Relationships between neuro-endocrine, electrocardiogram, and gastric mucosal damage parameters in naїve and stressed rats
DOI:
https://doi.org/10.12775/JEHS.2023.18.01.014Keywords
Adaptation hormones, HRV, water-immersion and restraint stress, damage to the gastric mucosa and myocardium, relationships, ratsAbstract
Introduction
The first scientific publication on general adaption syndrome, or as we know today biologic stress has been published in Nature in 1936 by the 29-year old Hans Selye.1 Szabo et al2 in the anniversary review "Stress" is 80 Years Old” conclude that despite the extensive and multidisciplinary research on stress during the last 80 years, a lot of basic and clinical research is needed to better understand the manifestations, central and peripheral molecular regulators of stress response, especially the modes of prevention/management of distress or its transformation into eustress and the treatment of stress-related diseases.
In the vast majority of publications on stress, the HPA-, HPG- and autonomous systems are the objects of research, while the place in the general adaptation syndrome of such important hormones as calcitonin and PTH has been studied only in a few publications. Another methodological shortcoming of most studies is that the subjects of analysis are limited to a single neuro-endocrine system.
Therefore, we set ourselves the goal: to analyze relationships between some adaptation hormones, HRV, calcitonin, and PTH as well as electrocardiogram and gastric mucosal damage in naїve and post stressed rats.
Material and methods
Ethics approval
All animals were kept in room having temperature 22±2ºC, and relative humidity of 44-55% under 12/12 hours light and dark cycle with standard laboratory diet and water given ad libitum. Studies have been conducted in accordance with the rules and requirements of the “General Principles for the Work on Animals” approved by the I National Congress on Bioethics (Kyїv, Ukraine, 2001) and agreed with the provisions of the “European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes” (Council of Europe No 123, Strasbourg 1985), and the Law of Ukraine “On the Protection of Animals from Cruelty” of 26.02.2006. The removal of animals from the experiment was carried out under light inhalation (ether) anesthesia by decapitation.
Participants
The experiment is at 38 rats Wistar line: 18 males (Weight Mean=227 g; SD=25 g) and 20 females (Mean=214 g; SD=27 g).
Study design and procedure
Due to the purposeful formation of groups, the potential predictors of post-stress reactions of the neuro-endocrine-immune complex and the metabolome3,4,5 were almost identical both in mean values and, to a lesser extent, in variance (SD). In particular, the hypoxic test (sec) was: 136±59 and 133±81; swimming test (min): 19±11 and 19±17; HRV Stress index4 (units) as (AMo/2*Mo*MxDMn)1/3: 0,14±0,08 and 0,14±0,05 in intact animals and those exposed to acute stress.
Results and discussion
Adhering to the algorithm of the Truskavetsian Scientific School of Balneology, we recalculated the current values of the parameters in Z-scores. This approach makes it possible to adequately compare deviations from the norm of parameters expressed in different units and with different variability.10,11,12 This is all the more important in view of sexual dimorphism in endocrine parameters. In addition to drastically higher levels of testosterone (41.8±1.7 vs 3.53±0.24 nM/L), males have higher levels of calcitonin (36±6 vs 21±4 ng/L), but lower levels of parathyroid hormone (154±12 vs 185±3 ng/L), adrenals mass (44±5 vs 65±5 mg), corticosterone (340±45 vs 466±57 nM/L), and aldosterone (587±8 vs 639±24 pM/L).
Conclusion
The condition of the gastric mucosa and myocardium as essential targets of stressors is determined by the damaging and protective effects of adaptive hormones and the autonomic nervous system.
References
Selye H: A syndrome produced by diverse nocuous agents. 1936. J Neuropsychiatry Clin Neurosci. 1998;10(2):230–231. 10.1176/jnp.10.2.230a
Szabo S, Yoshida M, Filakovszky J, Juhasz G. "Stress" is 80 Years Old: From Hans Selye Original Paper in 1936 to Recent Advances in GI Ulceration. Curr Pharm Des. 2017;23(27):4029-4041. doi: 10.2174/1381612823666170622110046.
Popovych IL, Ivassivka SV, Barylyak LG, Fil VM, Korolyshyn TA, Shologin AI, Datsko OR. Особливості стресіндукованих змін слизової шлунку, нейроендокринно-імунного комплексу і метаболізму у щурів з різною резистентністю до гіпоксії [in Ukrainian]. Medical Hydrology and Rehabilitation. 2010;8(2): 96-109.
Kozyavkina OV. The state of post-stress parameters of autonomic homeostasis and endocrine, metabolic and immune status and the relationship between them in rats with alternative types of pre-stress autonomic homeostasis induced by bioactive water Naftussya [in Ukrainian]. Medical Hydrology and Rehabilitation. 2009;7(2):40-56.
