Heart Failure Reviews

, Volume 12, Issue 1, pp 66–86 | Cite as

Cardiac hypertrophy induced by sustained β-adrenoreceptor activation: pathophysiological aspects

  • Oleg E. Osadchii


Cardiac hypertrophy is promoted by adrenergic over-activation and represents an independent risk factor for cardiovascular morbidity and mortality. The basic knowledge about mechanisms by which sustained adrenergic activation promotes myocardial growth, as well as understanding how structural changes in hypertrophied myocardium could affect myocardial function has been acquired from studies using an animal model of chronic systemic β-adrenoreceptor agonist administration. Sustained β-adrenoreceptor activation was shown to enhance the synthesis of myocardial proteins, an effect mediated via stimulation of myocardial growth factors, up-regulation of nuclear proto-oncogenes, induction of cardiac oxidative stress, as well as activation of mitogen-activated protein kinases and phosphatidylinositol 3-kinase. Sustained β-adrenoreceptor activation contributes to impaired cardiac autonomic regulation as evidenced by blunted parasympathetically-mediated cardiovascular reflexes as well as abnormal storage of myocardial catecholamines. Catecholamine-induced cardiac hypertrophy is associated with reduced contractile responses to adrenergic agonists, an effect attributed to downregulation of myocardial β-adrenoreceptors, uncoupling of β-adrenoreceptors and adenylate cyclase, as well as modifications of downstream cAMP-mediated signaling. In compensated cardiac hypertrophy, these changes are associated with preserved or even enhanced basal ventricular systolic function due to increased sarcoplasmic reticulum Ca2+ content and Ca2+-induced sarcoplasmic reticulum Ca2+ release. The increased availability of Ca2+ to maintain cardiomyocyte contraction is attributed to prolongation of the action potential due to inhibition of the transient outward potassium current as well as stimulation of the reverse mode of the Na+–Ca2+ exchange. Further progression of cardiac hypertrophy towards heart failure is due to abnormalities in Ca2+ handling, necrotic myocardial injury, and increased myocardial stiffness due to interstitial fibrosis.


Catecholamines Cardiac hypertrophy β-adrenoreceptor Ventricular systolic function 



Editorial comments suggested by Prof. D. Paul Thomas (University of Wyoming, USA) are greatly appreciated.


  1. 1.
    Levy D, Garrison RJ, Savage DD et al (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322:1561–1566PubMedCrossRefGoogle Scholar
  2. 2.
    Haider AW, Larson MG, Benjamin EJ et al (1998) Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. J Am Coll Cardiol 32:1454–1459PubMedGoogle Scholar
  3. 3.
    Sundstrom J, Lind L, Arnlov J et al (2001) Echocardiographic and electrocardiographic diagnoses of left ventricular hypertrophy predict mortality independently of each other in a population of elderly men. Circulation 103:2346–2351PubMedGoogle Scholar
  4. 4.
    Okin PM, Devereux RB, Nieminen MS et al (2006) Electrocardiographic strain pattern and prediction of new-onset congestive heart failure in hypertensive patients: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. Circulation 113:67–73PubMedGoogle Scholar
  5. 5.
    Drazner MH, Rame JE, Marino EK et al (2004) Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years. J Am Coll Cardiol 43:2207–2215PubMedGoogle Scholar
  6. 6.
    Martini G, Rabbia F, Gastaldi L et al (2001) Heart rate variability and left ventricular diastolic function in patients with borderline hypertension with and without left ventricular hypertrophy. Clin Exp Hypertens 23:77–87PubMedGoogle Scholar
  7. 7.
    Schafer S, Kelm M, Mingers S et al (2002) Left ventricular remodeling impairs coronary flow reserve in hypertensive patients. J Hypertens 20:1431–1437PubMedGoogle Scholar
  8. 8.
    Passino C, Magagna A, Conforti F et al (2003) Ventricular repolarization is prolonged in nondipper hypertensive patients: role of left ventricular hypertrophy and autonomic dysfunction. J Hypertens 21:445–451PubMedGoogle Scholar
  9. 9.
    Verdecchia P, Schillaci G, Borgioni C et al (1998) Prognostic significance of serial changes in left ventricular mass in essential hypertension. Circulation 97:48–54PubMedGoogle Scholar
  10. 10.
    Mathew J, Sleight P, Lonn E et al (2001) Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation 104:1615–1621PubMedGoogle Scholar
  11. 11.
    Strand AH, Gudmundsdottir H, Os I et al (2006) Arterial plasma noradrenaline predicts left ventricular mass independently of blood pressure and body build in men who develop hypertension over 20 years. J Hypertens 24:905–913PubMedGoogle Scholar
  12. 12.
    Greenwood JP, Scott EM, Stoker JB et al (2001) Hypertensive left ventricular hypertrophy: relation to peripheral sympathetic drive. J Am Coll Cardiol 38:1711–1717PubMedGoogle Scholar
  13. 13.
    Schlaich MP, Kaye DM, Lambert E et al (2003) Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation 108:560–565PubMedGoogle Scholar
  14. 14.
    Kelm M, Schafer S, Mingers S et al (1996) Left ventricular mass is linked to cardiac noradrenaline in normotensive and hypertensive patients. J Hypertens 14:1365–1367Google Scholar
  15. 15.
    Schlaich MP, Kaye DM, Lambert E et al (2005) Angiotensin II and norepinephrine release: interaction and effects on the heart. J Hypertens 23:1077–1082PubMedGoogle Scholar
  16. 16.
    Chappel CI, Rona G, Balazs T et al (1951) Severe myocardial necrosis produced by isoproterenol in the rat. Arch Int Pharmacodyn 72:123–128Google Scholar
  17. 17.
    Handforth CP (1962) Isoproterenol-induced myocardial infarction in animals. Arch Pathol 73:83–87Google Scholar
  18. 18.
    Maruffo CA (1967) Fine structural study of myocardial changes induced by isoproterenol in rhesus monkeys (Macaca mulatta). Am J Pathol 50:27–34PubMedGoogle Scholar
  19. 19.
    Ostadal B, Rychterova V, Poupa O (1968) Isoproterenol-induced acute experimental cardiac necrosis in the turtle (Testudo horsfieldi). Am Heart J 76:645–649PubMedGoogle Scholar
  20. 20.
    Rona G, Chappel CI, Balazs T et al (1959) The effect of breed, age, and sex on myocardial necrosis produced by isoproterenol in the rat. J Gerontol 14:169–173PubMedGoogle Scholar
  21. 21.
    Rona G, Chappel CI, Balazs T et al (1959) An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. Arch Pathol 67:443–455Google Scholar
  22. 22.
    Rona G, Chappel C, Kahn DS (1963) The significance of factors modifying the development of isoproterenol-induced myocardial necrosis. Am Heart J 66:389–395PubMedGoogle Scholar
  23. 23.
    Rona G (1985) Catecholamine cardiotoxicity. J Mol Cell Cardiol 17:291–306PubMedGoogle Scholar
  24. 24.
    Bloom S, Cancilla PA (1969) Myocytolysis and mitochondrial calcification in rat myocardium after low doses of isoproterenol. Am J Pathol 54:373–381PubMedGoogle Scholar
  25. 25.
    Stanton HC, Brenner G, Mayfield ED (1969) Studies on isoproterenol-induced cardiomegaly in rats. Am Heart J 77:72–80PubMedGoogle Scholar
  26. 26.
    Collins P, Billings CG, Barer GR et al (1975) Quantitation of isoprenaline-induced changes in the ventricular myocardium. Cardiovasc Res 9:797–806PubMedGoogle Scholar
  27. 27.
    Benjamin IJ, Jalil JE, Tan LB et al (1989) Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis. Circ Res 65:657–670PubMedGoogle Scholar
  28. 28.
