Regulation of the Cardiovascular System by Histamine

  • Yuichi HattoriEmail author
  • Kohshi Hattori
  • Naoyuki Matsuda
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 241)


Histamine mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in the central nervous system. Histamine also exerts a series of actions upon the cardiovascular system but may not normally play a significant role in regulating cardiovascular function. During tissue injury, inflammation, and allergic responses, mast cells (or non-mast cells) within the tissues can release large amounts of histamine that leads to noticeable cardiovascular effects. Owing to intensive research during several decades, the distribution, function, and pathophysiological role of cardiovascular H1- and H2-receptors has become recognized adequately. Besides the recognized H1- and H2-receptor-mediated cardiovascular responses, novel roles of H3- and H4-receptors in cardiovascular physiology and pathophysiology have been identified over the last decade. In this review, we describe recent advances in our understanding of cardiovascular function and dysfunction mediated by histamine receptors, including H3- and H4-receptors, their potential mechanisms of action, and their pathological significance.


Heart H3-receptors H4-receptors Vasculature 


  1. Aldi S, Takano K, Tomita K, Koda K, Chan NY, Marino A, Salazar-Rodriguez M, Thurmond RL, Levi R (2014) Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase Cε-dependent aldehyde dehydrogenase type-2 activation. J Pharmacol Exp Ther 349:508–517PubMedCrossRefPubMedCentralGoogle Scholar
  2. Ashina K, Tsubosaka Y, Nakamura T, Omori K, Kobayashi K, Hori M, Ozaki H, Murata T (2015) Histamine induces vascular hyperpermeability by increasing blood flow and endothelial barrier disruption in vivo. PLoS One 10:e0132367Google Scholar
  3. Bader M, Peters J, Baltatu O, Müller DN, Luft FC, Ganten D (2001) Tissue renin-angiotensin system: new insights from experimental animal models in hypertension research. J Mol Med 79:76–102PubMedCrossRefGoogle Scholar
  4. Benedict CR, Shelton B, Johnstone DE, Francis G, Greenberg B, Konstam M, Probstfield JL, Yusuf S (1996) Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. Circulation 94:690–697PubMedCrossRefGoogle Scholar
  5. Bennardini F, Amerini S, Franconi F, Ledda F, Maritelli L, Mutucci R, Mugelli A, Sorbi C (1984) On the presence of H1-receptors in various sections of guinea-pig heart: a correlation between binding and functional studies. Agents Actions 15:167–171PubMedCrossRefGoogle Scholar
  6. Bennett MR, Cheung A, Brain KL (1998) Sympathetic neuromuscular transmission at a varicosity in a syncytium. Microsc Res Tech 42:433–450PubMedCrossRefGoogle Scholar
  7. Borchard U, Hafner D (1986) Electrophysiological characterization of histamine receptor subtypes in mammalian heart preparations. Naunyn Schmiedebergs Arch Pharmacol 334:294–302PubMedCrossRefGoogle Scholar
  8. Braunwald E, Sobel BE (1988) Coronary blood flow and myocardial ischemia. In: Braunwald E (ed) Heart disease, a textbook of cardiovascular medicine. W.B. Saunders, Philadelphia, pp 1191–1221Google Scholar
  9. Bristow MR, Ginsburg R, Harrison DC (1982) Histamine and the human heart: the other receptor system. Am J Cardiol 49:249–251PubMedCrossRefGoogle Scholar
  10. Champion HC, Kadowitz PJ (1997) NO release and the opening of K+ATP channels mediate vasodilator responses to histamine in the cat. Am J Physiol 273:H928–H937PubMedGoogle Scholar
