Pennock G D, Raya T E, Bahl J J, Goldman S, Morkin E
Department of Internal Medicine, Tucson Veterans Administration Medical Center, AZ.
Circulation. 1993 Sep;88(3):1289-98. doi: 10.1161/01.cir.88.3.1289.
An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent.
To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 micrograms/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment decreased LV end-diastolic pressure compared with controls (21 +/- 2 and 26 +/- 2 mm Hg, respectively, vs 34 +/- 3 mm Hg, P < .05 for each). The addition of DITPA to captopril produced a 36% increase in resting cardiac index (P < .05) and shifted the cardiac function curve upward and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in tau, the time constant of LV pressure decline (17.5 +/- 1.0 vs 22.2 +/- 1.7 milliseconds, P < .05) and a larger absolute value for -dP/dtmax (-4561 +/- 361 vs -3346 +/- 232 mm Hg/s, P < .05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P > .05).
The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.
一种通过非环磷酸腺苷（cAMP）介导机制改善左心室（LV）功能的药物，在慢性心力衰竭治疗中具有重要价值。我们之前已经表明，甲状腺激素类似物3,5 - 二碘甲状腺丙酸（DITPA）与核受体结合，改变T3反应性基因的转录，并增加甲状腺功能减退大鼠的 +dP/dtmax，对心率和代谢的影响远小于甲状腺激素，这使其成为一种选择性强心剂。
为了确定DITPA是否可用于治疗心力衰竭，我们在冠状动脉结扎3周后，对Sprague - Dawley大鼠进行了生理盐水、卡托普利（2 g/L）或DITPA（375微克/100克）与卡托普利（2 g/L）联合治疗的比较。与对照组相比，DITPA/卡托普利组和卡托普利组的左心室舒张末期压力均降低（分别为21±2和26±2 mmHg，而对照组为34±3 mmHg，每组P <.05）。在卡托普利基础上加用DITPA使静息心指数增加36%（P <.05），并使心功能曲线向上和向左移位，表明心肌功能增强。此外，与卡托普利治疗组或对照组相比，DITPA/卡托普利组左心室舒张速率增加，表现为tau（左心室压力下降时间常数）降低（17.5±1.0对22.2±1.7毫秒，P <.05）以及 -dP/dtmax的绝对值更大（-4561±361对 -3346±232 mmHg/s，P <.05）。相对于卡托普利治疗组，这些变化发生时心率、左心室质量、左心室收缩压或外周阻力均无改变（P >.05）。
在大鼠心肌梗死后心力衰竭模型中，DITPA与卡托普利联合使用比卡托普利单独治疗能更有效地改善心输出量，增加 -dP/dtmax，并提高左心室舒张速率。使用甲状腺激素强心类似物代表了一种改善左心室功能的新方法，可能是心力衰竭治疗中减轻后负荷的有用辅助手段。
