Glass M G, Fuleihan F, Liao R, Lincoff A M, Chapados R, Hamlin R, Apstein C S, Allen P D, Ingwall J S, Hajjar R J
Cardiovascular Diseases and Muscle Research Laboratories, Charles A Dana Research Institute, Boston, MA 02115.
Circ Res. 1993 Dec;73(6):1077-89. doi: 10.1161/01.res.73.6.1077.
Turkey poults fed furazolidone (Fz) in high concentrations (700 ppm) develop dilated cardiomyopathy (Fz-DCM). We tested whether five cardioactive agents were cardioprotective in this model of heart failure, ie, whether they prevented dilatation and wall thinning and improved contractile performance. We compared the effects of chronic administration of a beta 1-selective and a nonselective beta-receptor antagonist, an alpha-receptor antagonist, and two Ca2+ channel antagonists in the presence of Fz administration. The greatest cardioprotection was found with treatment with either propranolol or nifedipine. At the gross morphological level, the effect of propranolol (a nonselective beta-adrenergic antagonist) was greater than the effect of atenolol (a selective beta 1-adrenergic antagonist), and the effect of nifedipine was greater than that of verapamil (Ca2+ channel antagonists), with all agents more cardioprotective than phenoxybenzamine (an alpha 1-adrenergic > alpha 2-adrenergic antagonist). Differences in cardioprotective efficacy of each agent increased with increased concentration. These data indicate that the dose and choice of a specific type of Ca2+ channel antagonist or beta-receptor antagonist might be important in the treatment of dilated cardiomyopathy. All agents that were cardioprotective caused similar functional improvements at both the whole heart and isolated muscle levels. Compared with control animals, Fz-DCM animals showed a significant reduction in peak left ventricular (LV) developed pressure (92 +/- 17 versus 143 +/- 24 mm Hg, P < .05), +dP/dt (1151 +/- 219 versus 2454 +/- 549 mm Hg/s), and -dP/dt (1128 +/- 291 versus 1875 +/- 396 mm Hg/s), with a significant increase in LV end-diastolic volumes (2.8 +/- 0.7 versus 0.16 +/- 0.1 mL for control animals, P < .05). In contradistinction, LV + dP/dt and -dP/dt values for animals receiving Fz plus a cardioactive agent that demonstrated cardioprotection were not significantly different from control values. Peak LV developed pressures were also similar for Fz animals receiving an agent that demonstrated cardioprotection and control animals not receiving any pharmacologic agent. Isolated muscles from Fz-DCM animals as well as animals receiving Fz plus cardioprotective pharmacologic agents responded normally with regard to increasing extracellular Ca2+ concentrations. Peak twitch forces were greater for animals receiving cardioprotective agents plus Fz than control animals not receiving any pharmacologic agents or Fz alone. At higher stimulation rates, Fz-DCM muscles demonstrated a significantly reduced peak twitch force (4 +/- 0.5 versus 1.5 +/- 0.4 g/mm2 for control muscles versus Fz-DCM muscles, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)
用高浓度（700 ppm）呋喃唑酮（Fz）喂养的火鸡雏会发生扩张型心肌病（Fz-DCM）。我们测试了五种具有心脏活性的药物在这种心力衰竭模型中是否具有心脏保护作用，即它们是否能防止心脏扩张和心肌壁变薄，并改善收缩功能。我们比较了在给予Fz的情况下，长期给予β1选择性和非选择性β受体拮抗剂、α受体拮抗剂以及两种钙通道拮抗剂的效果。发现普萘洛尔或硝苯地平治疗具有最大的心脏保护作用。在大体形态学水平上，普萘洛尔（一种非选择性β肾上腺素能拮抗剂）的作用大于阿替洛尔（一种选择性β1肾上腺素能拮抗剂），硝苯地平的作用大于维拉帕米（钙通道拮抗剂），所有药物的心脏保护作用均大于苯氧苄胺（一种α1肾上腺素能＞α2肾上腺素能拮抗剂）。每种药物的心脏保护功效差异随浓度增加而增大。这些数据表明，特定类型的钙通道拮抗剂或β受体拮抗剂的剂量和选择在扩张型心肌病的治疗中可能很重要。所有具有心脏保护作用的药物在全心和离体肌肉水平上都引起了类似的功能改善。与对照动物相比，Fz-DCM动物的左心室（LV）最大压力峰值显著降低（92±17对143±24 mmHg，P＜0.05），+dP/dt（1151±219对2454±549 mmHg/s），以及-dP/dt（1128±291对1875±396 mmHg/s），左心室舒张末期容积显著增加（对照动物为0.16±0.1 mL，Fz-DCM动物为2.8±0.7 mL，P＜0.05）。相反，接受Fz加具有心脏保护作用的心脏活性药物的动物的LV + dP/dt和-dP/dt值与对照值无显著差异。接受具有心脏保护作用药物的Fz动物的左心室最大压力峰值与未接受任何药物治疗的对照动物也相似。来自Fz-DCM动物以及接受Fz加心脏保护药物的动物的离体肌肉在细胞外钙浓度增加时反应正常。接受心脏保护药物加Fz的动物的峰值抽搐力大于未接受任何药物治疗或仅接受Fz的对照动物。在较高刺激频率下，Fz-DCM肌肉的峰值抽搐力显著降低（对照肌肉与Fz-DCM肌肉分别为4±0.
