脏。在高碳酸血症灌注期间，当收缩因酸中毒而受抑制时，ANG II [浓度为10⁻⁷ M]使左心室舒张末压增加19%，使 +dP/dt增加27%（P < 0.05），这与其在正常pH时缺乏正性肌力作用形成对比。在缺血期间用ANG II处理的大鼠心脏中观察到的正性肌力作用，在同时输注氨氯吡咪（5-(N-乙基-N-异丙基)（EIPA））（一种Na⁺/H⁺交换抑制剂）时显著减弱（P < 0.001）。
我们得出结论，在正常氧合时，ANG II在兔中的正性肌力作用强度与在大鼠中的不同。在这两个物种中，ANG II的相对正性肌力反应在低流量缺血期间均增强。这些结果与ANG II刺激Na⁺/H⁺交换作用继发相对细胞内碱化一致。
