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Histamine receptors in heart failure

Abstract

The biogenic amine, histamine, is found predominantly in mast cells, as well as specific histaminergic neurons. Histamine exerts its many and varied actions via four G-protein-coupled receptors numbered one through four. Histamine has multiple effects on cardiac physiology, mainly via the histamine 1 and 2 receptors, which on a simplified level have opposing effects on heart rate, force of contraction, and coronary vasculature function. In heart failure, the actions of the histamine receptors are complex, the histamine 1 receptor appears to have detrimental actions predominantly in the coronary vasculature, while the histamine 2 receptor mediates adverse effects on cardiac remodeling via actions on cardiomyocytes, fibroblasts, and even endothelial cells. Conversely, there is growing evidence that the histamine 3 receptor exerts protective actions when activated. Little is known about the histamine 4 receptor in heart failure. Targeting histamine receptors as a therapeutic approach for heart failure is an important area of investigation given the over-the-counter access to many compounds targeting these receptors, and thus the relatively straight forward possibility of drug repurposing. In this review, we briefly describe histamine receptor signaling and the actions of each histamine receptor in normal cardiac physiology, before describing in more detail the known role of each histamine receptor in adverse cardiac remodeling and heart failure. This includes information from both clinical studies and experimental animal models. It is the goal of this review article to bring more focus to the possibility of targeting histamine receptors as therapy for heart failure.

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References

  1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos G, Fonarow GC, Givertz MM et al (2016) 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 68(13):1476–1488

    PubMed  Article  Google Scholar 

  2. Ferreira JP, Kraus S, Mitchell S, Perel P, Piñeiro D, Chioncel O, Colque R, de Boer RA, Gomez-Mesa JE, Grancelli H et al (2019) World Heart Federation Roadmap for heart failure. Glob Heart 14(3):197–214

    PubMed  Article  Google Scholar 

  3. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, Nodari S, Lam CSP, Sato N, Shah AN et al (2014) The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 63(12):1123–1133

    PubMed  Article  Google Scholar 

  4. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA et al(2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 18(8):891–975

  5. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN et al (2020) Heart Disease and Stroke Statistics-2020 Update: a report From the American Heart Association. Circulation 141(9):e139–e596

    PubMed  Article  Google Scholar 

  6. Nieto-Alamilla G, Márquez-Gómez R, García-Gálvez AM, Morales-Figueroa GE, Arias-Montaño JA (2016) The histamine H3 receptor: structure, pharmacology, and function. Mol Pharmacol 90(5):649–673

    CAS  PubMed  Article  Google Scholar 

  7. Ghamari N, Zarei O, Arias-Montaño JA, Reiner D, Dastmalchi S, Stark H, Hamzeh-Mivehroud M (2019) Histamine H(3) receptor antagonists/inverse agonists: where do they go? Pharmacol Ther 200:69–84

    CAS  PubMed  Article  Google Scholar 

  8. He G, Hu J, Li T, Ma X, Meng J, Jia M, Lu J, Ohtsu H, Chen Z, Luo X (2012) Arrhythmogenic effect of sympathetic histamine in mouse hearts subjected to acute ischemia. Mol Med (Cambridge, Mass) 18(1):1–9

    CAS  Article  Google Scholar 

  9. Marone G, de Crescenzo G, Adt M, Patella V, Arbustini E, Genovese A (1995) Immunological characterization and functional importance of human heart mast cells. Immunopharmacology 31(1):1–18

    CAS  PubMed  Article  Google Scholar 

  10. Marone G, de Crescenzo G, Florio G, Granata F, Dente V, Genovese A (1999) Immunological modulation of human cardiac mast cells. Neurochem Res 24(9):1195–1202

    CAS  PubMed  Article  Google Scholar 

  11. Patella V, de Crescenzo G, Ciccarelli A, Marino I, Adt M, Marone G (1995) Human heart mast cells: a definitive case of mast cell heterogeneity. Int Arch Allergy Immunol 106(4):386–393

    CAS  PubMed  Article  Google Scholar 

  12. Batlle M, Perez-Villa F, Lazaro A, Garcia-Pras E, Ramirez J, Ortiz J, Orus J, Roque M, Heras M, Roig E (2007) Correlation between mast cell density and myocardial fibrosis in congestive heart failure patients. Transpl Proc 39(7):2347–2349

    CAS  Article  Google Scholar 

  13. Brower GL, Chancey AL, Thanigaraj S, Matsubara BB, Janicki JS (2002) Cause and effect relationship between myocardial mast cell number and matrix metalloproteinase activity. Am J Physiol Heart Circ Physiol 283(2):H518-525

    CAS  PubMed  Article  Google Scholar 

  14. Forman MF, Brower GL, Janicki JS (2006) Rat cardiac mast cell maturation and differentiation following acute ventricular volume overload. Inflamm Res 55(10):408–415

    CAS  PubMed  Article  Google Scholar 

  15. Levick SP, Brower GL, Janicki JS (2019) Substance P-mediated cardiac mast cell activation: an in vitro study. Neuropeptides 74:52–59

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Levick SP, McLarty JL, Murray DB, Freeman RM, Carver WE, Brower GL (2009) Cardiac mast cells mediate left ventricular fibrosis in the hypertensive rat heart. Hypertension (Dallas, Tex: 1979) 53(6):1041–1047

  17. Li J, Lu H, Plante E, Melendez GC, Levick SP, Janicki JS (2012) Stem cell factor is responsible for the rapid response in mature mast cell density in the acutely stressed heart. J Mol Cell Cardiol 53(4):469–474

