Abstract
Since the mechanisms responsible for gender differences in cardiac contractile function have not been fully elucidated, we focused to determine the effect of gender difference on β-adrenergic receptors (β-ARs) signal transduction in ventricular cardiomyocytes from insulin-dependent diabetic (streptozotocin-induced) rats. Dose-response curves of left ventricular developed pressure (LVDP) to isoproterenol (ISO) in females showed that there was only a ∼30% decrease in the maximum response without a significant shift in EC50 in diabetic females. On the other hand, diabetes induced a clear rightward shift in the potency (5–10 folds) without a significant change in the maximum response in the males. In order to further determine of the underlying mechanism for this difference, we measured cAMP production and obtained dose-response curves with ISO stimulation in isolated cardiomyocytes. In diabetic females, there was no obvious change in the cAMP dose-response curve. On the other hand, there was a significant decrease in the maximum response without any apparent change in the potency of diabetic males. Our findings indicate that male and female rats are affected differently by diabetes in terms of LVDP responses to β-ARs stimulation. Also, the difference between their β-ARs induced cAMP responses may underlie this disparity.
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References
Schaible TF, Scheuer J (1984) Comparison of heart function in male and female rats. Basic Res Cardiol 79:404–412
Schwertz DW, Beck JM, Kowalski JM, Ross JD (2004) Sex differences in the response of rat heart ventricle to calcium. Biol Res Nurs 5(4):286–298
Capasso JM, Remily RM, Smith RH, Sonnenblick EH (1983) Sex differences in myocardial contractility in the rat. Bas Res Cardiol 78:156–171
Curl CL, Wendt IR, Kotsanas G (2001) Effects of gender on intracellular [Ca2+] in rat myocytes. Eur J Physiol 441:709–716
Ayaz M, Ozdemir S, Ugur M, Vassort G, Turan B (2004) Effects of selenium on altered mechanical and electrical cardiac activities of diabetic rat. Arch Biochem Biophys 426:83–90
Ozdemir S, Ugur M, Gurdal H, Turan B (2005) Treatment with AT(1) receptor blocker restores diabetes-induced alterations in intracellular Ca(2+) transients and contractile function of rat myocardium. Arch Biochem Biophys 435:166–174
Bedinghaus J, Leshan L, Diehr S (2001) Coronary artery disease prevention: what’s different for women? Am Fam Physician 63:1393–1400
Johnson BE, Johnson CA (2001) Cardiovascular disease and differences between the sexes. Am Fam Physician 63:1290–1292
Stone PH, Thompson B, Anderson HV, Kronenberg MW, Gibson RS, Rogers WJ, Diver DJ, Theroux P, Warnica JW, Nasmith JB, Kells C, Kleiman N, McCabe CH, Schactman M, Knatterud GL, Braunwald E (1996) Influence of race, sex, and age on management of unstable angina and non-Q-wave myocardial infarction: the TIMI III registry. JAMA 275:1104–1112
Luzier AB, Nawarskas JJ, Anonuevo J, Wilson MF, Kazierad DJ (1998) The effects of gender on adrenergic receptor responsiveness. J Clin Pharmacol 38(7):618–624
Rodrigues B, McNeill JH (1987) Comparison of cardiac function in male and female diabetic rats. Gen Pharmacol 18(4):421–423
Sellers DJ, Chess-Williams R (2001) The effect of streptozotocin-induced diabetes on cardiac beta-adrenoceptor subtypes in the rat. J Autonomic Pharmacol 21(1):15–21
Gando S, Hattori Y, Akaishi Y, Nishihira J, Kanno M (1997) Impaired contractile response to beta adrenoceptor stimulation in diabetic rat hearts: alterations in beta adrenoceptors-G protein-adenylate cyclase system and phospholamban phosphorylation. J Pharmacol Exp Ther 282:475–484
