Abstract
Glucocorticoids affect the expression and density of neurotransmitter receptors in many tissues but data concerning the heart are contradictory and incomplete. We injected rats with hydrocortisone for 1–12 days and measured the densities of cardiac muscarinic receptors, α1-, β1- and β2-adrenoceptors and propranolol-resistant binding sites (formerly assumed to be the putative β4-adrenoceptor). Some aspects of intracellular signalling were also evaluated: we measured adenylyl cyclase activity (basal, isoprenaline- and forskolin-stimulated and carbachol-inhibited), the coupling between muscarinic receptors and G proteins and basal and isoprenaline-stimulated heart rate. The density of cardiac muscarinic receptors increased (in both the atria and the ventricles). The density of β1-adrenoceptors increased in the atria and was little changed in the ventricles. The density of β2-adrenoceptors increased in both the atria and the ventricles. The number of α1-adrenoceptors decreased initially, followed by a transient increase in the atria and did not change in the ventricles. The density of propranolol-resistant binding sites first increased and then diminished in the atria and did not change in the ventricles. Although there were noticeable changes in receptor densities, the stimulatory and inhibitory effects on adenylyl cyclase, basal and isoprenaline-stimulated heart rate and the coupling between muscarinic receptors and G proteins were not significantly altered. This may indicate that changes in receptor densities might be one of the mechanisms maintaining stable functional output.
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References
Abrass TB, Scarpace PJ (1981) Glucocorticoid regulation of myocardial β-adrenergic receptors. Endocrinology 108:977–980
Bian XP, Seidler FJ, Slotkin TA (1991) Promotional role for glucocorticoids in the development of intracellular signalling: enhanced cardiac and renal adenylate cyclase reactivity to beta-adrenergic and non-adrenergic stimuli after low-dose foetal dexamethasone exposure. J Dev Physiol 16:331–339
Bilski AJ, Halliday SE, Fitzgerald JD, Wale JL (1983) The pharmacology of a β2-selective adrenoceptor antagonist (ICI 118,551). J Cardiovasc Pharmacol 5:430–437
Caulfield MP (1993) Muscarinic receptors—characterization, coupling and function. Pharmacol Ther 58:319–379
Cheng JB, Goldfien A, Ballard PL, Roberts JM (1980) Glucocorticoids increase pulmonary β-adrenergic receptors in fetal rabbit. Endocrinology 107:1646–1648
Colecraft HM, Egamino JP, Sharma VK, Sheu SS (1998) Signaling mechanisms underlying muscarinic receptor-mediated increase in contraction rate in cultured heart cells. J Biol Chem 273:32158–32166
Collins S, Caron MG, Lefkowitz RJ (1988) β-Adrenergic receptors in hamster smooth muscle cells are transcriptionally regulated by glucocorticoids. J Biol Chem 263:9067–9070
Cornett LE, Hiller FC, Jacobi SE, Cao W, McGraw DW (1998) Identification of a glucocorticoid response element in the rat β2-adrenergic receptor gene. Mol Pharmacol 54:1016–1023
Dangel V, Giray J, Ratge D, Wisser H (1996) Regulation of β-adrenoreceptor density and mRNA levels in the rat heart cell-line H9c2. Biochem J 317. 925–931
Davies A, De Lean A, Lefkowitz RJ (1981) Myocardial beta-adrenergic receptors from adrenalectomized rats: impaired formation of high-affinity agonist-receptor complexes. Endocrinology 108:720–722
Emala CW, Clancy J, Hirshman CA (1997) Glucocorticoid treatment decreases muscarinic receptor expression in canine airway smooth muscle. Am J Physiol 272:L745–L751
Evans BA, Papaioannou M, Bonazzi VR, Summers RJ (1996) Expression of β3-adrenoceptor mRNA in rat tissues. Br J Pharmacol 117:210–216
Gallo MP, Alloatti G, Eva C, Oberto A, Levi RC (1993) M1 muscarinic receptors increase calcium current and phosphoinositide turnover in guinea-pig ventricular cardiocytes. J Physiol (Lond) 471:41–60
Gauthier C, Langin D, Balligand JL (2000) β3-Adrenoceptors in the cardiovascular system. Trends Pharmacol Sci 21:426–431
Granneman JG (2001) The putative β4-adrenergic receptor is a novel state of the β1-adrenergic receptor. Am J Physiol 43:E199–E202
Guest SJ, Hadcock JR, Watkins DC, Malbon CC (1990) Beta-1- and beta-2-adrenergic receptor expression in differentiating 3T3-L1 cells. Independent regulation at the level of mRNA. J Biol Chem 265:5370–5375
Hanft H, Gross G (1989) Subclassification of α1-adrenoceptor recognition sites by urapidil derivatives and other selective antagonists. Br J Pharmacol 97:691–700
Jacobsson BA, Bergh CH, Hjalmarson A (1983) Corticosteroid modulation of muscarinic receptors in rat myocardial membranes. Biochim Biophys Acta 760:77–83
Jacoby DB, Yost BL, Kumaravel B, Chan-Li Y, Xiao HQ, Kawashima K, Fryer AD (2001) Glucocorticoid treatment increases inhibitory M2 muscarinic receptor expression and function in the airways. Am J Resp Cell Mol Biol 24:485–491
Kaumann AJ (2000) Gs protein-coupled receptors in human heart. In: Kenakin T, Angus JA (eds) The pharmacology of functional, biochemical and recombinant receptor systems. Springer, Berlin Heidelberg New York, pp 73–116
