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The changes in β-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac β3-adrenoceptors

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Abstract

Thyroid hormone deficiency has been reported to decrease expression and function of both β1- and β2-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of β3-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on β1- and β2-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to β-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of β-adrenoceptors, Giα, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and −dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a β3-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac β2- and β3-adrenoceptor, Giα2, Giα3, GRK3, and eNOS mRNA expressions. However, β1-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of β3-adrenoceptors as well as the signalling pathway components mediated through β3-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

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References

  1. Xiao RP, Ji X, Lakatta EG (1995) Functional coupling of the beta 2 adrenoceptor to a pertussis toxine sensitive G protein in cardiac myocytes. Mol Pharmacol 47:322–329

    Google Scholar 

  2. Xiao RP, Avdonin P, Zhou YY, Cheng H, Akhter SA, Eschenhagen T, Lefkowitz RJ, Koch WJ, Lakatta EG (1999) Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ Res 84:43–52

    CAS  PubMed  Google Scholar 

  3. Steinberg SF (1999) The molecular basis for distinct b-adrenergic receptor subtype actions in cardiomyocytes. Circ Res 85:1101–1111

    CAS  PubMed  Google Scholar 

  4. Kuschel M, Zhou YY, Cheng H, Zhang SJ, Chen Y, Lakatta EG, Xiao RP (1999) Gi protein mediated functional compartementalization of cardiac beta 2 adrenergic signaling. J Biol Chem 274:22048–22052

    Article  CAS  PubMed  Google Scholar 

  5. Gauthier C, Tavernier G, Charpentier F, Langin D, Le marec H (1996) Functional beta 3 adrenoceptor in the human heart. J Clin Invest 98:556–562

    Article  CAS  PubMed  Google Scholar 

  6. Lowell BB, Spiegelman BM (2000) Towards a molecular understanding of adaptive thermogenesis. Nature 404:652–660

    CAS  PubMed  Google Scholar 

  7. Gauthier C, Leblais V, Kobzik L, Trochu JN, Khandoudi N, Bril A (1998) The negative inotropic effects of beta 3 adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J Clin Invest 102:1377–1384

    Article  CAS  PubMed  Google Scholar 

  8. Rozec B, Gauthier C (2006) Beta 3 adrenoceptors in the cardiovascular system: putative roles in human pathologies. Pharmacol Ther 111:652–673

    Article  CAS  PubMed  Google Scholar 

  9. Moniotte S, Balligand JL (2002) Potential use of beta 3 adrenoceptor antagonists in heart failure therapy. Cardiovasc Drug Rev 20:19–26

    CAS  PubMed  Google Scholar 

  10. Moniotte S, Kobzik L, Feron O, Trochu JN, Gauthier C, Balligand JL (2001) Upregulation of beta (3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation 103:1649–1655

    Google Scholar 

  11. Cheng HJ, Zhang ZS, Onishi K, Ukai T, Sane DC, cheng CP (2001) Upregulation of functional beta 3 adrenergic receptor in the failing canine myocardium. Circ Res 89:509–606

    Article  Google Scholar 

  12. Dincer UD, Bidasee KD, Guner S, Tay A, Ozcelikay AT, Altan VM (2001) The effect of diabetes on expression of beta1, 2-, 3- adrenoceptors in rat hearts. Diabetes 50:455–461

    Article  CAS  PubMed  Google Scholar 

  13. Mallem MY, Toumanıantz G, Serpillon S, Gauthier F, Gogyn M, Desfontis JC (2004) Impairment of the low affinity state beta 1 adrenoceptor induced relaxation in spontenously hypertensive rats. Br J Pharmacol 143:599–605

    Article  CAS  PubMed  Google Scholar 

  14. Bilezikian JP, Loeb JN (1983) The influence of hyperthyroidism and hypothyroidism on alpha and beta adrenergic receptor systems and adrenergic responsiveness. Endocr Rev 14:378–387

    Article  Google Scholar 

  15. Biondi B, Palmieri EA, Lombardi G, Fazio S (2002) Effects of thyroid hormone on cardiac function: the relative importance of heart rate, loading conditions, and myocardial contractility in the regulation of cardiac performance in human hyperthyroidism. J Clin Endocrinol Metab 87:968–974

    Article  CAS  PubMed  Google Scholar 

  16. Klein I (2003) Thyroid hormone and cardiac contractility. Am J Cardiol 91:1331–1332

    Article  PubMed  Google Scholar 

  17. Franklyn JA, Gammage MD, Ramsden DB, Sheppard MC (1984) Thyroid status in patients after acute myocardial infarction. Clin Sci 67:585–590