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Melendez GC, Li J, Law BA, Janicki JS, Supowit SC, Levick SP (2011) Substance P induces adverse myocardial remodeling via a mechanism involving cardiac mast cells. Cardiovasc Res 92:420–429

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Morgan LG, Levick SP, Voloshenyuk TG, Murray DB, Forman MF, Brower GL, Janicki JS (2008) A novel technique for isolating functional mast cells from the heart. Inflamm Res 57:1–6

    Article  CAS  Google Scholar 

  20. Widiapradja A, Manteufel EJ, Dehlin HM, Pena J, Goldspink PH, Sharma A, Kolb LL, Imig JD, Janicki JS, Lu B et al (2019) Regulation of cardiac mast cell maturation and function by the neurokinin-1 receptor in the fibrotic heart. Sci Rep 9(1):11004

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. Dvorak AM (1986) Mast-cell degranulation in human hearts. N Engl J Med 315(15):969–970

    CAS  PubMed  Google Scholar 

  22. Patella V, de Crescenzo G, Lamparter-Schummert B, De Rosa G, Adt M, Marone G (1997) B L-S, G DR, Adt M, G M: Increased cardiac mast cell density and mediator release in patients with dilated cardiomyopathy. Inflamm Res 46(1):S31–S32

    CAS  PubMed  Article  Google Scholar 

  23. Marone G, Patella V (1995) de CG, Genovese A, Adt M: Human heart mast cells in anaphylaxis and cardiovascular disease. Int Arch Allergy Immunol 107(1–3):72–75

    CAS  PubMed  Article  Google Scholar 

  24. Patella V, Marino I, Lamparter B, Arbustini E, Adt M, Marone G (1995) Human heart mast cells. Isolation, purification, ultrastructure, and immunologic characterization. J Immunol 154(6):2855–2865

  25. Ingason AB, Mechmet F, Atacho DAM, Steingrímsson E, Petersen PH (2019) Distribution of mast cells within the mouse heart and its dependency on Mitf. Mol Immunol 105:9–15

    CAS  PubMed  Article  Google Scholar 

  26. Marone G, Genovese A, Varricchi G, Granata F (2014) Human heart as a shock organ in anaphylaxis. Allergo J Int 23(2):60–66

    PubMed  PubMed Central  Article  Google Scholar 

  27. Morrey C, Brazin J, Seyedi N, Corti F, Silver RB, Levi R (2010) Interaction between sensory C-fibers and cardiac mast cells in ischemia/reperfusion: activation of a local renin-angiotensin system culminating in severe arrhythmic dysfunction. J Pharmacol Exp Ther 335(1):76–84

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, Levi R (2004) Mast cells: a unique source of renin. Proc Natl Acad Sci USA 101(37):13607–13612

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Arizono N, Matsuda S, Hattori T, Kojima Y, Maeda T, Galli SJ (1990) Anatomical variation in mast cell nerve associations in the rat small intestine, heart, lung, and skin. Similarities of distances between neural processes and mast cells, eosinophils, or plasma cells in the jejunal lamina propria. Lab Invest 62(5):626–634

  30. Brower GL, Janicki JS (2005) Pharmacologic inhibition of mast cell degranulation prevents left ventricular remodeling induced by chronic volume overload in rats. J Cardiac Fail 11(7):548–556

    CAS  Article  Google Scholar 

  31. Stewart JA, Wei CC, Brower GL, Rynders PE, Hankes GH, Dillon AR, Lucchesi PA, Janicki JS, Dell’Italia LJ (2003) Cardiac mast cell- and chymase-mediated matrix metalloproteinase activity and left ventricular remodeling in mitral regurgitation in the dog. J Mol Cell Cardiol 35(3):311–319

    CAS  PubMed  Article  Google Scholar 

  32. Zhang W, Chancey AL, Tzeng HP, Zhou Z, Lavine KJ, Gao F, Sivasubramanian N, Barger PM, Mann DL (2011) The development of myocardial fibrosis in transgenic mice with targeted overexpression of tumor necrosis factor requires mast cell-fibroblast interactions. Circulation 124(19):2106–2116

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 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(3):375–381

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Li QY, Raza-Ahmad A, MacAulay MA, Lalonde LD, Rowden G, Trethewey E, Dean S (1992) The relationship of mast cells and their secreted products to the volume of fibrosis in posttransplant hearts. Transplantation 53(5):1047–1051

    CAS  PubMed  Article  Google Scholar 

  35. Zweifel M, Hirsiger H, Matozan K, Welle M, Schaffner T, Mohacsi P (2002) Mast cells in ongoing acute rejection: increase in number and expression of a different phenotype in rat heart transplants. Transplantation 73(11):1707–1716

    CAS  PubMed  Article  Google Scholar 

  36. He A, Fang W, Zhao K, Wang Y, Li J, Yang C, Benadjaoud F, Shi GP (2019) Mast cell-deficiency protects mice from streptozotocin-induced diabetic cardiomyopathy. Translational research : the journal of laboratory and clinical medicine 208:1–14

    CAS  Article  Google Scholar 

  37. Huang ZG, Jin Q, Fan M, Cong XL, Han SF, Gao H, Shan Y (2013) Myocardial remodeling in diabetic cardiomyopathy associated with cardiac mast cell activation. PLoS One 8(3):e60827

  38. Palaniyandi SS, Watanabe K, Ma M, Tachikawa H, Kodama M, Aizawa Y (2005) Involvement of mast cells in the development of fibrosis in rats with postmyocarditis dilated cardiomyopathy. Biol Pharm Bull 28(11):2128–2132

    Article  Google Scholar 

  39. Janicki JS, Brower GL, Levick SP (2015) The emerging prominence of the cardiac mast cell as a potent mediator of adverse myocardial remodeling. Methods in molecular biology (Clifton, NJ) 1220:121–139