Melnyk OI, Chendey IV, Zukow W, Plyska OI, Popovych IL. The features of reactions to acute stress of neuro-endocrine-immune complex, metabolome, ECG and gastric mucosa in rats with various state of innate muscular endurance and resistance to hypoxia. JEHS. 2023;38(1):96-128.
Nakamura J, Takada S, Ohtsuka N, Heya T, Ueda S, Hamaura T, et al. An assessment of gastric ulcers in vivo: enhancement of urinary recovery after oral administration of phenolsulfonphthalein in rats. J Pharmacobiodynamics. 1984;7(7):485–491. doi.org/10.1248/bpb1978.7.485
Popovych IL. Factor and canonical analyzes of the parameters of the neuro-endocrine-immune complex, metabolism and erosive-ulcerative lesions of the gastric mucosa in rats under acute water-immersion stress [in Ukrainian]. Medical Hydrology and Rehabilitation. 2007;5(2):68-80.
Baevsky RM, Berseneva AP. Use KARDIVAR system for determination of the stress level and estimation of the body adaptability. Standards of measurements and physiological interpretation. Moscow-Prague;2008:41.
Harrington EC. The Desirability Function. Industrial Quality Control. 1965;21:494-498.
Polovynko IS, Zajats LM, Popovych AI, Popovych IL. Іntegral quantification of neuroendocrine and immune responses to chronic stress in male rats [in Ukrainian]. In: Pathophysiology and Pharmacy: ways of integration: Abstracts VII National Congress pathophysiologists Ukraine with international participation (5-7 October 2016). Kharkiv: NPhU;2016:182-182.
Popovych IL, Gozhenko AI, Korda MM, Klishch IM, Popovych DV, Zukow W (editors). Mineral Waters, Metabolism, Neuro-Endocrine-Immune Complex. Odesa: Feniks;2022:252. doi.org/10.5281/zenodo.6604298
Gozhenko АІ, Korda MM, Smagliy SS, Badiuk NS, Zukow W, Klishch IM, Korda IV, Bombushkar IS, Popovych IL. Uric Acid, Metabolism, Neuro-Endocrine-Immune Complex [in Ukrainian]. Odesa: Feniks;2023:266. doi.org/10.5281/zenodo.7575158
Zavodskaya IS, Moreva YeV, Novikova NA. Influence of Neurotropic Means on Neurogenic Damage of Heart [in Russian]. Moskva: Meditsina;1977:192.
Berger EN. Neurohumoral Mechanisms of Disturbed Tissue Trophism [in Russian]. Kyїv: Zdorovya;1980:104.
Zavodskaya IS & Moreva YeV. Pharmacological Analysis of Mechanism of Stress and its Effects [in Russian]. Moskva: Meditsina;1981:216.
Markova OO, Popovych IL, Tserkovnyuk AV, Barylyak LG. Adrenaline Myocardiodystrophy and Reactivity of the Organism [in Ukrainian]. Kyїv: Computerpress;1997:126.
Clementi G, Caruso A, Fiore CE, Leone MG, Prato A. Effect of parathyroid hormone, centrally or peripherally injected, on gastric activity in male rats. Eur J Pharmacol. 1989;166(3):549-552. doi: 10.1016/0014-2999(89)90374-9.
Castle C, Tietjens J. Perforated gastric ulcer as the initial manifestation of hyperparathyroidism. BMJ Case Rep. 2021;14(4):e240570. doi: 10.1136/bcr-2020-240570.
Clementi G, Prato A, Rapisarda E, Conforto G, Mangano O, Caruso A, Scapagnini U. Inhibition of restraint stress by systemic (Asu1,7) eel-calcitonin. J Endocrinol Invest. 1985;8(6):543-546. doi: 10.1007/BF03348558.
Ohno H, Noguchi M, Takayanagi N. Effect of elcatonin on experimental gastric and duodenal ulcers. Jpn J Pharmacol. 1985;37(1):67-75. doi: 10.1254/jjp.37.67.
Guidobono F, Netti C, Pagani F, Bettica P, Sibilia V, Pecile A, Zanelli J. Effect of unmodified eel calcitonin on gastric acid secretion and gastric ulcers in the rat. Farmaco. 1991;46(4):555-563.
Taché Y, Kolve E, Maeda-Hagiwara M, Kauffman GL Jr. Central nervous system action of calcitonin to alter experimental gastric ulcers in rats. Gastroenterology. 1988;94(1):145-150. doi: 10.1016/0016-5085(88)90622-1.