Kaumann AJ, Molenaar P (1997) Modulation of human cardiac function through 4 β-adrenoceptor populations. Naunyn-Schmiedeberg’s Arch Pharmacol 355:667–681
Kiely J, Hadcock JR, Bahouth SW, Malbon CC (1994) Glucocorticoids down-regulate beta1-adrenergic-receptor expression by suppressing transcription of the receptor gene. Biochem J 302:397–403
Klett CPR and Bonner TI (1999) Identification and characterization of the rat M1 muscarinic receptor promoter. J Neurochem 72:900–909
Luetje CW, Tietje KM, Christian JL, Nathanson NM (1988) Differential tissue expression and developmental regulation of guanine nucleotide binding regulatory proteins and their messenger RNAs in rat heart. J Biol Chem 263:13557–13365
Mende U, Kagen A, Meister M, Neer EJ (1999) Signal transduction in atria and ventricles of mice with transient cardiac expression of activated G protein αq. Circ Res 85:1085–1091
Morris AJ, Malbon CC (1999) Physiological regulation of G protein-linked signaling. Physiol Rev 79:1373–1430
Moura MJ, De Moraes S (1994) Forced swim stress: supersensitivity of the isolated rat pacemaker to the chronotropic effect of isoprenaline and the role of corticosterone. Gen Pharmacol 25:1341–1347
Mysliveček J, Trojan S, Tuček S (1996) Biphasic changes of muscarinic and β-adrenergic receptors in rat heart atria during DFP treatment. Life Sci 58:2423–2430
Mysliveček J, Lisá V, Trojan S, Tuček S (1998) Heterologous regulation of muscarinic and beta-adrenergic receptors in rat cardiomyocytes in culture. Life Sci 63:1169–1182
Peterson GL (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83:346–356
Říčný J, Gualtieri F, Tuček S (2002) Constitutive inhibitory action of muscarinic receptors on adenylyl cyclase in cardiac membranes and its stereospecific suppression by hyoscyamine. Physiol Res 51:131–137
Sakaue M, Hoffmann BB (1991) Glucocorticoids induce transcription and expression of the alpha 1B adrenergic receptor gene in DTT1 MF-2 smooth muscle cells. J Clin Invest 88:385–389
Santos IN, Spadari-Bartfish RC (2001) Chronotropic response to (±)-CGP12177 in right atria of stressed rats. Can J Physiol 79:393–399
Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrinol Rev 21:55–89
Sarsero D, Molenaar P, Kaumann AJ (1998) Validity of (−)-[3H]-CGP 12177A as a radioligand for the ‘putative β4-adrenoreceptor’ in rat atrium. Br J Pharmacol 123:371–380
Sarsero D, Russell FD, Lynham JA, Rabnott G, Yang I, Fong KM, Li L, Kaumann AJ, Molenaar P (2003) (−)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the β1-adrenoceptor. Naunyn-Schmiedeberg’s Arch Pharmacol 367:10–21
Scherrer D, Lach E, Landry Y, Gies JP (1997) Glucocorticoid modulation of muscarinic and β-adrenergic receptors in guinea pig lung. Fundam Clin Pharmacol 11:111–116
Sharma VK, Colecraft HM, Wang DX, Levey AI, Grigorenko EV, Yeh HH, Sheu SS (1996) Molecular and functional identification of m1 muscarinic acetylcholine receptors in rat ventricular myocytes. Circ Res 79:86–93
Shi H, Wang H, Wang Z (1999) Identification and characterization of multiple subtypes of muscarinic acetylcholine receptors and their physiological functions in canine hearts. Mol Pharmacol 55:497–507
Stein HM, Oyama K, Martinez A, Chappell BA, Buhl E, Blount L, Padbury JF (1993) Effects of corticosteroids in preterm sheep on adaptation and sympathoadrenal mechanisms at birth. Am J Physiol 264:E763–E769
Steinberg SF (1999) The molecular basis for distinct β-adrenergic receptor subtype actions in cardiomyocytes. Circ Res 85:1101–1111
Tseng YT, Stabila JP, Nguyen TT, McGonnigal BG, Waschek JA, Padbury JF (2001) A novel glucocorticoid regulatory unit mediates the hormone responsiveness of the β1-adrenergic receptor gene. Mol Cell Endocrinol 181:165–178
Tuček S, Michal P, Vlachová V (2002) Modelling the consequences of receptor-G-protein promiscuity. Trends Pharmacol Sci 23:171–176
Wang H, Han H, Zhang L, Shi H, Schram G, Nattel S, Wang Z (2001) Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart. Mol Pharmacol 59:1029–1036
Xiao RP, Ji X, Lakatta EG (1995) Functional coupling of the β2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. Mol Pharmacol 47:322–329
Zhong H, Minneman KP (1993) Close reciprocal regulation of beta-1- and beta-2-adrenergic receptors by dexamethasone in C6 glioma cells: effects on catecholamine responsiveness. Mol Pharmacol 44:1085–1093
Acknowledgements
We appreciate technical assistance by Mrs. Dana Ungerová and Romana Ondřejová. Work was supported by grants of the Grant Agency of the Academy of Sciences of the Czech Republic (A7011910/1999) and the Grant Agency of the Czech Republic (309/00/D031).
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Mysliveček, J., Říčný, J., Kolář, F. et al. The effects of hydrocortisone on rat heart muscarinic and adrenergic α1, β1 and β2 receptors, propranolol-resistant binding sites and on some subsequent steps in intracellular signalling. Naunyn-Schmiedeberg's Arch Pharmacol 368, 366–376 (2003). https://doi.org/10.1007/s00210-003-0825-1
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DOI: https://doi.org/10.1007/s00210-003-0825-1