    Alderman EL, Harrison DC (1971) Myocardial hypertrophy resulting from low dosage isoproterenol administration in rats. Proc Soc Exp Biol Med 136:268–270PubMedGoogle Scholar
  29. 29.
    Gordon AL, Inchiosa MA, Lehr D (1972) Isoproterenol-induced cardiomegaly: assessment of myocardial protein content, actomyosin ATPase and heart rate. J Mol Cell Cardiol 4:543–557PubMedGoogle Scholar
  30. 30.
    Pagano VT, Inchiosa MA (1977) Cardiomegaly produced by chronic beta-adrenergic stimulation in the rat: comparison with alpha-adrenergic effects. Life Sci 21:619–624PubMedGoogle Scholar
  31. 31.
    Tse J, Powell JR, Baste CA et al (1979) Isoproterenol-induced cardiac hypertrophy: modifications in characteristics of β-adrenergic receptor, adenylate cyclase, and ventricular contraction. Endocrinology 105:246–255PubMedCrossRefGoogle Scholar
  32. 32.
    Baldwin KM, Ernst SB, Mullin WJ et al (1982) Exercise capacity and cardiac function of rats with drug-induced cardiac enlargement. J Appl Physiol 52:591–595PubMedGoogle Scholar
  33. 33.
    Chang HY, Klein RM, Kunos G (1982) Selective desensitization of cardiac beta-adrenoceptors by prolonged in vivo infusion of catecholamines in rats. J Pharmacol Exp Ther 221:784–789PubMedGoogle Scholar
  34. 34.
    Chatelain P, Robberecht P, De Neef P et al (1982) Early decrease in secretin-, glucagon-, and isoproterenol-stimulated cardiac adenylate cyclase activity in rats treated with isoproterenol. Biochem Pharmacol 31:347–352PubMedGoogle Scholar
  35. 35.
    Nomura Y, Kajiyama H, Segawa T (1982) Alteration in sensitivity to isoproterenol and acetylcholine in the rat heart after repeated administration of isoproterenol. J Pharmacol Exp Ther 220:411–416PubMedGoogle Scholar
  36. 36.
    Clarke K, Ward LC (1983) Protein synthesis in the early stages of cardiac hypertrophy. Int J Biochem 15:1267–1271PubMedGoogle Scholar
  37. 37.
    Taylor PB, Tang Q (1984) Development of isoproterenol-induced cardiac hypertrophy. Can J Physiol Pharmacol 62:384–389PubMedGoogle Scholar
  38. 38.
    Gengo P, Skattebol A, Moran JF et al (1988) Regulation by chronic drug administration of neuronal and cardiac calcium channel, beta-adrenoceptor and muscarinic receptor levels. Biochem Pharmacol 37:627–633PubMedGoogle Scholar
  39. 39.
    Nanoff C, Freissmuth M, Tuisl E et al (1989) A different desensitization pattern of cardiac β-adrenoceptor subtypes by prolonged in vivo infusion of isoprenaline. J Cardiovasc Pharmacol 13:198–203PubMedGoogle Scholar
  40. 40.
    Bowling N, Wyss VL, Gengo PJ et al (1990) Cardiac inotropic responses to calcium and forskolin are not altered by prolonged isoproterenol infusion. Eur J Pharmacol 187:155–164PubMedGoogle Scholar
  41. 41.
    Brand T, Sharma HS, Schaper W (1993) Expression of nuclear proto-oncogenes in isoproterenol-induced cardiac hypertrophy. J Mol Cell Cardiol 25:1325–1337PubMedGoogle Scholar
  42. 42.
    Golomb E, Abassi ZA, Cuda G et al (1994) Angiotensin II maintains, but does not mediate, isoproterenol-induced cardiac hypertrophy in rats. Am J Physiol 267:H1496–1506PubMedGoogle Scholar
  43. 43.
    Boluyt MO, Long X, Eschenhagen T et al (1995) Isoproterenol infusion induces alterations in expression of hypertrophy-associated genes in rat heart. Am J Physiol 269:H638–647PubMedGoogle Scholar
  44. 44.
    Muller FU, Boknik P, Horst A et al (1995) In vivo isoproterenol treatment leads to downregulation of the mRNA encoding the cAMP response element binding protein in the rat heart. Biochem Biophys Res Commun 215:1043–1049PubMedGoogle Scholar
  45. 45.
    Sarsero D, Molenaar P (1995) Effects of chronic infusion of (-)-isoprenaline on rat cardiac muscarinic M2-cholinoceptors and β1-and β2-adrenoceptors. J Auton Pharmacol 15:239–255PubMedGoogle Scholar
  46. 46.
    Hakamata N, Hamada H, Ohsuzu F et al (1997) Cardiac β-adrenergic signaling pathway alteration in isoproterenol-induced cardiac hypertrophy in male Sprague-Dawley rats. Jpn Heart J 38:849–857PubMedGoogle Scholar
  47. 47.
    Masson S, Arosio B, Luvara G et al (1998) Remodelling of cardiac extracellular matrix during β-adrenergic stimulation: upregulation of SPARC in the myocardium of adult rats. J Mol Cell Cardiol 30:1505–1514PubMedGoogle Scholar
  48. 48.
    Suzuki J, Ohno I, Nawata J et al (1999) Overexpression of insulin-like growth factor-I in hearts of rats with isoproterenol-induced cardiac hypertrophy. J Cardiovasc Pharmacol 34:635–644PubMedGoogle Scholar
  49. 49.
    Takemoto Y, Yoshiyama M, Takeuchi K et al (1999) Increased JNK, AP-1 and NF-kB DNA binding activities in isoproterenol-induced cardiac remodelling. J Mol Cell Cardiol 31:2017–2030PubMedGoogle Scholar
  50. 50.
    Morisco C, Zebrowski DC, Vatner DE et al (2001) β-adrenergic cardiac hypertrophy is mediated primarily by the β1-subtype in the rat heart. J Mol Cell Cardiol 33:561–573PubMedGoogle Scholar
  51. 51.
    Brouri F, Findji L, Mediani O et al (2002) Toxic cardiac effects of catecholamines: role of β-adrenoceptor downregulation. Eur J Pharmacol 456:69–75PubMedGoogle Scholar
  52. 52.
    Brouri F, Hanoun N, Mediani O et al (2004) Blockade of β1- and desensitization of β2-adrenoceptors reduce isoprenaline-induced cardiac fibrosis. Eur J Pharmacol 485:227–234PubMedGoogle Scholar
  53. 53.
    Miura S, Ohno I, Suzuki J et al (2003) Inhibition of matrix metalloproteinases prevents cardiac hypertrophy induced by β-adrenergic stimulation in rats. J Cardiovasc Pharmacol 42:174–181PubMedGoogle Scholar
  54. 54.
    Tomita H, Nazmy M, Kajimoto K et al (2003) Inducible cAMP early repressor is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to β-adrenergic receptor stimulation. Circ Res 93:12–22PubMedGoogle Scholar
  55. 55.
    Zhang GX, Kimura S, Nishiyama A et al (2005) Cardiac oxidative stress in acute and chronic isoproterenol-infused rats. Cardiovasc Res 65:230–238PubMedGoogle Scholar
  56. 56.
    Robbins RJ, Swain JL (1992) C-myc protooncogene modulates cardiac hypertrophic growth in transgenic mice. Am J Physiol 262:H590–597PubMedGoogle Scholar
  57. 57.
    Soonpaa MH, Field LJ (1994) Assessment of cardiomyocyte DNA synthesis during hypertrophy in adult mice. Am J Physiol 266:H1439–1445PubMedGoogle Scholar
  58. 58.
    Kudej RK, Iwase M, Uechi M et al (1997) Effects of chronic β-adrenergic receptor stimulation in mice. J Mol Cell Cardiol 29:2735–2746PubMedGoogle Scholar
  59. 59.