  11. Champion HC, Kadowitz PJ (1998) R-(-)-alpha-methyl-histamine has nitric oxide-mediated vasodilator activity in the mesenteric vascular bed of the cat. Eur J Pharmacol 343:209–216PubMedCrossRefGoogle Scholar
  12. Chan NY, Robador PA, Levi R (2012) Natriuretic peptide-induced catecholamine release from cardiac sympathetic neurons: inhibition by histamine H3 and H4 receptor activation. J Pharmacol Exp Ther 343:568–577PubMedCrossRefPubMedCentralGoogle Scholar
  13. Chang RSL, Tran VT, Snyder SH (1979) Characterization of histamine H1-receptors in peripheral tissues labeled with [3H]mepyramine. J Pharmacol Exp Ther 209:437–442PubMedGoogle Scholar
  14. Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (2008) Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321:1493–1495PubMedCrossRefPubMedCentralGoogle Scholar
  15. Dale HH, Laidlaw PP (1910) The physiological action of beta-imidazolyl ethylamine. J Physiol 41:318–344PubMedCrossRefPubMedCentralGoogle Scholar
  16. Dart AM, Du XJ (1993) Unexpected drug effects on autonomic function during myocardial ischemia. Cardiovasc Res 27:906–914PubMedCrossRefGoogle Scholar
  17. Dell’Italia LJ, Meng QC, Balcells E, Wei CC, Palmer R, Hageman GR, Durand J, Hankes GH, Oparil S (1997) Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces. J Clin Invest 100:253–258PubMedCrossRefPubMedCentralGoogle Scholar
  18. Dostel DE, Baker KM (1999) The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ Res 85:643–650CrossRefGoogle Scholar
  19. Drutel G, Peitsaro N, Karistedt K, Wieland K, Smit MJ, Timmerman H, Panula P, Leurs R (2001) Identification of rat H3 receptor isoforms with different brain expression and signaling properties. Mol Pharmacol 59:1–8PubMedGoogle Scholar
  20. Du XY, Schoemaker RG, Bax WA, Bos E, Saxena PR (1993) Effects of histamine on porcine isolated myocardium: differentiation from effects on human tissue. J Cardiovasc Pharmacol 22:468–473PubMedCrossRefGoogle Scholar
  21. Ea Kim LE, Javellaud A, Oudart N (1992) Endothelium-dependent relaxation of rabbit middle cerebral artery to histamine H3-agonist is reduced by inhibitors of nitric oxide and prostacyclin synthesis. Br J Pharmacol 105:103–106PubMedCrossRefPubMedCentralGoogle Scholar
  22. Eckel L, Gristwood RW, Nawrath H, Owen DAA, Satter P (1982) Inotropic and electrophysiological effects of histamine on human ventricular heart muscle. J Physiol 330:111–123PubMedCrossRefPubMedCentralGoogle Scholar
  23. Endou M, Poli E, Levi R (1994) Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca2+ channels. J Pharmacol Exp Ther 269:221–229PubMedGoogle Scholar
  24. Eto M, Kitazawa T, Yazawa M, Mukai H, Ono Y, Brautigan DL (2001) Histamine-induced vasoconstriction involves phosphorylation of a specific inhibitor protein for myosin phosphatase by protein kinase C α and δ isoforms. J Biol Chem 276:29072–29078PubMedCrossRefGoogle Scholar
  25. Foreman JC, Norris DB, Rising TJ, Webber SE (1985) The binding of [3H]-tiotidine to homogenates of guinea-pig lung parenchyma. Br J Pharmacol 86:475–482PubMedCrossRefPubMedCentralGoogle Scholar
  26. Förstermann U, Sessa WC (2012) Nitric oxide syntheses: regulation and function. Eur Heart J 33:829–837PubMedCrossRefGoogle Scholar
  27. Fullerton DA, Agrafojo J, McIntyre RC Jr (1996) Pulmonary vascular smooth muscle relaxation by cAMP-mediated pathways. J Surg Res 61:444–448PubMedCrossRefGoogle Scholar
  28. Garbarg M, Barbin G, Feger J, Schwartz JC (1974) Histminergic pathway in rat brain evidenced by lesions of the medial forebrain bundle. Science 186:833–835PubMedCrossRefGoogle Scholar