    CAS  Article  Google Scholar 

  40. Levick SP, Melendez GC, Plante E, McLarty JL, Brower GL, Janicki JS (2011) Cardiac mast cells: the centrepiece in adverse myocardial remodelling. Cardiovasc Res 89(1):12–19

    CAS  PubMed  Article  Google Scholar 

  41. Levick SP, Widiapradja A (2018) Mast cells: key contributors to cardiac fibrosis. Int J Mol Sci 19(1)

  42. Li J, Jubair S, Levick SP, Janicki JS (2016) The autocrine role of tryptase in pressure overload-induced mast cell activation, chymase release and cardiac fibrosis. IJC Metab Endocr 10:16–23

    PubMed  Article  Google Scholar 

  43. McLarty JL, Melendez GC, Brower GL, Janicki JS, Levick SP (2011) Tryptase/protease-activated receptor 2 interactions induce selective mitogen-activated protein kinase signaling and collagen synthesis by cardiac fibroblasts. Hypertension (Dallas, Tex: 1979) 58(2):264–270

  44. Akasu M, Urata H, Kinoshita A, Sasaguri M, Ideishi M, Arakawa K (1998) Differences in Tissue Angiotensin IIûForming Pathways by Species and Organs In Vitro. Hypertension (Dallas, Tex : 1979) 1998, 32(3):514–520

  45. Akgul A, Skrabal CA, Thompson LO, Loebe M, Lafuente JA, Noon GP, Youker KA (2004) Role of mast cells and their mediators in failing myocardium under mechanical ventricular support. J Heart Lung Transplant 23(6):709–715

    PubMed  Article  Google Scholar 

  46. Jenne DE, Tschopp J (1991) Angiotensin II-forming heart chymase is a mast-cell-specific enzyme. In: Biochem J vol 276,  pp 567–568

  47. Frangogiannis NG, Burns AR, Michael LH, Entman ML (1999) Histochemical and morphological characteristics of canine cardiac mast cells. Histochem J 31(4):221–229

    CAS  PubMed  Article  Google Scholar 

  48. Jin D, Takai S, Yamada M, Sakaguchi M, Yao Y, Miyazaki M (2001) Possible roles of cardiac chymase after myocardial infarction in hamster hearts. Jpn J Pharmacol 86(2):203–214

    CAS  PubMed  Article  Google Scholar 

  49. Kanemitsu H, Takai S, Tsuneyoshi H, Nishina T, Yoshikawa K, Miyazaki M, Ikeda T, Komeda M (2006) Chymase inhibition prevents cardiac fibrosis and dysfunction after myocardial infarction in rats. Hypertens Res 29(1):57–64

    CAS  PubMed  Article  Google Scholar 

  50. Kanemitsu H, Takai S, Tsuneyoshi H, Yoshikawa E, Nishina T, Miyazaki M, Ikeda T, Komeda M (2008) Chronic chymase inhibition preserves cardiac function after left ventricular repair in rats. Eur J Cardiothorac Surg 33(1):25–31

    PubMed  Article  Google Scholar 

  51. Kitaura-Inenaga K, Hara M, Higuchi K, Yamamoto K, Yamaki A, Ono K, Nakano A, Kinoshita M, Sasayama S, Matsumori A (2003) Gene expression of cardiac mast cell chymase and tryptase in a murine model of heart failure caused by viral myocarditis. Circ J 67(10):881–884

    CAS  PubMed  Article  Google Scholar 

  52. Matsumoto C, Hayashi T, Kitada K, Yamashita C, Miyamura M, Mori T, Ukimura A, Ohkita M, Jin D, Takai S et al (2009) Chymase plays an important role in left ventricular remodeling induced by intermittent hypoxia in mice. Hypertension (Dallas, Tex: 1979) 54(1):164–171

  53. Oyamada S, Bianchi C, Takai S, Chu LM, Sellke FW (2011) Chymase inhibition reduces infarction and matrix metalloproteinase-9 activation and attenuates inflammation and fibrosis after acute myocardial ischemia/reperfusion. J Pharmacol Exp Ther 339(1):143–151

    CAS  PubMed  Article  Google Scholar 

  54. Shiota NJD, Takai S, Kawamura T, Koyama M, Nakamura N, Miyazakai M (1997) Chymase is activated in the hamster heart following ventricular fibrosis during the chronic stage of hypertension. FEBS Lett 406:301–304

    CAS  PubMed  Article  Google Scholar 

  55. Somasundaram P, Ren G, Nagar H, Kraemer D, Mendoza L, Michael LH, Caughey GH, Entman ML, Frangogiannis NG (2005) Mast cell tryptase may modulate endothelial cell phenotype in healing myocardial infarcts. J Pathol 205(1):102–111

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Takai S, Jin D, Muramatsu M, Okamoto Y, Miyazaki M (2004) Therapeutic applications of chymase inhibitors in cardiovascular diseases and fibrosis. Eur J Pharmacol 501(1–3):1–8

    CAS  PubMed  Article  Google Scholar 

  57. Takai S, Jin D, Sakaguchi M, Katayama S, Muramatsu M, Sakaguchi M, Matsumura E, Kim S, Miyazaki M (2003) A novel chymase inhibitor, 4-[1-([bis-(4-methyl-phenyl)-methyl]-carbamoyl)3-(2-ethoxy-benzyl)-4-oxo-azetidin e-2-yloxy]-benzoic acid (BCEAB), suppressed cardiac fibrosis in cardiomyopathic hamsters. J Pharmacol Exp Ther 305(1):17–23