    Iaccarino G, Tomhave ED, Lefkowitz RJ et al (1998) Reciprocal in vivo regulation of myocardial G-protein-coupled receptor kinase expression by β-adrenergic receptor stimulation and blockade. Circulation 98:1783–1789PubMedGoogle Scholar
  60. 60.
    Iaccarino G, Dolber PC, Lefkowitz RJ et al (1999) β-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy. Hypertension 33:396–401PubMedGoogle Scholar
  61. 61.
    Saadane N, Alpert L, Chalifour LE (1999) Expression of immediate early genes, GATA-4, and Nkx-2.5 in adrenergic-induced cardiac hypertrophy and during regression in adult mice. Br J Pharmacol 127:1165–1176PubMedGoogle Scholar
  62. 62.
    Saadane N, Alpert L, Chalifour LE (2000) Altered molecular response to adrenoreceptor-induced cardiac hypertrophy in EGR-1 deficient mice. Am J Physiol 278:H796–805Google Scholar
  63. 63.
    Zou Y, Yao A, Zhu W et al (2001) Isoproterenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin. Circulation 104:102–108PubMedGoogle Scholar
  64. 64.
    Ozaki M, Kawashima S, Yamashita T et al (2002) Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusion. Circ J 66:851–856PubMedGoogle Scholar
  65. 65.
    Chattopadhyay A, Biswas S, Bandyopadhyay D et al (2003) Effect of isoproterenol on lipid peroxidation and antioxidant enzymes of myocardial tissue of mice and protection by quinidine. Mol Cell Biochem 245:43–49PubMedGoogle Scholar
  66. 66.
    Oudit GY, Crackower MA, Eriksson U et al (2003) Phosphoinositide 3-kinase γ-deficient mice are protected from isoproterenol-induced heart failure. Circulation 108:2147–2152PubMedGoogle Scholar
  67. 67.
    Yin F, Li P, Zheng M et al (2003) Interleukin-6 family of cytokines mediates isoproterenol-induced delayed STAT3 activation in mouse heart. J Biol Chem 278:21070–21075PubMedGoogle Scholar
  68. 68.
    Zahabi A, Picard S, Fortin N et al (2003) Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse hearts. J Biol Chem 278:47694–47699PubMedGoogle Scholar
  69. 69.
    Dostanic S, Servant N, Wang C et al (2004) Chronic β-adrenoreceptor stimulation in vivo decreased Bcl-2 and increased Bax expression but did not activate apoptotic pathways in mouse heart. Can J Physiol Pharmacol 82:167–174PubMedGoogle Scholar
  70. 70.
    Gava AL, Peotta VA, Cabral AM et al (2004) Decreased baroreflex sensitivity in isoproterenol-treated mice with cardiac hypertrophy. Auton Neurosci 114:47–54PubMedGoogle Scholar
  71. 71.
    Jaffre F, Callebert J, Sarre A et al (2004) Involvement of the serotonin 5-HT2b receptor in cardiac hypertrophy linked to sympathetic stimulation. Circulation 110:969–974PubMedGoogle Scholar
  72. 72.
    Faulx MD, Ernsberger P, Vatner D et al (2005) Strain dependent beta-adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice. Am J Physiol 289:H30–36Google Scholar
  73. 73.
    Hohimer AR, Davis LE, Hatton DC (2005) Repeated daily injections and osmotic pump infusion of isoproterenol cause similar increases in cardiac mass but have different effects on blood pressure. Can J Physiol Pharmacol 83:191–197PubMedGoogle Scholar
  74. 74.
    Maisel AS, Phillips C, Michel MC et al (1989) Regulation of cardiac β-adrenergic receptors by captopril. Implications for congestive heart failure. Circulation 80:669–675PubMedGoogle Scholar
  75. 75.
    Gillis AM, Mathison HJ, Patel C et al (1996) Quinidine pharmacodynamics in normal and isoproterenol-induced hypertrophied blood-perfused working rabbit hearts. J Cardiovasc Pharmacol 27:916–926PubMedGoogle Scholar
  76. 76.
    Kim N, Kim H, Youm JB et al (2006) Site specific differential activation of ras/raf/ERK signaling in rabbit isoproterenol-induced left ventricular hypertrophy. Biochim Biophys Acta 1763:1067–1075PubMedGoogle Scholar
  77. 77.
    Gans JH, Cater MR (1970) Norepinephrine-induced cardiac hypertrophy in dogs. Life Sci 9:731–740Google Scholar
  78. 78.
    Laks MM, Morady F, Swan HJC (1973) Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in the dog. Chest 64:75–78PubMedGoogle Scholar
  79. 79.
    King BD, Sack D, Kichuk MR et al (1987) Absence of hypertension despite chronic marked elevations in plasma norepinephrine in conscious dogs. Hypertension 9:582–590PubMedGoogle Scholar
  80. 80.
    Patel MB, Stewart JM, Loud AV et al (1991) Altered function and structure of the heart in dogs with chronic elevation in plasma norepinephrine. Circulation 84:2091–2100PubMedGoogle Scholar
  81. 81.
    Stewart JM, Patel MB, Wang J et al (1992) Chronic elevation of norepinephrine in conscious dogs produces hypertrophy with no loss of LV reserve. Am J Physiol 262:H331–339PubMedGoogle Scholar
  82. 82.
    Bishopric NH, Kedes L (1991) Adrenergic regulation of the skeletal α-actin gene promoter during myocardial cell hypertrophy. Proc Natl Acad Sci USA 88:2132–2136PubMedGoogle Scholar
  83. 83.
    Bogoyevitch MA, Andersson MB, Gillespie-Brown J et al (1996) Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. Biochem J 314:115–121PubMedGoogle Scholar
  84. 84.
    Jeppsson AB, Waldeck B, Widmark E (1986) Further studies on the cardiomegaly induced by β-adrenoceptor agonists. Acta Pharmacol Toxicol 58:121–125CrossRefGoogle Scholar
  85. 85.
    Schafer M, Frischkopf K, Taimor G et al (2000) Hypertrophic effect of selective β1-adrenoceptor stimulation on ventricular cardiomyocytes from adult rat. Am J Physiol 279:C495–503Google Scholar
  86. 86.
    Decker RS, Cook MG, Behnke-Barclay MM et al (1993) Catecholamines modulate protein turnover in cultured, quiescent rabbit cardiac myocytes. Am J Physiol 265:H329–339PubMedGoogle Scholar
  87. 87.
    Pinson A, Schluter KD, Zhou XJ et al (1993) Alpha- and beta-adrenergic stimulation of protein synthesis in cultured adult cardiomyocytes. J Mol Cell Cardiol 25:477–490PubMedGoogle Scholar
  88. 88.
    Schluter KD, Zhou XJ, Piper HM (1995) Induction of hypertrophic responsiveness to isoproterenol by TGF-β1 in adult rat cardiomyocytes. Am J Physiol 269:C1311–1316PubMedGoogle Scholar
  89. 89.
    Yamazaki T, Komuro I, Zou Y et al (1997) Norepinephrine induces the raf-1 kinase/mitogen-activated protein kinase cascade through both α1-and β-adrenoceptors. Circulation 95:1260–1268PubMedGoogle Scholar
  90. 90.
    Schluter KD, Goldberg Y, Taimor G et al (1998) Role of phosphatidylinositol 3-kinase activation in the hypertrophic growth of adult ventricular cardiomyocytes. Cardiovasc Res 40:174–181PubMedGoogle Scholar
  91. 91.
    Ueyama T, Kawashima S, Sakoda T et al (2000) Requirement of activation of the extracellular signal-regulated kinase cascade in myocardial cell hypertrophy. J Mol Cell Cardiol 32:947–960PubMedGoogle Scholar
  92. 92.