  29. Ghosh AK, Hirasawa N, Ohtsu H, Watanabe T, Ohuchi K (2002) Defective angiogenesis in the inflammatory granulation tissue in histidine decarboxylase-deficient mice but not in mast cell-deficient mice. J Exp Med 195:973–982PubMedCrossRefPubMedCentralGoogle Scholar
  30. Guidotti A, Zilletti L, Giotti A (1967) Correlation between mast cell population and histamine concentration of guinea-pig heart. Sperimentale 117:113–123PubMedGoogle Scholar
  31. Haass M, Hock M, Richardt G, Schömig A (1989) Neuropeptide Y differentiates between exocytotic and nonexocytotic noradrenaline release in guinea-pig heart. Naunyn Schmiedebergs Arch Pharmacol 340:509–515PubMedCrossRefGoogle Scholar
  32. Harvey SC (1978) Studies on myocardial histamine. Effects of catecholamine-depleting drugs. Arch Int Pharmacodyn Ther 232:141–149PubMedGoogle Scholar
  33. 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 340:185–191Google Scholar
  34. Hatta E, Yasuda K, Levi R (1997) Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in human model of protracted myocardial ischemia. J Pharmacol Exp Ther 283:494–500PubMedGoogle Scholar
  35. Hattori Y (1999) Cardiac histamine receptors: their pharmacological consequences and signal transduction pathways. Methods Find Exp Clin Pharmacol 21:123–131PubMedCrossRefGoogle Scholar
  36. Hattori Y, Sakuma I, Kanno M (1988) Differential effects of histamine mediated by histamine H1- and H2-receptors on contractility, spontaneous rate and cyclic nucleotides in the rabbit heart. Eur J Pharmacol 153:221–230PubMedCrossRefGoogle Scholar
  37. Hattori Y, Nakaya H, Endou M, Kanno M (1990) Inotropic, electrophysiological, and biochemical responses to histamine in rabbit papillary muscles: evidence for coexistence of H1- and H2-receptors. J Pharmacol Exp Ther 253:250–256PubMedGoogle Scholar
  38. Hattori Y, Endou M, Gando S, Kanno M (1991) Identification and characterization of histamine H1- and H2-receptors in guinea-pig left atrial membranes by [3H]-mepyramine and [3H]-tiotidine binding. Br J Pharmacol 103:1573–1579PubMedCrossRefPubMedCentralGoogle Scholar
  39. Hattori Y, Gando S, Nagashima M, Kanno M (1994) Histamine receptors mediating a positive inotropic effect in guinea pig and rabbit ventricular myocardium: distribution of the receptors and their possible intracellular coupling processes. Jpn J Pharmacol 65:327–336PubMedCrossRefGoogle Scholar
  40. Hekimian G, Côte S, Van Sande J, Boeynaems JM (1992) H2 receptor-mediated responses of aortic endothelial cells to histamine. Am J Physiol 262:H220–H224PubMedGoogle Scholar
  41. Hey JA, del Prado M, Egan RW, Kreutner W, Chapman RW (1992) Inhibition of sympathetic hypertensive responses in the guinea-pig by prejunctional histamine H3-receptors. Br J Pharmacol 107:347–351PubMedCrossRefPubMedCentralGoogle Scholar
  42. Hide M, Fukui H, Watanabe T, Wada H, Yamamoto S (1988) Histamine H1-receptor in endothelial and smooth muscle cells of guinea-pig aorta. Eur J Pharmacol 148:161–169PubMedCrossRefGoogle Scholar
  43. Hill SJ, Young JM (1980) Histamine H1-receptors in the brain of the guinea-pig and the rat: differences in ligand binding properties and regional distribution. Br J Pharmacol 68:687–696PubMedCrossRefPubMedCentralGoogle Scholar
  44. 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
  45. Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP (2003) Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J Pharmacol Exp Ther 305:1212–1221PubMedCrossRefGoogle Scholar
