Basic Research in Cardiology

, Volume 105, Issue 6, pp 787–794 | Cite as

A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade

  • Hiroyuki Takahama
  • Hiroshi Asanuma
  • Shoji Sanada
  • Masashi Fujita
  • Hideyuki Sasaki
  • Masakatsu Wakeno
  • Jiyoong Kim
  • Masanori Asakura
  • Seiji Takashima
  • Tetsuo Minamino
  • Kazuo Komamura
  • Masaru Sugimachi
  • Masafumi KitakazeEmail author
Original Contribution


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.


Heart 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



  1. 1.
    Asanuma H, Minamino T, Ogai A, Kim J, Asakura M, Komamura K, Sanada S, Fujita M, Hirata A, Wakeno M, Tsukamoto O, Shinozaki Y, Myoishi M, Takashima S, Tomoike H, Kitakaze M (2006) Blockade of histamine H2 receptors protects the heart against ischemia and reperfusion injury in dogs. J Mol Cell Cardiol 40:666–674CrossRefPubMedGoogle Scholar
  2. 2.
    Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Krueger S, Young S, Shusterman N (1996) Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 94:2807–2816PubMedGoogle Scholar
  3. 3.
    Bristow MR, Ginsburg R, Harrison DC (1982) Histamine and the human heart: the other receptor system. Am J Cardiol 49:249–251CrossRefPubMedGoogle Scholar
  4. 4.
    Bristow MR (1997) Mechanism of action of beta-blocking agents in heart failure. Am J Cardiol 80:26L–40LCrossRefPubMedGoogle Scholar
  5. 5.
    Brodde OE, Hillemann S, Kunde K, Vogelsang M, Zerkoski HR (1992) Receptor systems affecting force of contraction in the human heart and their alterations in chronic heart failure. J Heart Lung Transplant 11:S164–S174PubMedGoogle Scholar
  6. 6.
    Brown L, Lorenz B, Erdmann E (1986) Reduced positive inotropic effects in diseased human ventricular myocardium. Cardiovasc Res 20:516–520CrossRefPubMedGoogle Scholar
  7. 7.
    CIBIS II Investigators and Committees (1999) The cardiac insufficiency bisoprolol study II (CIBIS II): a randomized trial. Lancet 353:9–13CrossRefGoogle Scholar
  8. 8.
    Dvorak AM (1986) Mast-cell degranulation in human hearts. N Engl J Med 315:969–970PubMedGoogle Scholar
  9. 9.
    Eichhorn EJ (1998) Restoring function in failing hearts: the effects of beta blockers. Am J Med 104:163–169CrossRefPubMedGoogle Scholar
  10. 10.
    Gantz I, Schaffer M, DelValle J, Logsdon C, Campbell V, Uhier M, Yamada T (1991) Molecular cloning of a gene encoding the histamine H2 receptor. Proc Natl Acad Sci USA 88:5937CrossRefPubMedGoogle Scholar
  11. 11.
    Hara M, Ono K, Hwang MW, Iwasaki A, Okada M, Nakatani K, Sasayama S, Matsumori A (2002) Evidence for a role of mast cells in the evolution to congestive heart failure. J Exp Med 195:375–381CrossRefPubMedGoogle Scholar
  12. 12.
    Hattori Y (1999) Cardiac histamine receptors: their pharmacological consequences and signal transduction pathways. Methods Find Exp Clin Pharmacol 21:123–131CrossRefPubMedGoogle Scholar
  13. 13.
    Hinrichsen H, Halabi A, Kirsch W (1990) Hemodynamic effects of different H2-receptor antagonists. Clin Pharmacol Ther 48:302–308CrossRefPubMedGoogle Scholar
  14. 14.
    Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL (1997) International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev 49:253–278PubMedGoogle Scholar
  15. 15.
    Jessup M, Brozena S (2003) Heart failure. N Engl J Med 348:2007–2018CrossRefPubMedGoogle Scholar
  16. 16.
    Kim J, Ogai A, Nakatani S, Hashimura K, Kanzaki H, Komamura K, Asakura M, Asanuma H, Kitamura S, Tomoike H, Kitakaze M (2006) Impact of blockade of histamine H2 receptors on chronic heart failure revealed by retrospective and prospective randomized studies. J Am Coll Cardiol 48:1378–1384CrossRefPubMedGoogle Scholar
  17. 17.
    Leineweber K, Bohm M, Heusch G (2006) Cyclic adenosine monophosphate in acute myocardial infarction with heart failure Slayer or savior? Circulation 114:365–367CrossRefPubMedGoogle Scholar
  18. 18.
    Matsuda N, Jesmin S, Takahashi Y, Hatta E, Kobayashi M, Matsuyama K, Kawakami N, Sakuma I, Gando S, Fukui H, Hattori Y, Levi R (2004) Histamine H1 and H2 receptor gene and protein levels are differentially expressed in the hearts of rodents and humans. J Pharmacol Exp Ther 309:786–795CrossRefPubMedGoogle Scholar
  19. 19.
    Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Cas LD (2000) Differential effects of beta-blockers in patients with heart failure. Circulation 102:546–551PubMedGoogle Scholar
  20. 20.
    Movsesian MA (1999) Beta-adrenergic receptor agonists and cyclic nucleotide phosphodiesterase inhibitors: shifting the focus from inotropy to cyclic adenosine monophosphatase. J Am Coll Cardiol 34:318–324CrossRefPubMedGoogle Scholar