    Luo JD, Xie F, Zhang WW et al (2001) Simvastatin inhibits noradrenaline-induced hypertrophy of cultured neonatal rat cardiomyoytes. Br J Pharmacol 132:159–164PubMedGoogle Scholar
  93. 93.
    Singal PK, Kapur N, Dhillon KS et al (1982) Role of free radicals in catecholamine-induced cardiomyopathy. Can J Physiol Pharmacol 60:1390–1397PubMedGoogle Scholar
  94. 94.
    Teerlink JR, Pfeffer JM, Pfeffer MA (1994) Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats. Circ Res 75:105–113PubMedGoogle Scholar
  95. 95.
    Ng Y, Goldspink DF, Burniston JG et al (2002) Characterisation of isoprenaline myotoxicity on slow-twitch skeletal versus cardiac muscle. Int J Cardiol 86:299–309PubMedGoogle Scholar
  96. 96.
    Goldspink DF, Burniston JG, Ellison GM et al (2004) Catecholamine-induced apoptosis and necrosis in cardiac and skeletal myocytes of the rat in vivo: the same or separate death pathways? Exp Physiol 89:407–416PubMedGoogle Scholar
  97. 97.
    Li Z, Tran TT, Ma JY et al (2004) p38α mitogen-activated protein kinase inhibition improves cardiac function and reduces myocardial damage in isoproterenol-induced acute myocardial injury in rats. J Cardiovasc Pharmacol 44:486–492PubMedGoogle Scholar
  98. 98.
    Meng D, Feng L, Chen XJ et al (2006) Trimetazidine improved Ca2+ handling in isoprenaline-mediated myocardial injury of rats. Exp Physiol 91:591–601PubMedGoogle Scholar
  99. 99.
    Jalil JE, Doering CW, Janicki JS et al (1989) Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res 64:1041–1050PubMedGoogle Scholar
  100. 100.
    Jalil JE, Janicki JS, Pick R et al (1989) Fibrosis-induced reduction of endomyocardium in the rat after isoproterenol treatment. Circ Res 65:258–264PubMedGoogle Scholar
  101. 101.
    Allard MF, De Venny MF, Doss LK et al (1990) Alterations in dietary sodium affect isoproterenol-induced cardiac hypertrophy. J Mol Cell Cardiol 22:1135–1145PubMedGoogle Scholar
  102. 102.
    Bhambi B, Eghbali M (1991) Effect of norepinephrine on myocardial collagen gene expression and response of cardiac fibroblasts after norepinephrine treatment. Am J Pathol 139:1131–1142PubMedGoogle Scholar
  103. 103.
    Omura T, Kim S, Takeuchi K et al (1994) Transforming growth factor β1 and extracellular matrix gene expression in isoprenaline induced cardiac hypertrophy: effects of inhibition of the renin-angiotensin system. Cardiovasc Res 28:1835–1842PubMedGoogle Scholar
  104. 104.
    Grimm D, Elsner D, Schunkert H et al (1998) Development of heart failure following isoproterenol administration in the rat: role of the renin-angiotensin system. Cardiovasc Res 37:91–100PubMedGoogle Scholar
  105. 105.
    Grimm D, Holmer SR, Riegger GAJ et al (1999) Effects of beta-receptor blockade and angiotensin II type I receptor antagonism in isoproterenol-induced heart failure in the rat. Cardiovasc Pathol 8:315–323PubMedGoogle Scholar
  106. 106.
    Yoshiyama M, Takeuchi K, Kim S et al (1998) Effect of manidipine hydrochloride, a calcium antagonist, on isoproterenol-induced left ventricular hypertrophy. Jpn Circ J 62:47–52PubMedGoogle Scholar
  107. 107.
    Barth W, Deten A, Bauer M et al (2000) Differential remodeling of the left and right heart after norepinephrine treatment in rats: studies on cytokines and collagen. J Mol Cell Cardiol 32:273–284PubMedGoogle Scholar
  108. 108.
    Gallego M, Espina L, Vegas L et al (2001) Spironolactone and captopril attenuates isoproterenol-induced cardiac remodeling in rats. Pharmacol Res 44:311–315PubMedGoogle Scholar
  109. 109.
    Leenen FHH, White R, Yuan B (2001) Isoproterenol-induced cardiac hypertrophy: role of circulatory versus cardiac renin-angiotensin system. Am J Physiol 281:H2410–2416Google Scholar
  110. 110.
    Ocaranza MP, Diaz-Araya G, Chiong M et al (2002) Isoproterenol and angiotensin I-converting enzyme in lung, left ventricle, and plasma during myocardial hypertrophy and fibrosis. J Cardiovasc Pharmacol 40:246–254PubMedGoogle Scholar
  111. 111.
    Shizukuda Y, Buttrick PM, Geenen DL et al (1998) β-adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy. Am J Physiol 275:H961–968PubMedGoogle Scholar
  112. 112.
    Upsher ME, Weiss HR (1986) Heterogeneous distribution of beta-adrenoceptors in the dog left ventricle. J Mol Cell Cardiol 18:657–660PubMedGoogle Scholar
  113. 113.
    Mori H, Ishikawa S, Kojima S et al (1993) Increased responsiveness of left ventricular apical myocardium to adrenergic stimuli. Cardiovasc Res 27:192–198PubMedGoogle Scholar
  114. 114.
    Ennis IL, Escudero EM, Console GM et al (2003) Regression of isoproterenol-induced cardiac hypertrophy by Na+/H+ exchanger inhibition. Hypertension 41:1324–1329PubMedGoogle Scholar
  115. 115.
    Gianuzzi CE, Seidler FJ, Slotkin TA (1995) β-adrenoceptor control of cardiac adenylyl cyclase during development: agonist pre-treatment in the neonate uniquely causes heterologous sensitization, not desensitization. Brain Res 694:271–278Google Scholar
  116. 116.
    Zeiders JL, Seidler FJ, Slotkin TA (1997) Ontogeny of regulatory mechanisms for β-adrenoceptor control of rat cardiac adenylyl cyclase: targeting of G-proteins and the cyclase catalytic subunit. J Mol Cell Cardiol 29:603–615PubMedGoogle Scholar
  117. 117.
    Zeiders JL, Seidler FJ, Iaccarino G et al (1999) Ontogeny of cardiac β-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling. J Mol Cell Cardiol 31:413–423PubMedGoogle Scholar
  118. 118.
    Murad N, Tucci PJF (2000) Isoproterenol-induced hypertrophy may result in distinct left ventricular changes. Clin Exp Pharmacol Physiol 27:352–357PubMedGoogle Scholar
  119. 119.
    Pick R, Jalil JE, Janicki J et al (1989) The fibrillar nature and structure of isoproterenol-induced myocardial fibrosis in the rat. Am J Pathol 134:365–371PubMedGoogle Scholar
  120. 120.
    Tang Q, Taylor PB (1984) Regression of isoproterenol-induced cardiac hypertrophy. Can J Physiol Pharmacol 62:1141–1146PubMedGoogle Scholar
  121. 121.
    Deshaies Y, Willemot J, Leblanc J (1981) Protein synthesis, amino acid uptake, and pools during isoproterenol-induced hypertrophy of the rat heart and tibialis muscle. Can J Physiol Pharmacol 59:113–121PubMedGoogle Scholar
  122. 122.
    Dubus I, Samuel JL, Marotte F et al (1990) β-adrenergic agonists stimulate the synthesis of noncontractile but not contractile proteins in cultured myocytes isolated from adult rat heart. Circ Res 66:867–874PubMedGoogle Scholar
  123. 123.
    Schluter KD, Frischkopf K, Flesch M et al (2000) Central role for ornithine decarboxylase in β-adrenoceptor-mediated hypertrophy. Cardiovasc Res 45:410–417PubMedGoogle Scholar
  124. 124.