  46. Horowitz LF, Hirdes W, Suh BC, Hilgemann DW, Mackie K, Hille B (2005) Phospholipase C in living cells. Activation, inhibition, Ca2+ requirement, and regulation of M current. J Gen Physiol 126:243–262Google Scholar
  47. Ichiki T, Usui M, Kato M, Funakoshi Y, Ito K, Egashira K, Takeshita A (1998) Down-regulation of angiotensin II type 1 receptor gene transcription by nitric oxide. Hypertension 31:342–348PubMedCrossRefGoogle Scholar
  48. 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 271:1259–1266PubMedGoogle Scholar
  49. Imamura M, Seyedi N, Lander HM, Levi R (1995) Functional identification of histamine H3-receptors in the human heart. Circ Res 77:206–210PubMedCrossRefGoogle Scholar
  50. 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 α2-adrenoceptors. Circ Res 78:475–481PubMedCrossRefGoogle Scholar
  51. Ishikawa S, Sperelakis N (1987) A novel class of (H3) of histamine receptors on perivascular nerve terminals. Nature 327:158–160PubMedCrossRefGoogle Scholar
  52. Johnson HL (1970) Non-mast cell histamine kinetics. III. Uptake, metabolism and decline of H3-histamine in the female rat and effects of endogenous histamine release. J Pharmacol Exp Ther 171:88–97PubMedGoogle Scholar
  53. Kaneko H, Ye F, Iijima R, Kachi S, Kato S, Nagaya M, Higuchi A, Terasaki H (2014) Histamine H4 receptor as a new therapeutic target for choroidal neovascularization in age-related macular degeneration. Br J Pharmacol 171:3754–3763PubMedCrossRefPubMedCentralGoogle Scholar
  54. Karlstedt K, Jin C, Panula P (2013) Expression of histamine receptor genes Hrh3 and Hrh4 in rat brain endothelial cells. Br J Pharmacol 170:58–66PubMedCrossRefPubMedCentralGoogle Scholar
  55. Karmazyn M, Gan XT, Humphreys RA, Yoshida H, Kusumoto K (1999) The myocardial Na+-H+ exchange: structure, regulation, and its role in heart disease. Circ Res 85:777–786PubMedCrossRefGoogle Scholar
  56. Kawano T, Matsuse H, Kondo Y, Machida I, Saeki S, Tomari S, Mitsuta K, Obase Y, Fukushima C, Shimoda T, Kohno S (2004) Acetaldehyde induces histamine release from human airway mast cells to cause bronchoconstriction. Int Arch Allergy Immunol 134:233–239PubMedCrossRefGoogle Scholar
  57. Kishi F, Nakaya Y, Ito S (1998) Histamine H2-receptor-mediated nitric oxide release from porcine endothelial cells. J Cardiovasc Pharmacol 32:177–182PubMedCrossRefGoogle Scholar
  58. Koda K, Salazar-Rodriguez M, Corti F, Chan NY, Estephan R, Silver RB, Mochly-Rosen D, Levi R (2010) Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells. Circulation 122:771–781PubMedCrossRefPubMedCentralGoogle Scholar
  59. Koivisto T, Kaihovaara P, Salaspuro M (1999) Acetaldehyde induces histamine release from purified rat peritoneal mast cells. Life Sci 64:183–190PubMedCrossRefGoogle Scholar
  60. Koyama M, Seyedi N, Fung-Leung WP, Lovenberg TW, Levi R (2003a) Norepinephrine release from the ischemic heart is greatly enhanced in mice lacking histamine H3 receptors. Mol Pharmacol 63:378–382PubMedCrossRefGoogle Scholar
  61. Koyama M, Heerdt PM, Levi R (2003b) Increased severity of reperfusion arrhythmias in mouse hearts lacking histamine H3-receptors. Biochem Biophys Res Commun 306:792–796PubMedCrossRefGoogle Scholar
  62. Kübler W, Strasser RH (1994) Signal transduction in myocardial ischaemia. Eur Heart J 15:437–445PubMedCrossRefGoogle Scholar
  63. Laher IE, McNeill JH (1980) Effects of histamine on rat isolated atria. Can J Physiol Pharmacol 58:1256–1261PubMedCrossRefGoogle Scholar
