We studied the changes in the heart and the activity biorhythms in mice exposed to acute (one 120-minute session) and repeated (7 two-hour sessions) restraint stress in 129J1/CF1 mice (WT) and in mice without M2 muscarinic receptors (M2KO) during the prestress period, during stress (STR) and for five days after the last stress session (POST). There were changes in the mesor (a midline based on the distribution of values across the circadian cycles; decreased in M2KO by 6% over all POST), day means (inactive period of diurnal rhythm in mice; higher in M2KO and further increased on STR and on the second to the fifth POST) and night means (active period; lower by 13% in M2KO and remained decreased in STR and in POST). The total area under the curve was decreased both in the WT and M2KO on STR and in all POST. Repeated stress caused changes over all days of STR, but the initial values were restored in POST. The average night values were decreased, and the day means were increased by 16% over all STR in M2KO. The day means decreased by 14% in the 4 POST in WT. The activity biorhythm parameters were almost unchanged. We show here that stress can specifically affect heart biorhythm in M2KO mice, especially when the stress is acute. This implies the role of M2 muscarinic receptor in stress response.

Institute of Physiology 1st Faculty of Medicine Charles University Prague Czech Republic

See more in PubMed

Schroeder AM, Colwell CS. How to fix a broken clock. Trends Pharmacol. Sci. 2013;34:605–619. doi: 10.1016/j.tips.2013.09.002. PubMed DOI PMC

Witte K, Parsaparsi R, Vobig M, Lemmer B. Mechanisms of the circadian regulation of beta-adrenoceptor density and adenylyl cyclase activity in cardiac tissue from normotensive and spontaneously hypertensive rats. J. Mol. Cell. Cardiol. 1995;27:1195–1202. doi: 10.1016/0022-2828(95)90055-1. PubMed DOI

Foulkes NS, Duval G, Sassonecorsi P. Adaptive inducibility of CREM as transcriptional memory of circadian rhythms. Nature. 1996;381:83–85. doi: 10.1038/381083a0. PubMed DOI

Kim SM, et al. Persistence of circadian variation in arterial blood pressure in β1/β2-adrenergic receptor-deficient mice. Am J Physiol Reg Integr Comp Physiol. 2008;294:R1427–R1434. doi: 10.1152/ajpregu.00074.2008. PubMed DOI PMC

White K, Engelhardt S, Janssen BJA, Lohse M, Lemmer B. Circadian and Short-Term Regulation of Blood Pressure and Heart Rate in Transgenic Mice with Cardiac Overexpression of The β1-Adrenoceptor. Chronobiol. Int. 2004;21:205–216. doi: 10.1081/cbi-120037801. PubMed DOI

Shaw E, Tofler GH. Circadian rhythm and cardiovascular disease. Curr Atheroscler Rep. 2009;11:289–295. doi: 10.1007/s11883-009-0044-4. PubMed DOI

Manfredini R, et al. Sex and Circadian Periodicity of Cardiovascular Diseases: Are Women Sufficiently Represented in ChronobiologicalStudies? Heart Fail. Clin. 2017;13:719–738. doi: 10.1016/j.hfc.2017.05.008. PubMed DOI

Rauchenzauner M, et al. Arrhythmias and increased neuro-endocrine stress response during physicians’ night shifts: a randomized cross-over trial. Eur. Heart J. 2009;30:2606–2613. doi: 10.1093/eurheartj/ehp268. PubMed DOI

Cooke HM, Lynch A. Biorhythms and chronotherapy in cardiovascular disease. Am. J. Hosp. Pharm. 1994;51:2569–2580. PubMed

Lemaire V, Mormede P. Telemetered recording of blood pressure and heart rate in different strains of rats during chronic social stress. Physiol. Behav. 1995;58:1181–1188. doi: 10.1016/0031-9384(95)02064-0. PubMed DOI

Kuwahara M, et al. Effects of pair housing on diurnal rhythms of heart rate and heart rate variability in miniature swine. Exp. Anim. 2004;53:303–309. doi: 10.1538/expanim.53.303. PubMed DOI

Spani D, Arras M, Konig B, Rulicke T. Higher heart rate of laboratory mice housed individually vs in pairs. Lab. Anim. 2003;37:54–62. doi: 10.1258/002367703762226692. PubMed DOI

Harper DG, Tornatzky W, Miczek KA. Stress induced disorganization of circadian and ultradian rhythms: comparisons of effects of surgery and social stress. Physiol. Behav. 1996;59:409–419. doi: 10.1016/0031-9384(95)02012-8. PubMed DOI

Takeuchi H, Enzo A, Minamitani H. Circadian rhythm changes in heart rate variability during chronic sound stress. Med. Biol. Eng. Comput. 2001;39:113–117. doi: 10.1007/BF02345274. PubMed DOI

Meerlo P, Sgoifo A, De Boer SF, Koolhaas JM. Long-lasting consequences of a social conflict in rats: Behavior during the interaction predicts subsequent changes in daily rhythms of heart rate, temperature, and activity. Behav. Neurosci. 1999;113:1283–1290. doi: 10.1037/0735-7044.113.6.1283. PubMed DOI

Sikora M, Konopelski P, Pham K, Wyczalkowska-Tomasik A, Ufnal M. Repeated restraint stress produces acute and chronic changes in hemodynamic parameters in rats. Stress. 2016;19:621–629. doi: 10.1080/10253890.2016.1244667. PubMed DOI

Thompson RS, et al. Effects of stressor controllability on diurnal physiological rhythms. Physiol. Behav. 2013;112–113:32–39. doi: 10.1016/j.physbeh.2013.02.009. PubMed DOI PMC