    Mallov S (1973) Effect of sympathomimetic drugs on protein synthesis in rat heart. J Pharmacol Exp Ther 187:482–494PubMedGoogle Scholar
  125. 125.
    Wood WG, Lindenmayer GE, Schwartz A (1971) Myocardial synthesis of ribonucleic acid. I. Stimulation by isoproterenol. J Mol Cell Cardiol 3:127–138PubMedGoogle Scholar
  126. 126.
    Tang Q, Taylor PB, Helbing RK (1987) Catecholamine-induced cardiac hypertrophy. Can J Cardiol 3:311–316PubMedGoogle Scholar
  127. 127.
    Bartolome J, Huguenard J, Slotkin TA (1980) Role of ornithine decarboxylase in cardiac growth and hypertrophy. Science 210:793–794PubMedGoogle Scholar
  128. 128.
    Larson DF, Copeland JG, Russell DH (1985) Catecholamine-induced cardiac hypertrophy in a denervated, hemodynamically non-stressed heart transplant. Life Sci 36:2477–2489PubMedGoogle Scholar
  129. 129.
    Mallov S (1975) Effect of sympathomimetic amines and monoamine oxidase inhibitors on protein synthesis in rat heart. Biochem Pharmacol 25:1645–1651Google Scholar
  130. 130.
    Clark WA, Rudnick SJ, LaPres JJ et al (1991) Hypertrophy of isolated adult feline heart cells following β-adrenergic-induced beating. Am J Physiol 261:C530–542PubMedGoogle Scholar
  131. 131.
    Irlbeck M, Muhling O, Iwai T et al (1996) Different response of the rat left and right heart to norepinephrine. Cardiovasc Res 31:157–162PubMedGoogle Scholar
  132. 132.
    Kizaki K, Momozaki M, Akatsuka K et al (2004) Impaired gene expression of β1-adrenergic receptor, but not stimulatory G-protein G, in rat ventricular myocardium treated with isoproterenol. Biol Pharm Bull 27:1130–1132PubMedGoogle Scholar
  133. 133.
    Osadchii O, Woodiwiss A, Alves N et al (2005) Mechanisms of preserved baseline cardiac systolic function in rats with adrenergic inotropic downregulation. Life Sci 78:366–375PubMedGoogle Scholar
  134. 134.
    Osadchii O, Woodiwiss A, Norton G (2006) Contractile responses to selective phosphodiesterase inhibitors following chronic β-adrenoreceptor activation. Pflugers Arch 452:155–163PubMedGoogle Scholar
  135. 135.
    Tang L, Gao W, Taylor PB (1996) Force-frequency response in isoproterenol-induced hypertrophied rat heart. Eur J Pharmacol 318:349–356PubMedGoogle Scholar
  136. 136.
    Tang L, Taylor PB (1996) Altered contractile function in isoproterenol-induced hypertrophied rat heart. J Hypertens 14:751–757PubMedGoogle Scholar
  137. 137.
    Lin YC (1973) Hemodynamics in the rat with isoproterenol-induced cardiac hypertrophy. Res Commun Chem Pathol Pharmacol 6:213–220PubMedGoogle Scholar
  138. 138.
    Ishizawa M, Mizushige K, Noma T et al (2006) An antioxidant treatment potentially protects myocardial energy metabolism by regulating uncoupling protein 2 expression in a chronic β-adrenergic stimulation rat model. Life Sci 78:2974–2982PubMedGoogle Scholar
  139. 139.
    Lahlou S, Lima GC, Leao-Filho CSC et al (2000) Effects of long-term pretreatment with isoproterenol on bromocriptine-induced tachycardia in conscious rats. Can J Physiol Pharmacol 78:260–265PubMedGoogle Scholar
  140. 140.
    McQueen AP, Zhang D, Hu P et al (2005) Contractile dysfunction in hypertrophied hearts with deficient insulin receptor signaling: possible role of reduced capillary density. J Mol Cell Cardiol 39:882–892PubMedGoogle Scholar
  141. 141.
    Meszaros J (1992) Sodium-pump injury and arrhythmogenic transient depolarizations in catecholamine-induced cardiac hypertrophy. Eur J Pharmacol 210:325–331PubMedGoogle Scholar
  142. 142.
    Meszaros J, Khananshvili D, Hart G (2001) Mechanisms underlying delayed afterdepolarizations in hypertrophied left ventricular myocytes of rats. Am J Physiol 281:H903–914Google Scholar
  143. 143.
    Chorvatova A, Hart G, Hussain M (2004) Na+/Ca2+ exchange current (I Na/Ca) and sarcoplasmic reticulum Ca2+ release in catecholamine-induced cardiac hypertrophy. Cardiovasc Res 61:278–287PubMedGoogle Scholar
  144. 144.
    Hayes JS, Pollock GD, Fuller RW (1984) In vivo cardiovascular responses to isoproterenol, dopamine and tyramine after prolonged infusion of isoproterenol. J Pharmacol Exp Ther 231:633–639PubMedGoogle Scholar
  145. 145.
    Vleeming W, van Rooij HH, Wemer J et al (1990) Modulation of adrenoceptor-mediated cardiovascular effects by short-term in vivo infusion of isoproterenol in rats. J Cardiovasc Pharmacol 16:584–593PubMedGoogle Scholar
  146. 146.
    Butterfield MC, Chess-Williams R (1993) Potentiation of α-adrenoceptor-mediated responses following chronic β-adrenoceptor stimulation in the rat heart. Br J Pharmacol 108:658–662PubMedGoogle Scholar
  147. 147.
    Stein B, Bartel S, Kirchhefer U et al (1996) Relation between contractile function and regulatory cardiac proteins in hypertrophied hearts. Am J Physiol 270:H2021–2028PubMedGoogle Scholar
  148. 148.
    Linck B, Boknik P, Baba HA et al (1998) Long-term beta-adrenoceptor-mediated alteration in contractility and expression of phospholamban and sarcoplasmic reticulum Ca++-ATPase in mammalian ventricle. J Pharmacol Exp Ther 286:531–538PubMedGoogle Scholar
  149. 149.
    Woodiwiss AJ, Tsotetsi OJ, Sprott S et al (2001) Reduction in myocardial collagen cross-linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction. Circulation 103:155–160PubMedGoogle Scholar
  150. 150.
    Kitagawa Y, Yamashita D, Ito H et al (2004) Reversible effects of isoproterenol-induced hypertrophy on in situ left ventricular function in rat hearts. Am J Physiol 287:H277–285Google Scholar
  151. 151.
    Veliotes DG, Woodiwiss AJ, Deftereos DA et al (2005) Aldosterone receptor blockade prevents the transition to cardiac pump dysfunction induced by β-adrenoreceptor activation. Hypertension 45:914–920PubMedGoogle Scholar
  152. 152.
    Osadchii OE, Norton GR, McKechnie R et al (2007) Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation. Am J Physiol (in press). doi:10.1152/ajpheart.00740.2006Google Scholar
  153. 153.
    Boknik P, Fockenbrock M, Herzig S et al (2000) Protein phosphatase activity is increased in a rat model of long-term β-adrenergic stimulation. Naunyn-Schmiedeberg’s Arch Pharmacol 362:222–231Google Scholar
  154. 154.
    Tappia PS, Hata T, Hozaima L et al (2001) Role of oxidative stress in catecholamine-induced changes in cardiac sarcolemmal Ca2+ transport. Arch Biochem Biophys 387:85–92PubMedGoogle Scholar
  155. 155.
    Meyrelles SS, Mauad H, Mathias SC et al (1998) Effects of myocardial hypertrophy on neural reflexes controlling cardiovascular function. J Auton Nerv Syst 73:135–142PubMedGoogle Scholar
  156. 156.