  64. Lantoine F, Inouzalen L, Devynck MA, Millanvoye-Van Brussel E, David-Dufilho M (1998) Nitric oxide production in human endothelial cells stimulated by histamine requires Ca2+ influx. Biochem J 330:695–699PubMedCrossRefPubMedCentralGoogle Scholar
  65. Levi R (1972) Effects of exogenous and immunologically released histamine on the isolated heart: a quantitative comparison. J Pharmacol Exp Ther 182:227–238PubMedGoogle Scholar
  66. Levi R (1988) Cardiac anaphylaxis: models, mediators, mechanisms and clinical considerations. In: Marone G, Lichtenstein LM, Condorelli M, Fauci AS (eds) Human inflammatory disease, clinical immunology. BC Decker, Toronto, pp 93–105Google Scholar
  67. Levi R, Allan G (1980) Histamine-mediated cardiac effects. In: Bristow M (ed) Drug-induced heart disease. Elsevier/North-Holland, Amsterdam, pp 377–395Google Scholar
  68. Levi R, Smith NCE (2000) Histamine H3-receptors: a new frontier in myocardial ischemia. J Pharmacol Exp Ther 292:825–830PubMedGoogle Scholar
  69. Levi R, Capurro N, Lee CH (1975) Pharmacological characterization of cardiac histamine receptors: sensitivity to H1- and H2-receptor agonists and antagonists. Eur J Pharmacol 30:328–335PubMedCrossRefGoogle Scholar
  70. Levi R, Owen DAA, Trzeciakowski J (1982) Actions of histamine on the heart and vasculature. In: Ganellin CR, Parsons ME (eds) Pharmacology of histamine receptors. Wright, London, pp 236–297CrossRefGoogle Scholar
  71. Levi R, Rubin LE, Gross SS (1991) Histamine in cardiovascular function and dysfunction: recent developments. In: Uvnäs B (ed) Handbook of experimental pharmacology. Histamine and histamine antagonists, vol 97. Springer, Berlin, pp 347–383Google Scholar
  72. 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 73:1146–1156PubMedCrossRefPubMedCentralGoogle Scholar
  73. Li H, Burkhardt C, Heinrich UR, Brausch I, Xia N, Förstermann U (2003) Histamine upregulates gene expression of endothelial nitric oxide synthase in human vascular endothelial cells. Circulation 107:2348–2354PubMedCrossRefGoogle Scholar
  74. Liu YQ, Horio Y, Mizuguchi H, Fujimoto K, Imamura I, Abe Y, Fukui H (1992) Re-examination of 3H-mepyramine binding assay for histamine H1-receptor using quinine. Biochem Biophys Res Commun 189:378–384PubMedCrossRefGoogle Scholar
  75. Liu C, Ma X, Jiang X, Wilson SJ, Hofstra CL, Blevitt J, Pyati J, Li X, Chai W, Carruthers N, Lovenberg TW (2001a) Cloning and pharmacological characterization of a fourth histamine receptor (H4) expression in bone marrows. Mol Pharmacol 59:420–426PubMedGoogle Scholar
  76. Liu C, Wilson SJ, Kuei C, Lovenberg TW (2001b) Comparison of human, mouse, rat, and guinea pig histamine H4 receptors reveals substantial pharmacological species variation. J Pharmacol Exp Ther 299:121–130PubMedGoogle Scholar
  77. Lu Q, Wang C, Pan R, Gao X, Wei Z, Xia Y, Dai Y (2013) Histamine synergistically promotes bFGF-induced angiogenesis by enhancing VEGF production via H1 receptor. J Cell Biochem 114:1009–1019PubMedCrossRefGoogle Scholar
  78. Luo XX, Tan YH, Sheng BH (1991) Histamine H3-receptors inhibit sympathetic neurotransmission in guinea pig myocardium. Eur J Pharmacol 204:311–314PubMedCrossRefGoogle Scholar
  79. Mackins CJ, Kano S, Seyedi N, Schäfer U, Reid AC, Machida T, Silver RB, Levi R (2006) Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 116:1063–1070PubMedCrossRefPubMedCentralGoogle Scholar
  80. Malinowska B, Schlicker E (1991) H3 receptor-mediated inhibition of the neurogenic vasopressor response in pithed rats. Eur J Pharmacol 205:307–310PubMedCrossRefGoogle Scholar
