A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade
A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade
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DOI：
10.1007/s00395-010-0119-y
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发表时间：
2010-09
影响因子：
9.5
通讯作者：
Hiroyuki Takahama;H. Asanuma;S. Sanada;M. Fujita;H. Sasaki;M. Wakeno;Jiyoong Kim;M. Asakura;
中科院分区：
文献类型：
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作者：
Hiroyuki Takahama;H. Asanuma;S. Sanada;M. Fujita;H. Sasaki;M. Wakeno;Jiyoong Kim;M. Asakura;
组胺对心室肌有正性肌力作用，组胺H2受体的刺激可通过Gs蛋白增加细胞内cAMP水平，与β-肾上腺素能受体的剂量刺激一样，导致心力衰竭。为了测试组胺H2受体阻滞剂是否具有除了β-肾上腺素能受体阻滞剂之外的有益作用，我们在接受β-受体阻滞剂的犬中研究了组胺H2受体阻滞剂法莫替丁的心脏保护作用。我们通过快速心室起搏（230次/min）诱导犬心力衰竭。动物接受无药物（对照组）、法莫替丁（每日1 mg/kg）、卡维地洛（每日0.1 mg/kg）或卡维地洛加法莫替丁。在起搏前和起搏后4周进行心导管检查和超声心动图检查。免疫组织化学研究显示，肥大细胞和组胺在心肌起搏4周后的外观。对照组起搏4周后左室射血分数（LVEF）较起搏前下降（71 ± 2vs.27 ± 2%，p < 0.05），平均肺毛细血管楔压（PCWP）较起搏前升高（8 ± 1vs.19 ± 3 mmHg）。法莫替丁可改善左室射血分数的下降和PCWP的升高，而卡维地洛联合法莫替丁可进一步改善这两个参数。法莫替丁的这些有益作用与心肌cAMP水平降低相关。组胺H2受体阻滞剂可保护起搏诱导心力衰竭犬的心脏收缩功能，即使在β-肾上腺素能受体阻滞剂存在的情况下也是如此。这一发现加强了使用组胺H2受体阻滞剂治疗心力衰竭的理论基础。
Histamine has a positive inotropic effect on ventricular myocardium and stimulation of histamine H2receptors increases the intracellular cAMP level via Gs protein, as dose stimulation of β-adrenergic receptors, and worsens heart failure. To test whether a histamine H2receptor blocker had a beneficial effect in addition to β-adrenergic receptor blockade, we investigated the cardioprotective effect of famotidine, a histamine H2receptor blocker, in dogs receiving a β-blocker. We induced heart failure in dogs by rapid ventricular pacing (230 beats/min). Animals received no drugs (control group), famotidine (1 mg/kg daily), carvedilol (0.1 mg/kg daily), or carvedilol plus famotidine. Both cardiac catheterization and echocardiography were performed before and 4 weeks after the initiation of pacing. Immunohistochemical studies showed the appearance of mast cells and histamine in the myocardium after 4 weeks of pacing. In the control group, the left ventricular ejection fraction (LVEF) was decreased after 4 weeks compared with before pacing (71 ± 2 vs. 27 ± 2%,p< 0.05) and mean pulmonary capillary wedge pressure (PCWP) was increased (8 ± 1 vs. 19 ± 3 mmHg). Famotidine ameliorated the decrease of LVEF and increase of PCWP, while the combination of carvedilol plus famotidine further improved both parameters compared with the carvedilol groups. These beneficial effects of famotidine were associated with a decrease of the myocardial cAMP level. Histamine H2receptor blockade preserves cardiac systolic function in dogs with pacing-induced heart failure, even in the presence of β-adrenergic receptor blockade. This finding strengthens the rationale for using histamine H2blockers in the treatment of heart failure.