Carnevali L, et al. Metyrapone and fluoxetine suppress enduring behavioral but not cardiac effects of subchronic stress in rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2011;301:R1123–R1131. doi: 10.1152/ajpregu.00273.2011. PubMed DOI

Sgoifo A, et al. Intermittent Exposure to Social Defeat and Open-field Test in Rats: Acute and Long-term Effects on ECG, Body Temperature and Physical Activity. Stress. 2002;5:23–35. doi: 10.1080/102538902900012387. PubMed DOI

Meerlo P, Sgoifo A, Turek FW. The Effects of Social Defeat and Other Stressors on the Expression of Circadian Rhythms. Stress. 2002;5:15–22. doi: 10.1080/102538902900012323. PubMed DOI

Weil ZM, Norman GJ, DeVries AC, Berntson GG, Nelson RJ. Photoperiod alters autonomic regulation of the heart. Proc. Natl. Acad. Sci. USA. 2009;106:4525–4530. doi: 10.1073/pnas.0810973106. PubMed DOI PMC

Kitazawa T, et al. M3 Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice. J. Pharmacol. Exp. Ther. 2009;330:487–493. doi: 10.1124/jpet.109.153304. PubMed DOI PMC

Benes J, Varejkova E, Farar V, Novakova M, Myslivecek J. Decrease in heart adrenoceptor gene expression and receptor number as compensatory tool for preserved heart function and biological rhythm in M2 KO animals. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2012;385:1161–1173. doi: 10.1007/s00210-012-0800-9. PubMed DOI

Benes J, et al. Beta3 Adrenoceptors Substitute the Role of M2 Muscarinic Receptor in Coping with Cold Stress in the Heart: Evidence from M2KO Mice. Cell. Mol. Neurobiol. 2012;32:589–869. doi: 10.1007/s10571-011-9781-3. PubMed DOI PMC

Novakova M, Kvetnansky R, Myslivecek J. Sexual dimorphism in stress-induced changes in adrenergic and muscarinic receptor densities in the lung of wild type and CRH-knockout mice. Stress. 2010;13:22–35. doi: 10.3109/10253890902849840. PubMed DOI

Myslivecek J, Tillinger A, Novakova M, Kvetňanský R. Regulation of Adrenoceptor and Muscarinic Receptor Gene Expression after Single and Repeated Stress. Ann. N. Y. Acad. Sci. 2008;1148:367–376. doi: 10.1196/annals.1410.028. PubMed DOI

Tomankova H, et al. The M 2 muscarinic receptors are essential for signaling in the heart left ventricle during restraint stress in mice. Stress. 2015;18:208–220. doi: 10.3109/10253890.2015.1007345. PubMed DOI

Sabban EL, Schilt N, Serova LI, Masineni SN, Stier CT., Jr. Kinetics and persistence of cardiovascular and locomotor effects of immobilization stress and influence of ACTH treatment. Neuroendocrinology. 2009;89:98–108. doi: 10.1159/000150099. PubMed DOI PMC

Gomeza J, et al. Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. Sci. USA. 1999;96:1692–1697. doi: 10.1073/pnas.96.4.1692. PubMed DOI PMC

Arraj M, Lemmer B. Circadian Rhythms in Heart Rate, Motility, and Body Temperature of Wild type C57 and eNOS Knock out Mice Under Light dark, Free run, and After Time Zone Transition. Chronobiol. Int. 2006;23:795–812. doi: 10.1080/07420520600827111. PubMed DOI

Tornatzky W, Miczek KA. Long-term impairment of autonomic circadian rhythms after brief intermittent social stress. Physiol. Behav. 1993;53:983–993. doi: 10.1016/0031-9384(93)90278-N. PubMed DOI

Grundt A, Grundt C, Gorbey S, Thomas MA, Lemmer B. Strain-dependent differences of restraint stress-induced hypertension in WKY and SHR. Physiol. Behav. 2009;97:341–346. doi: 10.1016/j.physbeh.2009.02.029. PubMed DOI

Huang, C.-J., Webb, H. E., Zourdos, M. C. & Acevedo, E. O. Cardiovascular Reactivity, Stress, and Physical Activity. Front. Physiol. 4, 10.3389/fphys.2013.00314 (2013). PubMed PMC

Valuskova P, et al. Brain region-specific effects of immobilization stress on cholinesterases in mice. Stress. 2017;20:36–43. doi: 10.1080/10253890.2016.1263836. PubMed DOI

Kvetnansky R, et al. Sympathoadrenal system in stress. Interaction with the hypothalamic-pituitary-adrenocortical system. Ann. N. Y. Acad. Sci. 1995;771:131–158. PubMed

Kvetnansky, R., Lu, X. & Ziegler, M. G. In Adv. Pharmacol. Vol. 68 (ed. Lee, E. E.) 359–397 (Academic Press, 2013). PubMed

Jeong KH, et al. Impaired basal and restraint-induced epinephrine secretion in corticotropin-releasing hormone-deficient mice. Endocrinology. 2000;141:1142–1150. doi: 10.1210/endo.141.3.7370. PubMed DOI

Jeong KH, Jacobson L, Widmaier EP, Majzoub JA. Normal suppression of the reproductive axis following stress in corticotropin-releasing hormone-deficient mice. Endocrinology. 1999;140:1702–1708. doi: 10.1210/endo.140.4.6669. PubMed DOI

Looser RR, et al. Cortisol is significantly correlated with cardiovascular responses during high levels of stress in critical care personnel. Psychosom. Med. 2010;72:281–289. doi: 10.1097/PSY.0b013e3181d35065. PubMed DOI

LaCroix C, Freeling J, Giles A, Wess J, Li Y-F. Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress. Am. J. Physiol. Heart Circ. Physiol. 2008;294:H810–820. doi: 10.1152/ajpheart.00724.2007. PubMed DOI