  81. Marshall I (1984) Characterization and distribution of histamine H1- and H2-receptors in precapillary vessels. J Cardiovasc Pharmacol 6(Suppl 4):S587–S597Google Scholar
  82. Martinel Lamas DJ, Croci M, Carabajal E, Crescenti EJ, Sambuco L, Massari NA, Bergoc RM, Rivera ES, Medina VA (2013) Therapeutic potential of histamine H4 receptor agonists in triple-negative human breast cancer experimental model. Br J Pharmacol 170:188–199PubMedCrossRefPubMedCentralGoogle Scholar
  83. Maruyama R, Hatta E, Levi R (1999) Norepinephrine release and ventricular fibrillation in myocardial ischemia/reperfusion: roles of angiotensin and bradykinin. J Cardiovasc Pharmacol 34:913–915PubMedCrossRefGoogle Scholar
  84. Matsuda N, Hattori Y, Sakuraya F, Kobayashi M, Zhang XH, Kemmotsu O, Gando S (2002) Hemodynamic significance of histamine synthesis and histamine H1- and H2-receptor gene expression during endotoxemia. Naunyn Schmidebergs Arch Pharmacol 366:513–521CrossRefGoogle Scholar
  85. Matsuda N, Hattori Y, Zhang XH, Fukui H, Kemmotsu O, Gando S (2003) Contractions to histamine in pulmonary and mesenteric arteries from endotoxemic rabbits: modulation by vascular expressions of inducible nitric-oxide synthase and histamine H1-receptors. J Pharmacol Exp Ther 307:175–181PubMedCrossRefGoogle Scholar
  86. Matsuda N, Hattori Y, Takahashi Y, Nishihira J, Jesmin S, Kobayashi M, Gando S (2004a) Therapeutic effect of in vivo transfection of transcription factor decoy to NF-kB on septic lung in mice. Am J Physiol Lung Cell Mol Physiol 287:L1248–L1255PubMedCrossRefGoogle Scholar
  87. Matsuda N, Jesmin S, Takahashi Y, Hatta E, Kobayashi M, Matsuyama K, Kawakami N, Sakuma I, Gando S, Fukui H, Hattori Y, Levi R (2004b) Histamine H1 and H2 receptor gene and protein levels are differentially expressed in the hearts of rodents and humans. J Pharmacol Exp Ther 309:786–795PubMedCrossRefGoogle Scholar
  88. Mazenot C, Ribuot C, Durand R, Joulin Y, Demenge P, Godin-Ribuot D (1999) In vivo demonstration of H3-histaminergic inhibition of cardiac sympathetic stimulation by R-α-methyl-histamine and its prodrug BP 2.94 in the dog. Br J Pharmacol 126:264–268PubMedCrossRefPubMedCentralGoogle Scholar
  89. McNeill JH (1984) Histamine and the heart. Can J Physiol Pharmacol 62:720–726PubMedCrossRefGoogle Scholar
  90. Molderings GJ, Weissenborn G, Schlicker E, Likungu J, Göthert M (1992) Inhibition of noradrenaline release from sympathetic nerves of the human saphenous vein by pre-synaptic histamine H3 receptors. Naunyn Schmiedebergs Arch Pharmacol 346:46–50PubMedCrossRefGoogle Scholar
  91. Morgado M, Cairrão E, Santos-Silva AJ, Verde I (2012) Cyclic nucleotide-dependent relaxation pathways in vascular smooth muscle. Cell Mol Life Sci 69:247–266PubMedCrossRefGoogle Scholar
  92. Natori T, Sata M, Nagai R, Makuuchi M (2005) Cimetidine inhibits angiogenesis and suppresses tumor cell growth. Biomed Pharmacother 59:56–60PubMedCrossRefGoogle Scholar
  93. Neumann D, Beermann S, Mägel L, Jonigk D, Weber-Steffens D, Männel D, Seifert R (2012) Problems associated with the use of commercial and non-commercial antibodies against the histamine H4 receptor. Naunyn Schmiedebergs Arch Pharmacol 385:855–860CrossRefGoogle Scholar
  94. Niimi N, Noso N, Yamamoto S (1992) The effect of histamine on cultured endothelial cells. A study of the mechanism of increased vascular permeability. Eur J Pharmacol 221:325–331PubMedCrossRefGoogle Scholar
