title: A histamine H₂ receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, 565-8565, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujita
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Wakeno
authors.forename: Jiyoong
authors.initials: J
authors.lastname: Kim
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Kazuo
authors.initials: K
authors.lastname: Komamura
authors.forename: Masaru
authors.initials: M
authors.lastname: Sugimachi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D006328:Cardiac Catheterization; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000077261:Carvedilol; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004452:Echocardiography; D015738:Famotidine / Q000494:pharmacology*; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006632:Histamine / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007150:Immunohistochemistry; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D002316:Cardiotonic Agents; D006635:Histamine H2 Antagonists; D011412:Propanolamines; D000077261:Carvedilol; D015738:Famotidine; D006632:Histamine; D000242:Cyclic AMP