    CAS  PubMed  Article  Google Scholar 

  58. Zhao XY, Zhao LY, Zheng QS, Su JL, Guan H, Shang FJ, Niu XL, He YP, Lu XL (2008) Chymase induces profibrotic response via transforming growth factor-beta 1/Smad activation in rat cardiac fibroblasts. Mol Cell Biochem 310(1–2):159–166

    CAS  PubMed  Article  Google Scholar 

  59. Triggiani M, Genovese A, Vigorito C, Marone G (1985) Histamine and human heart. Int Arch Allergy Appl Immunol 77(1–2):174–176

    CAS  PubMed  Article  Google Scholar 

  60. Wolff AA, Levi R (1986) Histamine and cardiac arrhythmias. Circ Res 58(1):1–16

    CAS  PubMed  Article  Google Scholar 

  61. Bristow MR, Kantrowitz NE, Harrison WD, Minobe WA, Sageman WS, Billingham ME (1983) Mediation of subacute anthracycline cardiotoxicity in rabbits by cardiac histamine release. J Cardiovasc Pharmacol 5(6):913–919

    CAS  PubMed  Article  Google Scholar 

  62. Decorti G, Candussio L, Klugmann FB, Strohmayer A, Mucci MP, Mosco A, Baldini L (1997) Adriamycin-induced histamine release from heart tissue in vitro. Cancer Chemother Pharmacol 40(4):363–366

    CAS  PubMed  Article  Google Scholar 

  63. Kondru SK, Potnuri AG, Allakonda L, Konduri P (2018) Histamine 2 receptor antagonism elicits protection against doxorubicin-induced cardiotoxicity in rodent model. Mol Cell Biochem 441(1–2):77–88

    CAS  PubMed  Article  Google Scholar 

  64. Zdravkovic V, Pantovic S, Rosic G, Tomic-Lucic A, Zdravkovic N, Colic M, Obradovic Z, Rosic M (2011) Histamine blood concentration in ischemic heart disease patients. J Biomed Biotechnol 2011:315709

  65. Asanuma H, Minamino T, Ogai A, Kim J, Asakura M, Komamura K, Sanada S, Fujita M, Hirata A, Wakeno M et al (2006) Blockade of histamine H2 receptors protects the heart against ischemia and reperfusion injury in dogs. J Mol Cell Cardiol 40(5):666–674

    CAS  PubMed  Article  Google Scholar 

  66. Valen G, Kaszaki J, Szabo I, Nagy S, Vaage J (1994) Histamine release and its effects in ischaemia-reperfusion injury of the isolated rat heart. Acta Physiol Scand 150(4):413–424

    CAS  PubMed  Article  Google Scholar 

  67. Potnuri AG, Allakonda L, Appavoo A, Saheera S, Nair RR (2018) Association of histamine with hypertension-induced cardiac remodeling and reduction of hypertrophy with the histamine-2-receptor antagonist famotidine compared with the beta-blocker metoprolol. Hypertension research : official journal of the Japanese Society of Hypertension 41(12):1023–1035

    CAS  Article  Google Scholar 

  68. Kantrowitz NE, Bristow MR, Minobe WA, Billingham ME, Harrison DC (1982) Histamine-mediated myocardial damage in rabbits. J Mol Cell Cardiol 14(9):551–555

    CAS  PubMed  Article  Google Scholar 

  69. He GH, Cai WK, Meng JR, Ma X, Zhang F, Lu J, Xu GL (2015) Relation of polymorphism of the histidine decarboxylase gene to chronic heart failure in Han Chinese. Am J Cardiol 115(11):1555–1562

    CAS  PubMed  Article  Google Scholar 

  70. Walter M, Stark H (2012) Histamine receptor subtypes: a century of rational drug design. Front Biosci (Schol Ed) 4:461–488

    Article  Google Scholar 

  71. Monczor F, Fernandez N (2016) Current knowledge and perspectives on histamine H1 and H2 receptor pharmacology: functional selectivity, receptor crosstalk, and repositioning of classic histaminergic ligands. Mol Pharmacol 90(5):640–648

    CAS  PubMed  Article  Google Scholar 

  72. Simons FE, Simons KJ (2011) Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol 128(6):1139-1150.e1134

    CAS  PubMed  Article  Google Scholar 

  73. Mills JG, Wood JR (1989) The pharmacology of histamine H2-receptor antagonists. Methods Find Exp Clin Pharmacol 11(Suppl 1):87–95

    CAS  PubMed  Google Scholar 

  74. Schunack W (1989) Pharmacology of H2-receptor antagonists: an overview. J Int Med Res 17(Suppl 1):9a–16a

    CAS  PubMed  Google Scholar 

  75. Micallef S, Stark H, Sasse A (2013) Polymorphisms and genetic linkage of histamine receptors. Life Sci 93(15):487–494

    CAS  PubMed  Article  Google Scholar 

  76. Tanimoto A, Sasaguri Y, Ohtsu H (2006) Histamine network in atherosclerosis. Trends Cardiovasc Med 16(8):280–284

    CAS  PubMed  Article  Google Scholar 

  77. Matsuda N, Jesmin S, Takahashi Y, Hatta E, Kobayashi M, Matsuyama K, Kawakami N, Sakuma I, Gando S, Fukui H et al (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(2):786–795

    CAS  PubMed  Article  Google Scholar 

  78. Nault MA, Milne B, Parlow JL (2002) Effects of the selective H1 and H2 histamine receptor antagonists loratadine and ranitidine on autonomic control of the heart. Anesthesiology 96(2):336–341

    CAS  PubMed  Article  Google Scholar 

  79. Felix SB, Baumann G, Helmus S, Sattelberger U (1988) The role of histamine in cardiac anaphylaxis; characterization of histaminergic H1- and H2-receptor effects. Basic Res Cardiol 83(5):531–539