    CAS  PubMed  Google Scholar 

  18. Polikar R, Kennedy B, Ziegler M, O’Connor DT, Smith J, Nicod P (1990) Plasma norepinephrine kinetics, dopamin beta hydroxylase and chromogranin A in hypothyroid patients before and following replacement therapy. J Clin Endocrinol Metab 70:277–281

    Article  CAS  PubMed  Google Scholar 

  19. Dowell RT, Atkıns FL, Love S (1994) Beta adrenergic receptors, adenylate cyclase activation and myofibril enzyme activity in hypothyroid rats. Am J Physiol 266:H2527–H2534

    CAS  PubMed  Google Scholar 

  20. Revelli JP, Pescini R, muzzin P, Seydoux J, Fitzgerald MG, Fraser CM, Giacobino JP (1991) Changes in beta 1 and beta 2 adrenergic receptor mRNA levels in brown adipose tissue and heart of hypothyroid rats. Biochem J 277:625–629

    CAS  PubMed  Google Scholar 

  21. Wibo M, Kilar F, Zheng I, Godfraind T (1995) Influence of thyroid status on postnatal maturation of calcium channels, beta adrenoceptors, and cation transport ATPases in rat ventricular tissue. J Mol Cell Cardiol 27:1731–1743

    Article  CAS  PubMed  Google Scholar 

  22. Wieshammer S, Keck FS, Waitzinger J, Henze E, Loos U, Hombach V, Pfeiffer EF (1989) Acute hypothyroidism slows the rate of left ventricular diastolic relaxation. Can J Physiol Pharmacol 67:1007–1010

    CAS  PubMed  Google Scholar 

  23. Klein I, Ojamaa K (2001) Thyroid hormone and the cardiovascular system. N Engl J Med 344:501–509

    Article  CAS  PubMed  Google Scholar 

  24. Moolman JA (2002) Thyroid hormone and the heart. Cardiovasc J S Afr 13:159–163

    CAS  PubMed  Google Scholar 

  25. Iwata T, Honda H, Matsuda H, Kondo M, Taniguchi J, Miwa T, Kumasaka K, Moroe H, Notoya Y (2005) Hypothyroidism changes adrenoceptor and muscarinic receptor mediated blood pressure responses. Eur J Pharmacol 507:311–316

    Article  CAS  PubMed  Google Scholar 

  26. Ungerer M, Bohm M, Elce JS, Erdman E, Lohse MJ (1993) Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation 87:454–463

    CAS  PubMed  Google Scholar 

  27. Whitsett JA, Pollinger J, Matz S (1982) Beta-adrenergic receptors and catecholamine sensitive adenylate cyclase in developing rat ventricular myocardium: effect of thyroid status. Pediatr Res 16:463–469

    CAS  PubMed  Google Scholar 

  28. Fox AW, Juberg EN, May JM, Johnson LD, Abel PW, Minneman KP (1985) Thyroid status and adrenergic receptor subtypes in the rat: comparison of receptor density and responsiveness. J Pharmacol Exp Ther 235:715–723

    CAS  PubMed  Google Scholar 

  29. Germack R, Starzec A, Perret GY (2000) Regulation of beta 1- and beta 3-adrenergic agonist stimulated lipolytic response in hyperthyroid and hypothyroid rat white adipocytes. Br J Pharmacol 129:448–456

    Article  CAS  PubMed  Google Scholar 

  30. Brown KJ, Summers RJ (2001) Beta 1 and beta 3 adrenoceptor mediated smooth muscle relaxation in hypothyroid rat ileum. Eur J Pharmacol 415:257–263

    Article  CAS  PubMed  Google Scholar 

  31. Brown I, Nankernis R, Kerr D, Sernia C (1994) Adrenoceptor mediated cardiac and vascular responses in hypothyroid rats. Biochem Pharmacol 47:281–288

    Article  CAS  PubMed  Google Scholar 

  32. Klein I, Danzi S (2007) Thyroid disease and the heart. Circulation 116:1725–1735

    Article  PubMed  Google Scholar 

  33. Hawthorn MH, Genqo P, Wei XY, Ruhedge A, Moran JF, Gallant S, Triggle DJ (1988) Effect of thyroid status on beta-adrenoceptors and calcium channels in rat cardiac and vascular tissue. Naunyn Schmiedebergs Arch Pharmacol 337:539–544

    Article  CAS  PubMed  Google Scholar 

  34. Brodde OE, Michel MC (1999) Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 51:651–690

    CAS  PubMed  Google Scholar 

  35. Aragay AM, Ruiz-Gomez A, Penela P, Sarnago S, Elorza A, Jimenez-Sainz MC, JrF Mayor (1998) G protein coupled receptor kinase 2: mechanisms of regulation and physiological functions. FEBS Lett 430:37–40