    Matthews JM, Falckh PHJ, Molenaar P et al (1996) Chronic (-)-isoprenaline infusion down-regulates β1- and β2-adrenoreceptors but does not transregulate muscarinic cholinoceptors in rat heart. Naunyn-Schmiedeberg’s Arch Pharmacol 353:213–225Google Scholar
  157. 157.
    Mueller RA, Axelrod J (1968) Abnormal cardiac norepinephrine storage in isoproterenol-treated rats. Circ Res 23:771–778PubMedGoogle Scholar
  158. 158.
    Mueller RA, Thoenen H (1971) Cardiac catecholamine synthesis, turnover and metabolism with isoproterenol-induced myocytolisis. Cardiovasc Res 5:364–370PubMedGoogle Scholar
  159. 159.
    Dhalla NS, Balasubramanian V, Goldman J (1971) Biochemical basis of heart function, III. Influence of isoproterenol on the norepinephrine stores in the rat heart. Can J Physiol Pharmacol 49:302–311PubMedGoogle Scholar
  160. 160.
    Raum WJ, Laks MM, Garner D et al (1984) Norepinephrine increases β-receptors and adenylate cyclase in canine myocardium. Am J Physiol 246:H31–36PubMedGoogle Scholar
  161. 161.
    Himura Y, Felten SY, Kashiki M et al (1993) Cardiac noradrenergic nerve terminal abnormalities in dogs with experimental congestive heart failure. Circulation 88:1299–1309PubMedGoogle Scholar
  162. 162.
    Dong DE, Yatani A, Mohan A et al (1999) Myocardial β-adrenoceptor down-regulation by norepinephrine is linked to reduced norepinephrine uptake activity. Eur J Pharmacol 384:17–24PubMedGoogle Scholar
  163. 163.
    Lai LP, Fan THM, Delehanty JM et al (1996) Elevated myocardial interstitial norepinephrine concentration contributes to the regulation of Na+, K+-ATPase in heart failure. Eur J Pharmacol 309:235–241PubMedGoogle Scholar
  164. 164.
    Meszaros J, Levai G (1992) Catecholamine-induced cardiac hypertrophy uncouples β-adrenoceptors from slow calcium channels. Eur J Pharmacol 210:333–338PubMedGoogle Scholar
  165. 165.
    Meszaros J, Coutihno JJ, Bryant SM et al (1997) L-type calcium current in catecholamine-induced cardiac hypertrophy in the rat. Exp Physiol 82:71–83PubMedGoogle Scholar
  166. 166.
    Bryant SM, Shipsey SJ, Hart G (1999) Normal regional distribution of membrane current density in rat left ventricle is altered in catecholamine-induced hypertrophy. Cardiovasc Res 42:391–401PubMedGoogle Scholar
  167. 167.
    Meszaros J, Ryder K, Hart G (1996) Transient outward current in catecholamine-induced cardiac hypertrophy in the rat. Am J Physiol 271:H2360–2367PubMedGoogle Scholar
  168. 168.
    Kim CH, Fan THM, Kelly PF et al (1994) Isoform-specific regulation of myocardial Na,K-ATPase α-subunit in congestive heart failure. Circulation 89:313–320PubMedGoogle Scholar
  169. 169.
    Baek M, Weiss M (2005) Down-regulation of Na+ pump α2 isoform in isoprenaline-induced cardiac hypertrophy in rat: evidence for increased receptor binding affinity but reduced inotropic potency of digoxin. J Pharmacol Exp Ther 313:731–739PubMedGoogle Scholar
  170. 170.
    Vatner DE, Vatner SF, Nejima J et al (1989) Chronic norepinephrine elicits desensitization by uncoupling the β-receptor. J Clin Invest 84:1741–1748PubMedGoogle Scholar
  171. 171.
    Chang DHT, Einstein R (1996) Changes in cardiovascular responsiveness to dopexamine and β1- and β2-adrenoceptor function after the chronic treatment of β-adrenoceptor antagonists and agonists in anaesthetized dogs. J Auton Pharmacol 16:269–279PubMedGoogle Scholar
  172. 172.
    Hayes JS, Wyss VL, Schenck KS et al (1986) Effects of prolonged isoproterenol infusion on cardiac and vascular responses to adrenoceptor agonists. J Pharmacol Exp Ther 237:757–763PubMedGoogle Scholar
  173. 173.
    Martin SW, Broadley KJ (1994) Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D1-, β1-and β2-receptor-mediated responses. Br J Pharmacol 112:595–603PubMedGoogle Scholar
  174. 174.
    Russell FD, Kompa AR, Molenaar P et al (1994) Regulation of β-adrenoceptors in the guinea-pig sinoatrial node. Naunyn-Schmiedeberg’s Arch Pharmacol 349:463–472Google Scholar
  175. 175.
    Kaumann AJ, Birnbaumer L (1976) Desensitization of kitten atria to chronotropic, inotropic and adenylyl cyclase stimulating effects of (-) isoprenaline. Naunyn-Schmiedeberg’s Arch Pharmacol 293:199–202Google Scholar
  176. 176.
    Hedberg A, Mattsson H, Nerme V et al (1984) Effects of in vivo treatment with isoprenaline or prenalterol on beta-adrenoceptor mechanisms in the heart and soleus muscle of the cat. Naunyn-Schmiedeberg’s Arch Pharmacol 325:251–258Google Scholar
  177. 177.
    Brown L, Sernia C, Newling R et al (1992) Cardiac responses after norepinephrine-induced ventricular hypertrophy in rats. J Cardiovasc Pharmacol 20:316–323PubMedGoogle Scholar
  178. 178.
    Laycock SK, McMurray J, Kane KA et al (1995) Effects of chronic norepinephrine administration on cardiac function in rats. J Cardiovasc Pharmacol 26:584–589PubMedGoogle Scholar
  179. 179.
    Marsh JD, Barry WH, Neer EJ et al (1980) Evidence for uncoupling of the beta receptor-adenylate cyclase complex. Circ Res 47:493–501PubMedGoogle Scholar
  180. 180.
    Marsh JD, Barry WH, Smith TW (1982) Desensitization to the inotropic effect of isoproterenol in cultured ventricular cells. J Pharmacol Exp Ther 223:60–67PubMedGoogle Scholar
  181. 181.
    Wynne DG, Poole-Wilson PA, Harding SE (1993) Incomplete reversal of β-adrenoceptor desensitization in human and guinea-pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors. Br J Pharmacol 109:1071–1078PubMedGoogle Scholar
  182. 182.
    Vescovo G, Jones SM, Harding SE et al (1989) Isoproterenol sensitivity of isolated cardiac myocytes from rats with monocrotaline-induced right-sided hypertrophy and heart failure. J Mol Cell Cardiol 21:1047–1061PubMedGoogle Scholar
  183. 183.
    Jones SM, Kirby MS, Harding SE et al (1990) Adriamycin cardiomyopathy in the rabbit: alterations in contractile proteins and myocyte function. Cardiovasc Res 24:834–842PubMedGoogle Scholar
  184. 184.
    Vleeming W, van der Wouw PA, Biesebeek JD et al (1989) Density of β-adrenoceptors in rat heart and lymphocytes 48 hours and 7 days after acute myocardial infarction. Cardiovasc Res 23:859–866PubMedGoogle Scholar
  185. 185.
    Lu X, Barnett DB (1990) Differential rates of down regulation and recovery of rat myocardial β-adrenoceptor subtypes in vivo. Eur J Pharmacol 182:481–486PubMedGoogle Scholar
  186. 186.
    Kimura H, Miyamoto A, Ohshika H (1993) Down-regulation of β-adrenoceptors and loss of G subunit levels in ventricular myocardium of rats treated with isoproterenol. Life Sci 53:PL171–176PubMedGoogle Scholar
  187. 187.