Austin C, Williams RC (1993) The in-vitro effects of insulin and the effects of acute fasting on cardiac β-Adrenoceptor responses in the short-term streptozotocin-diabetic rat. J Pharm Pharmacol 46:326–331
Atkins FL, Dowell RT, Love S (1985) β-Adrenergic receptors, adenylate cyclase activity and cardiac dysfunction in the diabetic rat. J Cardiovasc Pharmacol 7:66–70
Kaul CL, Grewal RS (1980) Increased urinary excretion of catecholamines and their metabolites in streptozotocin diabetic rats. Pharmacology 21:223–228
Neubauer B, Christensen NJ (1976) Norepinephrine, epinephrine and dopamine contents of the cardiovascular system in long-term diabetes. Diabetes 25:6–10
Sato N, Hashimoto H, Takiguchi Y, Nakashima M (1989) Altered responsiveness to sympathetic nerve stimulation and agonists of isolated left atria of diabetic rats: no evidence for involvement of hypothyroidism. J Pharmacol Exp Ther 248:367–371
Sayar K, Ugur M, Gurdal H, Onaran O, Hotomaroglu O, Turan B (2000) Dietary selenium and vitamin E intakes alter β-Adrenergic response of L-Type Ca-current and β-Adrenoceptor-Adenylate cyclase coupling in rat heart. J Nutr 130:733–740
Brodde OE, Michel MC (1999) Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 51(4):651–690
Heyliger C, Pierce G, Singal P, Beamish R, Dhalla NS (1982) Cardiac alpha and beta-adrenergic receptor alterations in diabetic cardiomyopathy. Basic Res Cardiol 77:610–618
Ramanadham S, Tenner TE (1987) Alterations in the myocardial β-AR system of streptozotocin-diabetic rats. Eur J Pharmacol 136:377–389
Yu Z, McNeill JH (1991) Altered inotropic responses in diabetic cardiomyopathy and hypertensive-diabetic cardiomyopathy. J Pharmacol Exp Ther 257:257–264
Sunderesan PR, Sharma VK, Gingold SL, Banerjee PS (1984) Decreased beta adrenergic receptors in rat heart in streptozotocin-induced diabetes: role of thyroid hormones. Endocrinology 114:1358–1363
Du XJ (2004) Gender modulates cardiac phenotype development in genetically modified mice. Cardiovasc Res 63:510–519
Dincer UD, Bidasee KR, Guner S, Tay A, Ozcelikay AT, Altan VM (2001) The effect of diabetes on expression of β1-, β2-, and β3-adrenoreceptors in rat hearts. Diabetes 50:455–461
Matsuda N, Hattori Y, Gando S, Akaishi Y, Kemnotsu O, Kanno M (1999) Diabetes-induced down-regulation of β1-AR mRNA expression in rat heart. Biochem Pharmacol 58:881–885
Minneman KP, Hedberg A, Molinoff PB (1979) Comparison of beta-adenergic receptor subtypes in mammalian tissues. J Pharmacol Exp Ther 211:502–508
Bryan LJ, Cole JJ, O’Donnell SR, Wantstall JC (1981) A study designed to explore the hypothesis that beta-1 ARs are “innervated” receptors and beta-2 ARs are “hormonal” receptors. J Pharmacol Exp Ther 216:395–400
Babiker FA, De Windt LJ, van Eickels M, Groke C, Meyer R, Doevendans PA (2002) Estrogenic hormone action in the heart: regulatory network and function. Cardiovasc Res 53:709–719
Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N, HERS Research Group (2002) Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). JAMA 288(1):49–57. Erratum in: JAMA 2002, 288(9):1064
Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M, Women’s Health Initiative Investigators (2003) Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 49(6):523–534
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This work has been supported by grants of Ankara University project 2006-080-9233 and projects of TUBITAK-SBAG-PIA-10 (105S149) and TUBITAK-SBAG-3056 (104S591).
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Bilginoglu, A., Amber Cicek, F., Ugur, M. et al. The role of gender differences in beta-adrenergic receptor responsiveness of diabetic rat heart. Mol Cell Biochem 305, 63–69 (2007). https://doi.org/10.1007/s11010-007-9528-0
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DOI: https://doi.org/10.1007/s11010-007-9528-0