    Article  CAS  PubMed  Google Scholar 

  36. Mayor F Jr, Penela P, Ruiz-Gomez A (1998) Role of G protein coupled receptor kinase 2 and arrestins in beta adrenergic receptor internalisation. Trends Cardiovasc Med 8:234–240

    Article  CAS  PubMed  Google Scholar 

  37. Penela P, Barradas M, Alvarez-Dolado M, Munoz A, JrF Mayor (2001) Effect of hypothyroidism on G protein coupled receptor kinase 2 expression levels in rat liver, lung, and heart. Endocrinology 142:987–991

    Article  CAS  PubMed  Google Scholar 

  38. Xiao RP, Zhu W, Zheng M, Chakir K, Bond R, Lakatta EG, Cheng H (2006) Subtype specific beta adrenoceptor signaling pathways in the heart and their potential clinical implications. Trends Pharmacol Sci 25:358–365

    Article  Google Scholar 

  39. Daaka Y, Luttrell LM, Lefkowitz RJ (1997) Switching of the coupling of the beta 2 adrenergic receptor to different G proteins by protein kinase A. Nature 390:88–91

    Article  CAS  PubMed  Google Scholar 

  40. Zou Y, Komuro I, Yamazaki T, Kudoh S, Uozumi H, Kadowaki T, Yazaki Y (1999) Both Gs and Gi proteins are critically involved in isoproterenol induced cardiomyocyte hypertrophy. J Biol Chem 274:9760–9770

    Article  CAS  PubMed  Google Scholar 

  41. Chesley A, Lundberg MS, Asai T, Xiao RP, Ohtani S, Lakatta EG, Crow MT (2000) The beta(2)-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through G(i)-dependent coupling to phosphatidylinositol 3′-kinase. Circ Res 87:1172–1179

    CAS  PubMed  Google Scholar 

  42. Foerster K, Groner F, Matthes J, Koch WJ, Birnbaumer I, Herzıg S (2003) Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through beta 2 adrenoceptors. Proc Natl Acad Sci 100:14475–14480

    Article  CAS  PubMed  Google Scholar 

  43. Zwaveling J, Batink HD, Taguchi K, De Jong J, Michel MC, Pfaffendorf M, Van Zwieten A (1998) Thyroid status affects the rat cardiac beta adrenoceptor system transiently and time dependently. J Auton Pharmacol 18:1–11

    Article  CAS  PubMed  Google Scholar 

  44. Novotny J, Bourova I, Malkova O, Svoboda P, Kolar F (1999) G proteins, beta adrenoceptors, and beta adrenergic responsiveness in immature and adult rat ventricular myocardium: influence of neonatal hypo- and hyperthyroidism. J Mol Cell Cardiol 31:761–772

    Article  CAS  PubMed  Google Scholar 

  45. Singh R, Upadhyay G, Kumar S, Kapoor A, Kumar A, Tiwarı M, Godbole MM (2003) Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum. J Endocrinol 176:39–46

    Article  CAS  PubMed  Google Scholar 

  46. Chen PF, Wu KK (2000) Characterization of the roles of the 594–645 region in human endothelial nitric-oxide synthase in regulating calmoduline binding and electron transfer. J Biol Chem 275:13155–13163

    Article  CAS  PubMed  Google Scholar 

  47. Brixius K, Bloch W, Pott C, Napp A, Krahwinkel A, Ziskoven C, Koriller M, Mehlhorn U, Hescheler J, Fleischmann B, Schwinger RH (2004) Mechanisms of beta 3-adrenoceptor-induced eNOS activation in right atrial and left ventricular human myocardium. Br J Pharmacol 143:1014–1022

    Article  CAS  PubMed  Google Scholar 

  48. Kuzman JA, Gerdes AM, Kobayashi S, Liang Q (2005) Tyhroid hormona activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes. J Mol Cell Cardiol 39:841–844

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, Ankara University, 06100, Tandogan, Ankara, Turkey

    E. Arioglu, S. Guner, I. Ozakca, V. M. Altan & A. T. Ozcelikay

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  1. E. Arioglu
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  2. S. Guner
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  3. I. Ozakca
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Correspondence to A. T. Ozcelikay.

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Arioglu, E., Guner, S., Ozakca, I. et al. The changes in β-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac β3-adrenoceptors. Mol Cell Biochem 335, 59–66 (2010). https://doi.org/10.1007/s11010-009-0241-z

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