    Limas CJ, Limas C (1984) Rapid recovery of cardiac β-adrenergic receptors after isoproterenol-induced “down”-regulation. Circ Res 55:524–531PubMedGoogle Scholar
  188. 188.
    Bobik A, Campbell JH, Carson V et al (1981) Mechanism of isoprenaline-induced refractoriness of the β-adrenoceptor-adenylate cyclase system in chick embryo cardiac cells. J Cardiovasc Pharmacol 3:541–553PubMedGoogle Scholar
  189. 189.
    Kompa AR, Molenaar P, Summers RJ (1994) Effect of chemical sympathectomy on (-)-isoprenaline-induced changes in cardiac β-adrenoceptor subtypes in the guinea-pig and rat. J Auton Pharmacol 14:411–423PubMedGoogle Scholar
  190. 190.
    Molenaar P, Smolich JJ, Russell FD et al (1990) Differential regulation of beta-1 and beta-2 adrenoceptors in guinea-pig atrioventricular conducting system after chronic (-)-isoproterenol infusion. J Pharmacol Exp Ther 255:393–400PubMedGoogle Scholar
  191. 191.
    Zhao M, Hagler HK, Muntz KH (1996) Regulation of α1-, β1-, and β2-adrenergic receptors in rat heart by norepinephrine. Am J Physiol 271:H1762–1768PubMedGoogle Scholar
  192. 192.
    Elfellah MS, Reid JL (1990) Regulation of β-adrenoceptors in the guinea-pig left ventricle and skeletal muscle following chronic agonist treatment. Eur J Pharmacol 182:387–392PubMedGoogle Scholar
  193. 193.
    Zhao M, Muntz KH (1993) Differential downregulation of β2-adrenergic receptors in tissue compartments of rat heart is not altered by sympathetic denervation. Circ Res 73:943–951PubMedGoogle Scholar
  194. 194.
    El-Demerdash E, Awad AS, Taha RM et al (2005) Probucol attenuates oxidative stress and energy decline in isoproterenol-induced heart failure in rat. Pharmacol Res 51:311–318PubMedGoogle Scholar
  195. 195.
    Leineweber K, Brandt K, Wludyka B et al (2002) Ventricular hypertrophy plus neurohumoral activation is necessary to alter the cardiac beta-adrenoceptor system in experimental heart failure. Circ Res 91:1056–1062PubMedGoogle Scholar
  196. 196.
    Schumacher C, Becker H, Conrads R et al (1995) Hypertrophic cardiomyopathy: a desensitized cardiac beta-adrenergic system in the presence of normal plasma catecholamine concentrations. Naunyn-Schmiedeberg’s Arch Pharmacol 351:398–407Google Scholar
  197. 197.
    Karliner JS, Simpson PC, Honbo N et al (1986) Mechanisms and time course of beta1-adrenoceptor desensitization in mammalian cardiac myocytes. Cardiovasc Res 20:221–228PubMedGoogle Scholar
  198. 198.
    Lau C, Burke S, Slotkin T (1982) Maturation of sympathetic neurotransmission in the rat heart. IX. Development of transsynaptic regulation of cardiac adrenergic sensitivity. J Pharmacol Exp Ther 223:675–680PubMedGoogle Scholar
  199. 199.
    Eschenhagen T, Mende U, Nose M et al (1991) Isoprenaline-induced increase in mRNA levels of inhibitory G-protein α-subunits in rat heart. Naunyn-Schmiedeberg’s Arch Pharmacol 343:609–615Google Scholar
  200. 200.
    Eschenhagen T, Mende U, Diederich M et al (1992) Long term β-adrenoceptor-mediated up-regulation of Giα and G mRNA levels and pertussis toxin-sensitive guanine nucleotide-binding proteins in rat heart. Mol Pharmacol 42:773–783PubMedGoogle Scholar
  201. 201.
    Mende U, Eschenhagen T, Geertz B et al (1992) Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart. Naunyn-Schmiedeberg’s Arch Pharmacol 345:44–50Google Scholar
  202. 202.
    Muller FU, Boheler KR, Eschenhagen T et al (1993) Isoprenaline stimulates gene transcription of the inhibitory G-protein α-subunit Giα2 in rat heart. Circ Res 72:696–700PubMedGoogle Scholar
  203. 203.
    Reithmann C, Gierschik P, Sidiropoulos D et al (1989) Mechanism of noradrenaline-induced heterologous desensitization of adenylate cyclase stimulation in rat heart muscle cells: increase in the level of inhibitory G-protein α-subunits. Eur J Pharmacol 172:211–221PubMedGoogle Scholar
  204. 204.
    Brown A, Harding SE (1992) Effect of pertussis toxin on β-adrenoceptor responses in isolated cardiac myocytes from noradrenaline-treated guinea-pigs and patients with cardiac failure. Br J Pharmacol 106:115–122PubMedGoogle Scholar
  205. 205.
    Jones SM, Hunt NA, Del Monte F et al (1990) Contraction of cardiac myocytes from noradrenaline-treated rats in response to isoprenaline, forskolin and dibutyryl cAMP. Eur J Pharmacol 191:129–140PubMedGoogle Scholar
  206. 206.
    McMartin L, Summers RJ (1999) Functional analysis of desensitization of the beta-adrenoceptor signalling pathway in rat cardiac tissues following chronic isoprenaline infusion. Br J Pharmacol 127:1012–1020PubMedGoogle Scholar
  207. 207.
    Tse J, Brackett NL, Kuo JF (1978) Alterations in activities of cyclic nucleotide systems and in β-adrenergic receptor-mediated activation of cyclic AMP-dependent protein kinase during progression and regression of isoproterenol-induced cardiac hypertrophy. Biochim Biophys Acta 542:399–411PubMedGoogle Scholar
  208. 208.
    Harrison SA, Reifsnyder DH, Gallis B et al (1986) Isolation and characterization of bovine cardiac muscle cGMP-inhibited phosphodiesterase: a receptor for new cardiotonic drugs. Mol Pharmacol 29:506–514PubMedGoogle Scholar
  209. 209.
    Sette C, Conti M (1996) Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. J Biol Chem 271:16526–16534PubMedGoogle Scholar
  210. 210.
    Byus CV, Chubb JM, Huxtable RJ et al (1976) Increase in type I adenosine 3’, 5’-monophosphate-dependent protein kinase during isoproterenol-induced cardiac hypertrophy. Biochem Biophys Res Commun 73:694–702PubMedCrossRefGoogle Scholar
  211. 211.
    Horwood DM, Singhal RL (1976) Myocardial protein kinases: II. Isoproterenol-induced changes in the activity of soluble and membrane-bound enzymes of rat left ventricle. J Mol Cell Cardiol 8:29–38PubMedGoogle Scholar
  212. 212.
    Simpson P, McGrath A, Savion S (1982) Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ Res 51:787–801PubMedGoogle Scholar
  213. 213.
    Bohm M, Deutsch HJ, Hartmann D et al (1997) Improvement of postreceptor events by metoprolol treatment in patients with chronic heart failure. J Am Coll Cardiol 30:992–996PubMedGoogle Scholar
  214. 214.
    Metra M, Nodari S, D’Aloia A et al (2002) Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure. J Am Coll Cardiol 40:1248–1258PubMedGoogle Scholar
  215. 215.
    Baker KM, Campanile CP, Trachte GJ et al (1984) Identification and characterization of the rabbit angiotensin II myocardial receptor. Circ Res 54:286–293PubMedGoogle Scholar
  216. 216.
    Katz AM (1990) Angiotensin II: hemodynamic regulator or growth factor? J Mol Cell Cardiol 22:739–747PubMedGoogle Scholar
  217. 217.
    Lindpaintner K, Ganten D (1991) The cardiac renin-angiotensin system. An appraisal of present experimental and clinical evidence. Circ Res 68:905–921PubMedGoogle Scholar
  218. 218.
