A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade
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Histamine has a positive inotropic effect on ventricular myocardium and stimulation of histamine H2 receptors increases the intracellular cAMP level via Gs protein, as dose stimulation of β-adrenergic receptors, and worsens heart failure. To test whether a histamine H2 receptor blocker had a beneficial effect in addition to β-adrenergic receptor blockade, we investigated the cardioprotective effect of famotidine, a histamine H2 receptor 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 H2 receptor 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 H2 blockers in the treatment of heart failure.
KeywordsHeart failure Histamine Histamine H2 receptor blocker β-Adrenergic receptor blocker
The authors thank Akiko Ogai for technical assistance; Masahiko Takahashi (Astellas Co. Ltd.) for providing information on famotidine; and the Evidence Finders’ Club for their encouragement of this study. This work was supported by a Grant-in-aid from the Japanese Ministry of Health, Labor, and Welfare; a Grant-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology; a Grant from the Japan Heart Foundation; and a Grant from the Japan Cardiovascular Research Foundation.
Conflict of interest
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