  21. 21.
    Nault MA, Milne B, Parlow JP (2002) Effects of the selective H1 and H2 histamine receptor antagonists loratadine and ranitidine on autonomic control of the heart. Anesthesiology 96:336–341CrossRefPubMedGoogle Scholar
  22. 22.
    Neumann T, Heusch G (1997) Myocardial, skeletal muscle, and renal blood flow during exercise in conscious dogs with heart failure. Am J Physiol 273:H2452–H2457PubMedGoogle Scholar
  23. 23.
    Neumann T, Vollmer A, Schaffner TH, Hess OM, Heusch G (1999) Diastolic dysfunction and collagen structure in canine pacing-induced heart failure. J Mol Cell Cardiol 31:179–192CrossRefPubMedGoogle Scholar
  24. 24.
    Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S, Hirata A, Fujita M, Nagamachi Y, Nakatani T, Yutani C, Ozawa K, Ogawa S, Tomoike H, Hori M, Kitakaze M (2004) Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110:705–712CrossRefPubMedGoogle Scholar
  25. 25.
    Packer M, Coats AJ, Fowler MB, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL, Carvedilol Prospective Randomized Cumulative Survival Study group (2001) Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344:1651–1658CrossRefPubMedGoogle Scholar
  26. 26.
    Patella V, Marino I, Arbustini E, Lamparter-Schummert B, Verga L, Adt M, Marone G (1998) Stem cell factor in mast cells and increased mast cell density in idiopathic and ischemic cardiomyopathy. Circulation 97:971–978PubMedGoogle Scholar
  27. 27.
    Sasaki H, Asanuma H, Fujita M, Takahama H, Wakeno M, Ito S, Ogai A, Asakura M, Kim J, Minamino T, Takashima S, Sanada S, Sugimachi M, Komamura K, Mochizuki N, Kitakaze M (2009) Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase. Circulation 119:2568–2577CrossRefPubMedGoogle Scholar
  28. 28.
    Schultz G, Rosenthal W, Hescheler J (1990) Role of G proteins in calcium channel modulation. Annu Rev Physiol 52:275–292CrossRefPubMedGoogle Scholar
  29. 29.
    Simons FE (2004) Advances in H1-antihistamines. N Engl J Med 351:2203–2217CrossRefPubMedGoogle Scholar
  30. 30.
    Sugiyama A, Satoh Y, Takahara A, Nakamura Y, Shimizu-Sasamata M, Sato S, Miyata K, Hashimoto K (2003) Famotidine does not induce long QT syndrome: experimental evidence from in vitro and in vivo test systems. Eur J Pharmacol 466:137–146CrossRefPubMedGoogle Scholar
  31. 31.
    Takahashi T, Tang T, Lai C, Roth DM, Rebolledo B, Saito M, Lew WYW, Clopton P, Hammond K (2006) Increased cardiac adenylyl cyclase expression is associated with increased survival after myocardial infarction. Circulation 114:388–396CrossRefPubMedGoogle Scholar
  32. 32.
    The MERIT-HF Study Group (1999) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353:2001–2007CrossRefGoogle Scholar
  33. 33.
    Trautwein W, Hescheler J (1990) Regulation of cardiac L-type calcium current by phosphorylation and G proteins. Annu Rev Physiol 52:257–274CrossRefPubMedGoogle Scholar
  34. 34.
    Xiao RP, Cheng H, Zhou YY, Kuschel M, Lakatta EG (1999) Recent advances in cardiac beta(2)-adrenergic signal transduction. Circ Res 85:1092–1100PubMedGoogle Scholar
  35. 35.
    Zeekowski HR, Broede A, Kunde K, Hillemann S, Schafer E, Vogelsang M, Michel MC, Brodde OE (1993) Comparison of the positive inotropic effects of serotonin, histamine, angiotensin II, endothelin and isoprenaline in the isolated human right atrium. Naunyn-Schemiedeberg’s Arch Phamacol 347:347–352CrossRefGoogle Scholar
  36. 36.
    Zhou R, Moench P, Heran C, Lu X, Mathias N, Faria TN, Wall DA, Hussain MA, Smith RL, Sun D (2005) pH-dependent dissolution in vitro and absorption in vivo of weakly basic drugs: development of canine model. Pharm Res 22:188–192CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Hiroyuki Takahama
    • 1
  • Hiroshi Asanuma
    • 2
    • 3
  • Shoji Sanada
    • 4
  • Masashi Fujita
    • 4
  • Hideyuki Sasaki
    • 2
  • Masakatsu Wakeno
    • 1
  • Jiyoong Kim
    • 1
  • Masanori Asakura
    • 1
  • Seiji Takashima
    • 4
  • Tetsuo Minamino
    • 4
  • Kazuo Komamura
    • 2
  • Masaru Sugimachi
    • 2
  • Masafumi Kitakaze
    • 1
    Email author
  1. 1.Department of Cardiovascular MedicineNational Cerebral and Cardiovascular CenterSuitaJapan
  2. 2.Cardiovascular Dynamics Research InstituteNational Cerebral and Cardiovascular CenterSuitaJapan
  3. 3.Department of Emergency Room MedicineKinki University School of MedicineOsaka-SayamaJapan
  4. 4.Department of Cardiovascular MedicineOsaka University Graduate School of MedicineSuitaJapan

Personalised recommendations