  95. Norrby K (1995) Evidence of a dual role of endogenous histamine in angiogenesis. Int J Exp Pathol 76:87–92PubMedPubMedCentralGoogle Scholar
  96. Norrby K (2002) Mast cells and angiogenesis. APMIS 110:355–371PubMedCrossRefGoogle Scholar
  97. Parsons ME, Ganellin CR (2006) Histamine and its receptors. Br J Pharmacol 147(Suppl 1):S127–S135PubMedPubMedCentralGoogle Scholar
  98. Pöch G, Kukovetz WR (1967) Drug-induced release and pharmacodynamics effects of histamine in the guinea-pig heart. J Pharmacol Exp Ther 156:522–527PubMedGoogle Scholar
  99. Reid AC, Mackins CJ, Seyedi N, Levi R (2004) Coupling of angiotensin II AT1 receptors to neuronal NHE activity and carrier-mediated norepinephrine release in myocardial ischemia. Am J Physiol Heart Circ Physiol 286:H1448–H1454PubMedCrossRefGoogle Scholar
  100. Reid AC, Silver RB, Levi R (2007) Renin: at the heart of the mast cell. Immunol Rev 217:123–140PubMedCrossRefGoogle Scholar
  101. Rhee SG (2001) Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 70:281–312PubMedCrossRefPubMedCentralGoogle Scholar
  102. Riley JF, West GB (1955) Tissue mast cells. Studies with histamine-liberator of low toxicity (compound 48/80). J Pathol Bacteriol 69:269–282PubMedCrossRefGoogle Scholar
  103. Rising TJ, Norris DB (1985) Histamine H2-receptor radioligand binding studies. In: Ganellin CR, Schwartz JC (eds) Frontiers in histamine research, advances in the biosciences. Pergamon, New York, pp 61–67Google Scholar
  104. Rizzo CA, Tozzi S, Monahan ME, Hey JA (1995) Pharmacological characterization of histamine H3 receptors in isolated guinea pig pulmonary artery and ileum. Eur J Pharmacol 294:329–335PubMedCrossRefGoogle Scholar
  105. Sanchez-Chapula J, Elizalde A (1987) Characterization of the effects of histamine on the transmembrane electrical activity of guinea-pig and rabbit SA- and AV-node cells. Naunyn Schmiedebergs Arch Pharmacol 336:218–223PubMedCrossRefGoogle Scholar
  106. Santos-Silva AJ, Cairrão E, Marques B, Verde I (2009) Regulation of human umbilical artery contractility by different serotonin and histamine receptors. Reprod Sci 16:1175–1185PubMedCrossRefGoogle Scholar
  107. Sato H, Inui J (1984) Endothelial cell-dependent relaxation and contraction induced by histamine in the isolated guinea-pig pulmonary artery. Euro J Pharmacol 97:321–324Google Scholar
  108. Seifert R (2014) Therapeutic efficacy of a H4 receptor antagonist in humans: a milestone in histamine research. J Pharmacol Exp Ther 350:2–4PubMedCrossRefGoogle Scholar
  109. Seifert R, Strasser A, Schneider EH, Neumann D, Dove S, Buschauer A. (2013) Molecular and cellular analysis of human histamine receptor subtypes. Trends Pharmacol Sci 34. doi: 10.1016/
  110. 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 reduction in intracellular calcium. J Pharmacol Exp Ther 312:272–280PubMedCrossRefGoogle Scholar
  111. Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Levenberg 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 U S A 99:501–506PubMedCrossRefGoogle Scholar
  112. 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 U S A 101:13607–13612PubMedCrossRefPubMedCentralGoogle Scholar
  113. Sörbo J, Jakobsson A, Norrby K (1994) Mast-cell histamine is angiogenic through receptors for histamine1 and histamine2. Int J Exp Pathol 75:43–50PubMedPubMedCentralGoogle Scholar
  114. Steinberg MI, Holland DR (1975) Separate receptors mediating the positive inotropic and chronotropic effect of histamine in guinea-pig atria. Eur J Pharmacol 34:95–104CrossRefGoogle Scholar
