Fraker L D, Van Eyk J, Solaro R J
Department of Emergency Medicine, College of Medicine, University of Illinois at Chicago 60612, USA.
Mol Cell Biochem. 1997 Nov;176(1-2):83-8.
UD-CG 212 Cl, (Fig. 1: 4,5-dihydro-6-[2-(4-hydroxyphenyl)-1 H-benzimidazole-5-yl]-5-methyl-3(2H)-pyridazinone), is the primary metabolite of the positive inotropic agent pimobendan (UDCG 115 BS, Acardi). Our previous studies showed in detergent extracted preparations of canine ventricular muscle that sub-nanomolar concentrations of UD-CG 212 Cl increased submaximal myofilament force, but only when the activation state had been altered by relatively high (5-10 mM) concentrations of inorganic phosphate (Pi) or relatively low (20 microM) concentrations of MgATP. In the present study, we investigated the effects of UD-CG 212 Cl on the pCa-force relationship of detergent extracted bundles of human cardiac fibers before and after addition of Pi. As expected, treatment with 5 mM Pi depressed maximal force at pCa 4.5 by 27.0 +/- 0.4% (mean +/- SEM). Force generated at the half-maximally activating Ca2+ concentration (pCa50) of control fibers (5.98 +/- 0.2) was significantly (p < .05) reduced following the addition of 5 mM Pi (pCa50 = 5.69 +/- 0.3). The addition of UD-CG 212 Cl over a range of concentrations (10(-11)-10(-6) M) had no effect on Ca(2+)-sensitivity under control conditions, but in the presence of 5 mM Pi, there was a 23.1 +/- 0.1% increase in the percent maximal force at pCa5.9. Ca(2+)-sensitivity was also significantly increased in the presence of Pi and 10(-8) M UD-CG 212 Cl (pCa50 = 5.74 +/- 0.3, p < .05). We conclude that UD-CG 212 Cl potentially increases sub-maximal force of human ventricular myofilaments with an inotropic action depending on a state of myofilament activation associated with ischemic conditions.
UD-CG 212 Cl（图1：4,5-二氢-6-[2-(4-羟基苯基)-1H-苯并咪唑-5-基]-5-甲基-3(2H)-哒嗪酮）是正性肌力药物匹莫苯丹（UDCG 115 BS，Acardi）的主要代谢产物。我们之前的研究表明，在犬心室肌去污剂提取物中，亚纳摩尔浓度的UD-CG 212 Cl可增加亚最大肌丝力，但仅当激活状态因相对高浓度（5-10 mM）的无机磷酸盐（Pi）或相对低浓度（20 μM）的MgATP而改变时才会如此。在本研究中，我们研究了添加Pi前后UD-CG 212 Cl对去污剂提取的人心脏纤维束的pCa-力关系的影响。正如预期的那样，用5 mM Pi处理使pCa 4.5时的最大力降低了27.0±0.4%（平均值±标准误）。添加5 mM Pi后，对照纤维在半最大激活Ca2+浓度（pCa50）（5.98±0.2）时产生的力显著（p<0.05）降低（pCa50 = 5.69±0.3）。在一系列浓度（10(-11)-10(-6) M）范围内添加UD-CG 212 Cl在对照条件下对Ca(2+)敏感性没有影响，但在存在5 mM Pi的情况下，pCa5.9时最大力百分比增加了23.1±0.1%。在存在Pi和10(-8) M UD-CG 212 Cl的情况下，Ca(2+)敏感性也显著增加（pCa50 = 5.74±0.3，p<0.05）。我们得出结论，UD-CG 212 Cl可能通过与缺血状态相关的肌丝激活状态的正性肌力作用增加人心室肌丝的亚最大力。