    Schorb W, Booz GW, Dostal DE et al (1993) Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ Res 72:1245–1254PubMedGoogle Scholar
  219. 219.
    Regitz-Zagrosek V, Friedel N, Heymann A et al (1995) Regulation, chamber localization, and subtype distribution of angiotensin II receptors in human hearts. Circulation 91:1461–1471PubMedGoogle Scholar
  220. 220.
    Crawford DC, Chobanian AV, Brecher P (1994) Angiotensin II induces fibronectin expression associated with cardiac fibrosis in the rat. Circ Res 74:727–739PubMedGoogle Scholar
  221. 221.
    Sadoshima J, Izumo S (1993) Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Circ Res 73:413–423PubMedGoogle Scholar
  222. 222.
    Dostal DE, Baker KM (1992) Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart. Am J Hypertens 5:276–280PubMedGoogle Scholar
  223. 223.
    Nagano M, Higaki J, Nakamura F et al (1992) Role of cardiac angiotensin II in isoproterenol-induced left ventricular hypertrophy. Hypertension 19:708–712PubMedGoogle Scholar
  224. 224.
    Bos R, Mougenot N, Mediani O et al (2004) Potassium canrenoate, an aldosterone receptor antagonist, reduces isoprenaline-induced cardiac fibrosis in the rat. J Pharmacol Exp Ther 309:1160–1166PubMedGoogle Scholar
  225. 225.
    Oliveira EM, Krieger JE (2005) Chronic β-adrenoceptor stimulation and cardiac hypertrophy with no induction of circulating renin. Eur J Pharmacol 520:135–141PubMedGoogle Scholar
  226. 226.
    Galvez AS, Fiedler JL, Ocaranza MP et al (2005) Perindopril regulates β-agonist-induced cardiac apoptosis. J Cardiovasc Pharmacol 46:255–261PubMedGoogle Scholar
  227. 227.
    Robert V, Silvestre JS, Charlemagne D et al (1995) Biological determinants of aldosterone-induced cardiac fibrosis in rats. Hypertension 26:971–978PubMedGoogle Scholar
  228. 228.
    Weinberger MH, Aoi W, Henry DP (1975) Direct effect of beta-adrenergic stimulation on renin release by the rat kidney slice in vitro. Circ Res 37:318–324PubMedGoogle Scholar
  229. 229.
    Dostal DE, Booz GW, Baker KM (2000) Regulation of angiotensinogen gene expression and protein in neonatal rat cardiac fibroblasts by glucocorticoid and β-adrenergic stimulation. Basic Res Cardiol 95:485–490PubMedGoogle Scholar
  230. 230.
    Borges JC, Silva JA, Gomes MA et al (2003) Tonin in rat heart with experimental hypertrophy. Am J Physiol 284:H2263–2268Google Scholar
  231. 231.
    Nakamuru M, Jackson EK, Inagami T (1986) β-adrenoceptor-mediated release of angiotensin II from mesenteric arteries. Am J Physiol 250:H144–148Google Scholar
  232. 232.
    Barki-Harrington L, Luttrell LM, Rockman HA (2003) Dual inhibition of β-adrenergic and angiotensin II receptors by a single antagonist. A functional role for receptor-receptor interaction in vivo. Circulation 108:1611–1618PubMedGoogle Scholar
  233. 233.
    Duerr RL, Huang S, Miraliakbar HR et al (1995) Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. J Clin Invest 95:619–627PubMedCrossRefGoogle Scholar
  234. 234.
    Duerr RL, McKirnan MD, Gim RD et al (1996) Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat. Circulation 93:2188–2196PubMedGoogle Scholar
  235. 235.
    Ito H, Hiroe M, Hirata Y et al (1993) Insulin-like growth factor-1 induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes. Circulation 87:1715–1721PubMedGoogle Scholar
  236. 236.
    Sun XW, Ng YC (1998) Effects of norepinephrine on expression of IGF-1/IGF-1R and SERCA2 in rat heart. Cardiovasc Res 37:202–209PubMedGoogle Scholar
  237. 237.
    Fisher SA, Absher M (1995) Norepinephrine and angiotensin II stimulate secretion of TGF-β by neonatal rat cardiac fibroblasts in vitro. Am J Physiol 268:C910–917PubMedGoogle Scholar
  238. 238.
    Takahashi N, Calderone A, Izzo NJ et al (1994) Hypertrophic stimuli induce transforming growth factor-β1 expression in rat ventricular myocytes. J Clin Invest 94:1470–1476PubMedGoogle Scholar
  239. 239.
    Briest W, Homagk L, Rabler B et al (2004) Norepinephrine-induced changes in cardiac transforming growth factor-β isoform expression pattern of female and male rats. Hypertension 44:410–418PubMedGoogle Scholar
  240. 240.
    Zimmer HG (1997) Catecholamine-induced cardiac hypertrophy: significance of proto-oncogene expression. J Mol Med 75:849–859PubMedGoogle Scholar
  241. 241.
    Hannan RD, West AK (1991) Adrenergic agents, but not triiodo-L-thyronine induce c-fos and c-myc expression in the rat heart. Basic Res Cardiol 86:154–164PubMedGoogle Scholar
  242. 242.
    Bishopric NH, Jayasena V, Webster KA (1992) Positive regulation of the skeletal α-actin gene by Fos and Jun in cardiac myocytes. J Biol Chem 267:25535–25540PubMedGoogle Scholar
  243. 243.
    Iwaki K, Sukhatme V, Shubeita HE et al (1990) α- and β-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. J Biol Chem 265:13809–13817PubMedGoogle Scholar
  244. 244.
    Zou Y, Komuro I, Yamazaki T et al (1999) Both Gs and Gi proteins are critically involved in isoproterenol-induced cardiomyocyte hypertrophy. J Biol Chem 274:9760–9770PubMedGoogle Scholar
  245. 245.
    Murray DR, Prabhu SD, Chandrasekar B (2000) Chronic β-adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation 101:2338–2341PubMedGoogle Scholar
  246. 246.
    Rathore N, John S, Kale M et al (1998) Lipid peroxidation and antioxidant enzymes in isoproterenol-induced oxidative stress in rat tissues. Pharmacol Res 38:297–303PubMedGoogle Scholar
  247. 247.
    Ondrejickova O, Dzurba A, Sedlak J et al (1991) Processes linked to the formation of reactive oxygen species are not necessarily involved in the development of isoproterenol-induced hypertrophy of the heart. The effect of stobadine. Biomed Biochim Acta 50:1251–1254PubMedGoogle Scholar
  248. 248.
    Muller FU, Neumann J, Schmitz W (2000) Transcriptional regulation by cAMP in the heart. Mol Cell Biochem 212:11–17PubMedGoogle Scholar
  249. 249.
    Muller FU, Boknik P, Horst A et al (1995) cAMP response element binding protein is expressed and phosphorylated in the human heart. Circulation 92:2041–2043PubMedGoogle Scholar
  250. 250.
    Goldspink PH, Russell B (1996) Physiological role of phosphorylation of the cyclic AMP response element binding protein in rat cardiac nuclei. Cell Tissue Res 285:379–385PubMedGoogle Scholar
  251. 251.
    Goldspink PH, Russel B (1994) The cAMP response element binding protein is expressed and phosphorylated in cardiac myocytes. Circ Res 74:1042–1049PubMedGoogle Scholar
  252. 252.
    Muller FU, Boknik P, Knapp J et al (2001) Activation and inactivation of cAMP-response element-mediated gene transcription in cardiac myocytes. Cardiovasc Res 52:95–102PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Cardiology Group, School of Clinical Sciences, University Clinical DepartmentsUniversity of LiverpoolLiverpoolUK

Personalised recommendations