    CAS  PubMed  Article  Google Scholar 

  80. Assem ES (1989) Anaphylactic reactions affecting the human heart. Agents Actions 27(1–2):142–145

    CAS  PubMed  Article  Google Scholar 

  81. Denizot Y, Boudet J, Burtin C, Marro I, Benveniste J (1990) Monoclonal IgE-mediated cardiac hypersensitivity reactions in the guinea-pig. Agents Actions 29(3–4):167–171

    CAS  PubMed  Article  Google Scholar 

  82. Levi R, Zavecz JH, Ovary Z (1978) IgE-mediated cardiac hypersensitivity reactions. An experimental model. Int Arch Allergy Appl Immunol 57(6):529–534

  83. Silva Machado FR, Assem ES, Ezeamuzie CI (1985) Cardiac anaphylaxis: the role of different mediators. Part I: histamine Allergol Immunopathol (Madr ) 13(3):259–272

    Google Scholar 

  84. Gebbia N, Flandina C, Leto G, Tumminello FM, Sanguedolce R, Candiloro V, Gagliano M, Rausa L (1987) The role of histamine in doxorubicin and teniposide-induced cardiotoxicity in dog and mouse. Tumori 73(3):279–287

    CAS  PubMed  Article  Google Scholar 

  85. Bristow MR, Cubicciotti R, Ginsburg R, Stinson EB, Johnson C (1982) Histamine-mediated adenylate cyclase stimulation in human myocardium. Mol Pharmacol 21(3):671–679

    CAS  PubMed  Google Scholar 

  86. Tozzi CA, Dorrell SG, Merrill GF (1985) Evidence of histamine-induced myocardial ischaemia: reversal by chlorpheniramine and potentiation by atherosclerosis. Cardiovasc Res 19(12):744–753

    CAS  PubMed  Article  Google Scholar 

  87. Ginsburg R, Bristow MR, Kantrowitz N, Baim DS, Harrison DC (1981) Histamine provocation of clinical coronary artery spasm: implications concerning pathogenesis of variant angina pectoris. Am Heart J 102(5):819–822

    CAS  PubMed  Article  Google Scholar 

  88. Shimokawa H, Tomoike H, Nabeyama S, Yamamoto H, Nakamura M (1985) Histamine-induced spasm not significantly modulated by prostanoids in a swine model of coronary artery spasm. J Am Coll Cardiol 6(2):321–327

    CAS  PubMed  Article  Google Scholar 

  89. Kounis NG, Zavras GM (1991) Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract 45(2):121–128

    CAS  PubMed  Google Scholar 

  90. Kounis NG (2006) Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 110(1):7–14

    PubMed  Article  Google Scholar 

  91. Erdogan O, Altun A, Gazi S, Ozbay G (2004) Loratidine improves ischemic parameters of exercise stress test in patients with acute myocardial infarction. Am Heart J 148(6):e24

  92. Miyazawa N, Watanabe S, Matsuda A, Kondo K, Hashimoto H, Umemura K, Nakashima M (1998) Role of histamine H1 and H2 receptor antagonists in the prevention of intimal thickening. Eur J Pharmacol 362(1):53–59

    CAS  PubMed  Article  Google Scholar 

  93. Rozenberg I, Sluka SH, Rohrer L, Hofmann J, Becher B, Akhmedov A, Soliz J, Mocharla P, Borén J, Johansen P et al (2010) Histamine H1 receptor promotes atherosclerotic lesion formation by increasing vascular permeability for low-density lipoproteins. Arterioscler Thromb Vasc Biol 30(5):923–930

    CAS  PubMed  Article  Google Scholar 

  94. Harman D (1962) Atherosclerosis; inhibiting effect of an antihistaminic drug, chlorpheniramine. Circ Res 11:277–282

    CAS  PubMed  Article  Google Scholar 

  95. Clejan S, Japa S, Clemetson C, Hasabnis SS, David O, Talano JV (2002) Blood histamine is associated with coronary artery disease, cardiac events and severity of inflammation and atherosclerosis. J Cell Mol Med 6(4):583–592

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Takagishi T, Sasaguri Y, Nakano R, Arima N, Tanimoto A, Fukui H, Morimatsu M (1995) Expression of the histamine H1 receptor gene in relation to atherosclerosis. Am J Pathol 146(4):981–988

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhou Y, Gao C, Wang H, Liu L, Huang Z, Fa X (2018) Histamine H1 type receptor antagonist loratadine ameliorates oxidized LDL induced endothelial dysfunction. Biomed Pharmacother 106:1448–1453

  98. Jacobson BC, Ferris TG, Shea TL, Mahlis EM, Lee TH, Wang TC (2003) Who is using chronic acid suppression therapy and why? Am J Gastroenterol 98(1):51–58

    PubMed  Article  Google Scholar 

  99. Reinhardt D, Schmidt U, Brodde OE, Schümann HJ (1977) H1 - and H2-receptor mediated responses to histamine on contractility and cyclic AMP of atrial and papillary muscles from guinea-pig hearts. Agents Actions 7(1):1–12

    CAS  PubMed  Article  Google Scholar 

  100. Gergs U, Bernhardt G, Buchwalow IB, Edler H, Fröba J, Keller M, Kirchhefer U, Köhler F, Mißlinger N, Wache H et al (2019) Initial characterization of transgenic mice overexpressing human histamine H(2) receptors. J Pharmacol Exp Ther 369(1):129–141

