Fujino K, Sperelakis N, Solaro R J
Department of Physiology and Biophysics, University of Cincinnati, Ohio.
Circ Res. 1988 Nov;63(5):911-22. doi: 10.1161/01.res.63.5.911.
We compared the effects of the newer inotropic drugs, pimobendan (UD-CG 115 BS) and milrinone (Win 47203), on the electrical, mechanical and biochemical activity of intact and detergent-skinned preparations of cardiac muscle. Both of these agents increased contractile force of guinea pig papillary muscle preparations bathed under physiological conditions or depolarized with 25 mM K+o. The positive inotropic action was associated with potentiation of the Ca2+-dependent slow action potentials (APS). Contractile force developed in the presence of 25 mM [K]o and 1 microM isoproterenol was increased further by addition of 50 microM pimobendan with no effect on the slow action potential. Milrinone (50 microM) did not produce a further increase in the force or potentiate the slow APs. Pimobendan, in a dose-dependent manner, increased active tension developed by chemically-skinned dog heart muscle fibers at submaximally activating concentrations of Ca2+, whereas milrinone did not. At pCa 6.25, the half-maximal concentration of pimobendan for stimulation of force development was about 40 microM. At maximally activating levels of Ca2+ (pCa 4.5), pimobendan had little or no effect on force development. The effect of pimobendan on force was paralleled by changes in the Ca2+-activated Mg-ATPase activity of the isometric skinned fiber preparations. Moreover, the tension-cost (unit increase in ATPase rate/unit increase in force) was unchanged in the presence of pimobendan. Milrinone did not affect ATP hydrolysis by the skinned fiber preparations. Force-pCa and ATPase-pCa relations of skinned fiber preparations contracting isometrically were shifted to the left by 0.15-0.20 pCa units in the presence of 50 microM pimobendan. In contrast, there was no effect of pimobendan on the ATPase activity of unloaded myofibrillar preparations. The stimulation of force and ATPase activity of the skinned heart muscle fibers could be accounted for by an effect of pimobendan on the affinity of the regulatory (low affinity, Ca2+-specific) binding sites of cardiac troponin C. Ca2+ binding to the "structural" high affinity sites of troponin C was slightly inhibited. The results indicate that the positive inotropic actions of pimobendan, but not milrinone, may involve activation of the cardiac myofilaments by a direct effect involving an increased affinity of the regulatory site on troponin C for Ca2+.
我们比较了新型正性肌力药物匹莫苯丹（UD - CG 115 BS）和米力农（Win 47203）对完整的和用去垢剂处理过的心肌膜片的电、机械及生化活性的影响。这两种药物均增加了在生理条件下灌流或用25 mM细胞外钾离子（K⁺o）使其去极化的豚鼠乳头肌标本的收缩力。正性肌力作用与钙依赖性慢动作电位（APS）的增强有关。在25 mM [K]o和1 microM异丙肾上腺素存在的情况下，加入50 microM匹莫苯丹可进一步增加收缩力，且对慢动作电位无影响。米力农（50 microM）未使收缩力进一步增加，也未增强慢动作电位。匹莫苯丹以剂量依赖性方式增加了在亚最大激活浓度的钙离子作用下化学去膜的犬心肌纤维产生的主动张力，而米力农则无此作用。在pCa 6.25时，匹莫苯丹刺激张力产生的半数最大浓度约为40 microM。在最大激活水平的钙离子（pCa 4.5）时，匹莫苯丹对张力产生几乎没有影响。匹莫苯丹对张力的影响与等长去膜纤维标本中钙激活的镁 - ATP酶活性的变化平行。此外，在匹莫苯丹存在的情况下，张力 - 消耗（ATP酶速率单位增加/张力单位增加）不变。米力农不影响去膜纤维标本的ATP水解。在50 microM匹莫苯丹存在的情况下，等长收缩的去膜纤维标本的力- pCa关系和ATP酶- pCa关系向左移动了0.15 - 0.20个pCa单位。相比之下，匹莫苯丹对未负载的肌原纤维标本的ATP酶活性没有影响。匹莫苯丹对去膜心肌纤维张力和ATP酶活性的刺激作用可能是由于其对心肌肌钙蛋白C调节（低亲和力、钙特异性）结合位点亲和力的影响。钙离子与肌钙蛋白C“结构”高亲和力位点的结合略有抑制。结果表明，匹莫苯丹而非米力农的正性肌力作用可能涉及通过直接作用激活心肌肌丝，该作用涉及肌钙蛋白C调节位点对钙离子的亲和力增加。
