Sprung J, Ogletree-Hughes M L, McConnell B K, Zakhary D R, Smolsky S M, Moravec C S
Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Anesth Analg. 2001 Sep;93(3):550-9. doi: 10.1097/00000539-200109000-00006.
We determined the direct effects of propofol on the contractility of human nonfailing atrial and failing atrial and ventricular muscles. Atrial and ventricular trabecular muscles were obtained from the failing human hearts of transplant patients or from nonfailing hearts of patients undergoing coronary artery bypass surgery. Isometric contraction variables were recorded before and after propofol was added to the bath in concentrations between 0.056 and 560 microM. The effects of propofol were compared with its commercial vehicle intralipid. To test beta-adrenergic effects in the presence of propofol, 1 microM isoproterenol was added at the end of each experiment. To determine the cellular mechanisms responsible for the actions of propofol, we examined its effects on actomyosin ATPase activity and sarcoplasmic reticulum (SR) Ca(2+) uptake in nonfailing atrial tissues. Propofol caused a concentration-dependent decrease in maximal developed tension in all muscles, which became significant (P < 0.05) at concentrations exceeding the clinical range (> or =56 microM). Isoproterenol restored contractility to the level achieved before exposure to propofol (P > 0.05 compared with baseline). Failing ventricular muscle exposed to propofol exhibited somewhat diminished ability to recover contractility in response to isoproterenol (P < 0.05 versus failing muscle exposed to intralipid only). Propofol induced a concentration-dependent decrease in the uptake of Ca(2+) into SR vesicles. At the same time, in the presence of 56 microM propofol, the Ca(2+)-activated actomyosin ATPase activity was shifted leftward, demonstrating an increase in myofilament sensitivity to Ca(2+). We conclude that propofol exerts a direct negative inotropic effect in nonfailing and failing human myocardium, but only at concentrations larger than typical clinical concentrations. Negative inotropic effects are reversible with beta-adrenergic stimulation. The negative inotropic effect of propofol is at least partially mediated by decreased Ca(2+) uptake into the SR; however, the net effect of propofol on contractility is insignificant at clinical concentrations because of a simultaneous increase in the sensitivity of the myofilaments to activator Ca(2+).
我们确定了丙泊酚对人类非衰竭心房肌、衰竭心房肌和心室肌收缩性的直接影响。心房和心室小梁肌取自移植患者的衰竭心脏或接受冠状动脉搭桥手术患者的非衰竭心脏。在浴槽中加入浓度为0.056至560微摩尔/升的丙泊酚前后，记录等长收缩变量。将丙泊酚的作用与其商业载体脂质乳剂进行比较。为了测试丙泊酚存在时的β-肾上腺素能效应，在每个实验结束时加入1微摩尔/升异丙肾上腺素。为了确定丙泊酚作用的细胞机制，我们研究了其对非衰竭心房组织中肌动球蛋白ATP酶活性和肌浆网（SR）钙摄取的影响。丙泊酚使所有肌肉的最大收缩张力呈浓度依赖性降低，在超过临床范围（≥56微摩尔/升）的浓度下，这种降低具有统计学意义（P<0.05）。异丙肾上腺素将收缩性恢复到暴露于丙泊酚之前的水平（与基线相比，P>0.05）。暴露于丙泊酚的衰竭心室肌对异丙肾上腺素反应时恢复收缩性的能力有所减弱（与仅暴露于脂质乳剂的衰竭心肌相比，P<0.05）。丙泊酚使钙摄取到SR囊泡中的量呈浓度依赖性减少。同时，在存在56微摩尔/升丙泊酚的情况下，钙激活的肌动球蛋白ATP酶活性向左移动，表明肌丝对钙的敏感性增加。我们得出结论，丙泊酚在人类非衰竭和衰竭心肌中发挥直接的负性肌力作用，但仅在高于典型临床浓度时才会出现。负性肌力作用可通过β-肾上腺素能刺激逆转。丙泊酚的负性肌力作用至少部分是由SR钙摄取减少介导的；然而，由于肌丝对激活钙的敏感性同时增加，丙泊酚在临床浓度下对收缩性的净影响不显著。