    CAS  PubMed  Article  Google Scholar 

  101. Gergs U, Kirchhefer U, Bergmann F, Künstler B, Mißlinger N, Au B, Mahnkopf M, Wache H, Neumann J (2020) Characterization of stressed transgenic mice overexpressing H(2)-histamine receptors in the heart. J Pharmacol Exp Ther 374(3):479–488

    CAS  PubMed  Article  Google Scholar 

  102. Takahama H, Asanuma H, Sanada S, Fujita M, Sasaki H, Wakeno M, Kim J, Asakura M, Takashima S, Minamino T et al (2010) A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade. Basic Res Cardiol 105(6):787–794

    CAS  PubMed  Article  Google Scholar 

  103. Zeng Z, Shen L, Li X, Luo T, Wei X, Zhang J, Cao S, Huang X, Fukushima Y, Bin J et al (2014) Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis. Clin Sci (London, England: 1979) 127(7):435–448

  104. Kingwell BA (2000) Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14(12):1685–1696

    CAS  Article  Google Scholar 

  105. Luo T, Chen B, Zhao Z, He N, Zeng Z, Wu B, Fukushima Y, Dai M, Huang Q, Xu D et al (2013) Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function. Basic Res Cardiol 108(3):342

    PubMed  Article  CAS  Google Scholar 

  106. Potnuri AG, Allakonda L, Saheera S (2020) Involvement of histamine 2 receptor in alpha 1 adrenoceptor mediated cardiac hypertrophy and oxidative stress in H9c2 cardio myoblasts. J Cardiovasc Transl Res

  107. Kim J, Washio T, Yamagishi M, Yasumura Y, Nakatani S, Hashimura K, Hanatani A, Komamura K, Miyatake K, Kitamura S et al (2004) A novel data mining approach to the identification of effective drugs or combinations for targeted endpoints–application to chronic heart failure as a new form of evidence-based medicine. Cardiovasc Drugs Ther 18(6):483–489

    CAS  PubMed  Article  Google Scholar 

  108. Kim J, Ogai A, Nakatani S, Hashimura K, Kanzaki H, Komamura K, Asakura M, Asanuma H, Kitamura S, Tomoike H et al (2006) Impact of blockade of histamine H2 receptors on chronic heart failure revealed by retrospective and prospective randomized studies. J Am Coll Cardiol 48(7):1378–1384

    CAS  PubMed  Article  Google Scholar 

  109. Bild DE, Bluemke DA, Burke GL, Detrano R, Diez Roux AV, Folsom AR, Greenland P, Jacob DR Jr, Kronmal R, Liu K et al (2002) Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol 156(9):871–881

    PubMed  Article  Google Scholar 

  110. Leary PJ, Tedford RJ, Bluemke DA, Bristow MR, Heckbert SR, Kawut SM, Krieger EV, Lima JA, Masri CS, Ralph DD et al (2016) Histamine H2 receptor antagonists, left ventricular morphology, and heart failure risk: the MESA study. J Am Coll Cardiol 67(13):1544–1552

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Adelborg K, Sundbøll J, Schmidt M, Bøtker HE, Weiss NS, Pedersen L, Sørensen HT (2018) Use of histamine H(2) receptor antagonists and outcomes in patients with heart failure: a nationwide population-based cohort study. Clin Epidemiol 10:521–530

    PubMed  PubMed Central  Article  Google Scholar 

  112. Leary PJ, Barr RG, Bluemke DA, Bristow MR, Kronmal RA, Lima JA, Ralph DD, Ventetuolo CE, Kawut SM (2014) H2 receptor antagonists and right ventricular morphology: the MESA right ventricle study. Ann Am Thorac Soc 11(9):1379–1386

    PubMed  PubMed Central  Article  Google Scholar 

  113. Yoshihisa A, Takiguchi M, Kanno Y, Sato A, Yokokawa T, Miura S, Abe S, Misaka T, Sato T, Suzuki S et al (2017) Associations of acid suppressive therapy with cardiac mortality in heart failure patients. J Am Heart Assoc 6(5)

  114. Halabi A, Kirch W (1991) Negative chronotropic effects of nizatidine. Gut 32(6):630–634

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Kirch W, Halabi A, Linde M, Santos SR, Ohnhaus EE (1989) Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements. Gastroenterology 96(6):1388–1392

    CAS  PubMed  Article  Google Scholar 

  116. Hinrichsen H, Halabi A, Kirch W (1990) Hemodynamic effects of different H2-receptor antagonists. Clin Pharmacol Ther 48(3):302–308

    CAS  PubMed  Article  Google Scholar 

  117. Halabi A, Nokhodian A, Kirch W (1992) Haemodynamic effects of roxatidine, an H2-receptor antagonist. Clin Investig 70(2):118–121

    CAS  PubMed  Article  Google Scholar 

  118. Kirch W, Halabi A, Hinrichsen H (1992) Hemodynamic effects of quinidine and famotidine in patients with congestive heart failure. Clin Pharmacol Ther 51(3):325–333

    CAS  PubMed  Article  Google Scholar 

  119. Lucas BD Jr, Williams MA, Mohiuddin SM, LaMadrid LJ, Schroeder LJ, Hilleman DE (1998) Effect of oral H2-receptor antagonists on left ventricular systolic function and exercise capacity in patients with chronic stable heart failure. Pharmacotherapy 18(4):824–830

    CAS  PubMed  Google Scholar 

  120. Endou M, Poli E, Levi R (1994) Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca++ channels. J Pharmacol Exp Ther 269(1):221–229

    CAS  PubMed  Google Scholar 

  121. Mazenot C, Ribuot C, Durand A, Joulin Y, Demenge P, Godin-Ribuot D (1999) In vivo demonstration of H3-histaminergic inhibition of cardiac sympathetic stimulation by R-alpha-methyl-histamine and its prodrug BP 2.94 in the dog. Br J Pharmacol 126(1):264–268