  115. Sun P, Jun X, Koyama T, Li S, Kitamura Y, Kawasaki H (2010) R-(-)-α-methylhistamine, a histamine H3 receptor agonist, induces endothelium-dependent vasodilation in rat mesenteric resistance arteries. Biol Pharm Bull 33:58–63PubMedCrossRefGoogle Scholar
  116. Szarek JL, Bailly DA, Stewart C, Gruetter CA (1992) Histamine H1-receptors mediate endothelium-dependent relaxation in rat isolated pulmonary arteries. Pulm Pharmacol 5:67–74PubMedCrossRefGoogle Scholar
  117. Tiligada E, Zampeli E, Sander K, Stark H (2009) Histamine H3 and H4 receptors as novel drug targets. Expert Opin Investig Drugs 18:1519–1531PubMedCrossRefGoogle Scholar
  118. Tiligada E, Kyriakidis K, Chazot PL, Passani MB (2011) Histamine pharmacology and new CNS drug targets. CNS Neurosci Ther 17:620–628PubMedCrossRefGoogle Scholar
  119. Toda N (1986) Mechanisms of histamine-induced relaxation in isolated monkey and dog coronary arteries. J Pharmacol Exp Ther 239:529–535PubMedGoogle Scholar
  120. Tomita K, Izumi K, Okabe S (2003) Roxatidine- and cimetidine-induced angiogenesis inhibition suppresses growth of colon cancer implants in syngeneic mice. J Pharmacol Sci 93:321–330PubMedCrossRefGoogle Scholar
  121. Trzeciakowski JP, Levi R (1981) Cardiac histamine: a mediator in search of a function. Trends Pharmacol Sci 2:14–17CrossRefGoogle Scholar
  122. Van de Voorde J, Leusen I (1983) Role of the endothelium in the vasodilator response of rat thoracic aorta to histamine. Eur J Pharmacol 87:113–120PubMedCrossRefGoogle Scholar
  123. Verma SC, McNeill JH (1977) Cardiac histamine receptors: differences between left and right atria and ventricle. J Pharmacol Exp Ther 200:352–362PubMedGoogle Scholar
  124. Wolff AA, Levi R (1986) Histamine and cardiac arrhythmias. Circ Res 58:1–16PubMedCrossRefGoogle Scholar
  125. Woodsome TP, Eto M, Everett A, Brautigan DL, Kitazawa T (2001) Expression of CPI-17 and myosin phosphatase correlates with Ca2+ sensitivity of protein kinase C-induced contraction in rabbit smooth muscle. J Physiol 535:553–564PubMedCrossRefPubMedCentralGoogle Scholar
  126. Zampeli E, Tiligada E (2009) The role of histamine H4 receptor in immune and inflammatory disorders. Br J Pharmacol 157:24–33PubMedCrossRefPubMedCentralGoogle Scholar
  127. Zauberman H, Michaelson IC, Bergmann F, Maurice DM (1969) Stimulation of neovascularization of the cornea by biogenic amines. Exp Eye Res 8:77–83PubMedCrossRefGoogle Scholar
  128. Zhang C, Xiong Y, Li J, Yang Y, Liu L, Wang W, Wang L, Li M, Fang Z (2012) Deletion and down-regulation of HRH4 gene in gastric carcinomas: a potential correlation with tumor progression. PLoS One 7:e31207PubMedCrossRefPubMedCentralGoogle Scholar
  129. Zhu Y, Michalovich D, Wu H, Tan KB, Dytko GM, Mannan IJ, Boyce R, Alston J, Tierney LA, Li X, Herrity NC, Vawter L, Sarau HM, Ames RS, Davenport CM, Hieble JP, Wilson S, Bergsma DJ, Fitzgerald LR (2001) Cloning, expression, and pharmacological characterization of a novel human histamine receptor. Mol Pharmacol 59:434–441PubMedGoogle Scholar

Copyright information

© SpringerInternationalPublishingSwitzerland 2016

Authors and Affiliations

  • Yuichi Hattori
    • 1
    Email author
  • Kohshi Hattori
    • 2
  • Naoyuki Matsuda
    • 3
  1. 1.Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  2. 2.Department of Anesthesiology and Pain Relief CenterThe University of Tokyo HospitalTokyoJapan
  3. 3.Department of Emergency and Critical Care MedicineNagoya University Graduate School of MedicineNagoyaJapan

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