  122. Imamura M, Poli E, Omoniyi AT, Levi R (1994) Unmasking of activated histamine H3-receptors in myocardial ischemia: their role as regulators of exocytotic norepinephrine release. J Pharmacol Exp Ther 271(3):1259–1266

    CAS  PubMed  Google Scholar 

  123. Chrusch C, Sharma S, Unruh H, Bautista E, Duke K, Becker A, Kepron W, Mink SN (1999) Histamine H3 receptor blockade improves cardiac function in canine anaphylaxis. Am J Respir Crit Care Med 160(4):1142–1149

    CAS  PubMed  Article  Google Scholar 

  124. Hatta E, Yasuda K, Levi R (1997) Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia. J Pharmacol Exp Ther 283(2):494–500

    CAS  PubMed  Google Scholar 

  125. Imamura M, Lander HM, Levi R (1996) Activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release during protracted myocardial ischemia. Comparison with adenosine A1-receptors and alpha2-adrenoceptors. Circ Res 78(3):475–481

  126. Imamura M, Seyedi N, Lander HM, Levi R (1995) Functional identification of histamine H3-receptors in the human heart. Circ Res 77(1):206–210

    CAS  PubMed  Article  Google Scholar 

  127. Böhm M, Maack C (2000) Treatment of heart failure with beta-blockers. Mechanisms and results. Basic Res Cardiol 95(1):I15–24

  128. Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, Levi R (2002) Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings. Proc Natl Acad Sci USA 99(1):501–506

    CAS  PubMed  Article  Google Scholar 

  129. Seyedi N, Mackins CJ, Machida T, Reid AC, Silver RB, Levi R (2005) Histamine H3-receptor-induced attenuation of norepinephrine exocytosis: a decreased protein kinase a activity mediates a reduction in intracellular calcium. J Pharmacol Exp Ther 312(1):272–280

    CAS  PubMed  Article  Google Scholar 

  130. Levi R, Seyedi N, Schaefer U, Estephan R, Mackins CJ, Tyler E, Silver RB (2007) Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway. Biochem Pharmacol 73(8):1146–1156

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Hashikawa-Hobara N, Chan NY, Levi R (2012) Histamine 3 receptor activation reduces the expression of neuronal angiotensin II type 1 receptors in the heart. J Pharmacol Exp Ther 340(1):185–191

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Morisset S, Sasse A, Gbahou F, Héron A, Ligneau X, Tardivel-Lacombe J, Schwartz JC, Arrang JM (2001) The rat H3 receptor: gene organization and multiple isoforms. Biochem Biophys Res Commun 280(1):75–80

    CAS  PubMed  Article  Google Scholar 

  133. McCaffrey SL, Lim G, Bullock M, Ksparian AO, Clifton-Bligh R, Campbell WB, Widiapradja A, Levick SP (2020) The histamine 3 receptor is expressed in the heart and its activation opposes adverse cardiac remodeling in the angiotensin II mouse model. Int J Mol Sci 21(24)

  134. Piera L, Olczak S, Kun T, Galdyszynska M, Ciosek J, Szymanski J, Drobnik J (2019) Disruption of histamine/H3 receptor signal reduces collagen deposition in cultures scar myofibroblasts. J Physiol Pharmacol 70(2)

  135. Henegar JR. Brower GL, Kabour A, Janicki JS (1995) Catecholamine response to chronic ANG II infusion and its role in myocyte and coronary vascular damage. In: Am J Physiol. Edited by GL B, A K, JS J, vol. 269; H1564-H1569

  136. Henegar JR, Schwartz DD, Janicki JS (1998) ANG II-related myocardial damage: role of cardiac sympathetic catecholamines and beta-receptor regulation. In: Am J Physiol. Edited by DD S, JS J, vol. 275; H534-H541

  137. Kabour A, Henegar JR, Janicki JS (1994) Angiotensin II (AII)-induced myocyte necrosis: role of the AII receptor. J Cardiovasc Pharmacol 23(4):547–553

    CAS  PubMed  Article  Google Scholar 

  138. Perlini S, Palladini G, Ferrero I, Tozzi R, Fallarini S, Facoetti A, Nano R, Clari F, Busca G, Fogari R et al (2005) Sympathectomy or doxazosin, but not propranolol, blunt myocardial interstitial fibrosis in pressure-overload hypertrophy. Hypertension (Dallas, Tex: 1979) 46(5):1213–1218

  139. Lameris TW, de Zeeuw S, Duncker DJ, Alberts G, Boomsma F, Verdouw PD, van den Meiracker AH (2002) Exogenous angiotensin II does not facilitate norepinephrine release in the heart. Hypertension (Dallas, Tex: 1979) 40(4):491–497

  140. Yadav CH, Najmi AK, Akhtar M, Khanam R (2015) Cardioprotective role of H3R agonist imetit on isoproterenol-induced hemodynamic changes and oxidative stress in rats. Toxicol Mech Methods 25(4):235–240

    CAS  PubMed  Article  Google Scholar 

  141. Chen Y, Paavola J, Stegajev V, Stark H, Chazot PL, Wen JG, Konttinen YT (2015) Activation of histamine H3 receptor decreased cytoplasmic Ca(2+) imaging during electrical stimulation in the skeletal myotubes. Eur J Pharmacol 754:173–178

    CAS  PubMed  Article  Google Scholar 

  142. Dehlin HM, Levick SP (2014) Substance P in heart failure: the good and the bad. Int J Cardiol 170(3):270–277

    PubMed  Article  Google Scholar 

  143. Dehlin HM, Manteufel EJ, Monroe AL, Reimer MH Jr, Levick SP (2013) Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension. Int J Cardiol 168(5):4643–4651

    PubMed  PubMed Central  Article  Google Scholar 

  144. Levick SP, Soto-Pantoja DR, Bi J, Hundley WG, Widiapradja A, Manteufel EJ, Bradshaw TW, Meléndez GC (2019) Doxorubicin-induced myocardial fibrosis involves the neurokinin-1 Receptor and direct effects on cardiac fibroblasts. Heart Lung Circ 28(10):1598–1605

    PubMed  Article  Google Scholar 

  145. Kramer JH, Phillips TM, Weglicki WB (1997) Magnesium-deficiency-enhanced post-ischemic myocardial injury is reduced by substance P receptor blockade. J Mol Cell Cardiol 29(1):97–110

    CAS  PubMed  Article  Google Scholar 

  146. Mak IT, Chmielinska JJ, Kramer JH, Spurney CF, Weglicki WB (2011) Loss of neutral endopeptidase activity contributes to neutrophil activation and cardiac dysfunction during chronic hypomagnesemia: Protection by substance P receptor blockade. Exp Clin Cardiol 16(4):121–124

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Mak IT, Kramer JH, Chmielinska JJ, Spurney CF, Weglicki WB (2015) EGFR-TKI, erlotinib, causes hypomagnesemia, oxidative stress, and cardiac dysfunction: attenuation by NK-1 receptor blockade. J Cardiovasc Pharmacol 65(1):54–61

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. Weglicki WB, Mak IT, Phillips TM (1994) Blockade of cardiac inflammation in Mg2+ deficiency by substance P receptor inhibition. Circ Res 74(5):1009–1013

    CAS  PubMed  Article  Google Scholar 

  149. D’Souza M, Garza MA, Xie M, Weinstock J, Xiang Q, Robinson P (2007) Substance P is associated with heart enlargement and apoptosis in murine dilated cardiomyopathy induced by Taenia crassiceps infection. J Parasitol 93(5):1121–1127

    CAS  PubMed  Article  Google Scholar 

  150. Robinson P, Garza A, Moore J, Eckols TK, Parti S, Balaji V, Vallejo J, Tweardy DJ (2009) Substance P is required for the pathogenesis of EMCV infection in mice. Int J Clin Exp Med 2(1):76–86

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Robinson P, Taffet GE, Engineer N, Khumbatta M, Firozgary B, Reynolds C, Pham T, Bulsara T, Firozgary G (2015) Substance P receptor antagonism: a potential novel treatment option for viral-myocarditis. BioMed Res Int 2015:645153

  152. He GH, Cai WK, Zhang JB, Ma CY, Yan F, Lu J, Xu GL (2016) Associations of polymorphisms in HRH2, HRH3, DAO, and HNMT genes with risk of chronic heart failure. Biomed Res Int 2016:1208476

    PubMed  PubMed Central  Google Scholar 

  153. Noguchi K, Ishida J, Kim JD, Muromachi N, Kako K, Mizukami H, Lu W, Ishimaru T, Kawasaki S, Kaneko S et al (2020) Histamine receptor agonist alleviates severe cardiorenal damages by eliciting anti-inflammatory programming. Proc Natl Acad Sci USA 117(6):3150–3156

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Pinacho-García M, Marichal-Cancino BA, Villalón CM (2016) Further evidence for the role of histamine H3, but not H1, H2 or H4, receptors in immepip-induced inhibition of the rat cardioaccelerator sympathetic outflow. Eur J Pharmacol 773:85–92

    PubMed  Article  CAS  Google Scholar 

  155. Stasiak A, Gola J, Kraszewska K, Mussur M, Kobos J, Mazurek U, Stark H, Fogel WA (2018) Experimental autoimmune myocarditis in rats and therapeutic histamine H1 - H4 receptor inhibition. J Physiol Pharmacol 69(6)

  156. Durante M, Sgambellone S, Lanzi C, Nardini P, Pini A, Moroni F, Masini E, Lucarini L (2019) Effects of PARP-1 deficiency and histamine H(4) receptor inhibition in an inflammatory model of lung fibrosis in mice. Front Pharmacol 10:525

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Rossbach K, Wahle K, Bruer G, Brehm R, Langeheine M, Rode K, Schaper-Gerhardt K, Gutzmer R, Werfel T, Kietzmann M et al (2020) Histamine 2 receptor agonism and histamine 4 receptor antagonism ameliorate inflammation in a model of psoriasis. Acta dermato-venereologica 100(19):adv00342

  158. Wechsler JB, Szabo A, Hsu CL, Krier-Burris RA, Schroeder HA, Wang MY, Carter RG, Velez TE, Aguiniga LM, Brown JB et al (2018) Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis. Mucosal Immunol 11(3):861–870

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. He GH, Xu GL, Cai WK, Zhang J (2016) Is histamine H(2) receptor a real promising target for prevention or treatment of heart failure? J Am Coll Cardiol 68(18):2029

    CAS  PubMed  Article  Google Scholar 

  160. Leary PJ, Bristow MR (2016) Reply: Is histamine H(2) receptor a real promising target for prevention or treatment of heart failure? J Am Coll Cardiol 68(18):2029–2030

    PubMed  Article  Google Scholar 

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This work was supported by the George and Mary Thompson Fellowship.

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Levick, S.P. Histamine receptors in heart failure. Heart Fail Rev 27, 1355–1372 (2022). https://doi.org/10.1007/s10741-021-10166-x

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Keywords

  • Histamine
  • Histamine receptors
  • Mast cell
  • Heart failure
  • Cardiomyopathy