Vasilenko VKh and Kochina EN (editors). Neurohumoral Regulation of Digestion [in Russian]. Moskva: Meditsina;1983:368.
Evangelista S. Role of calcitonin gene-related Peptide in gastric mucosal defence and healing. Curr Pharm Des. 2009;15(30):3571-3576. doi: 10.2174/138161209789207024.
Luo XJ, Liu B, Dai Z, Yang ZC, Peng J. Stimulation of calcitonin gene-related peptide release through targeting capsaicin receptor: a potential strategy for gastric mucosal protection. Dig Dis Sci. 2013;58(2):320-325. doi: 10.1007/s10620-012-2362-6.
Evangelista S, Renzi D. A protective role for calcitonin gene-related peptide in water-immersion stress-induced gastric ulcers in rats. Pharmacol Res. 1997;35(4):347-350. doi: 10.1006/phrs.1997.0142.
Hotta H, Onda A, Suzuki H, Milliken P, Sridhar A. Modulation of Calcitonin, Parathyroid Hormone, and Thyroid Hormone Secretion by Electrical Stimulation of Sympathetic and Parasympathetic Nerves in Anesthetized Rats. Front Neurosci. 2017;11:375. doi: 10.3389/fnins.2017.00375.
Fil V, Zukow W, Kovalchuk G, Voloshyn O, Kopko I, Lupak O, Stets V. The role of innate muscular endurance and resistance to hypoxia in reactions to acute stress of neuroendocrine, metabolic and ECGs parameters and gastric mucosa in rats. JPES. 2021;21(Sup. 5):3030-3039. doi:10.7752/jpes.2021.s5403.
Zukow W, Fil VM, Kovalchuk HY, Voloshyn OR, Kopko IY, Lupak OM, Ivasivka AS, Musiyenko OV, Bilas VR, Popovych IL. The role of innate muscular endurance and resistance to hypoxia in reactions to acute stress of immunity in rats. JPES. 2022;22(7):1608-1617. doi: 10.7752/jpes.2022.07202.
Meerson FZ. Pathogenesis and prevention of stress and ischemic heart damage [in Russian]. Moskva: Meditsina;1984:272.
Esplugues J, Lloris JM, Martí-Bonmatí E, Morcillo EJ. Effects of beta-adrenoceptor drug stimulation on various models of gastric ulcer in rats. Br J Pharmacol. 1982;76(4):587-94. doi: 10.1111/j.1476-5381.1982.tb09258.x.
Fan F, Li L, Liu W, Yang M, Ma X, Sun H. Astrocytes and neurons in locus coeruleus mediate restraint water immersion stress-induced gastric mucosal damage through the ERK1/2 signaling pathway. Neurosci Lett. 2018;675:95-102. doi: 10.1016/j.neulet.2018.03.054.
Fan F, Yang M, Geng X, Ma X, Sun H. Effects of Restraint Water-Immersion Stress-Induced Gastric Mucosal Damage on Astrocytes and Neurons in the Nucleus Raphe Magnus of Rats via the ERK1/2 Signaling Pathway. Neurochem Res. 2019;44(8):1841-1850. doi: 10.1007/s11064-019-02818-0.
Gao W, Wang Z, Wang H, Li H, Huang C, Shen Y, Ma X, Sun H. Neurons and Astrocytes in Ventrolateral Periaqueductal Gray Contribute to Restraint Water Immersion Stress-Induced Gastric Mucosal Damage via the ERK1/2 Signaling Pathway. Int J Neuropsychopharmacol. 2021;24(8):666-676. doi: 10.1093/ijnp/pyab028.
Romano TA, Felten SY, Felten DL, Olschowka JA. Neuropeptide-Y innervation of the rat spleen: another potential immunomodulatory neuropeptide. Brain Behav Immun. 1991;5(1):116-31. doi: 10.1016/0889-1591(91)90011-x.
Kaestner CL, Smith EH, Peirce SG, Hoover DB. Immunohistochemical analysis of the mouse celiac ganglion: an integrative relay station of the peripheral nervous system. J Comp Neurol. 2019;527:2742–2760, doi: 10.1002/cne.24705.
Forbes S, Herzog H, Cox H. A role for neuropeptide Y in the gender-specific gastrointestinal, corticosterone and feeding responses to stress. Br J Pharmacol.2012;166:2307-2316. doi:10.1111/j.1476-5381.2012.01939.x
Holzer P, Reichmann F, Farzi A. Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides. 2012;46(6):261-274. doi: 10.1016/j.npep.2012.08.005.
Kristt DA, Freimark SJ. Histopathology and pathogenesis of behaviorally induced gastric lesions in rats. Am J Pathol. 1973;73(2):411-424. PMID: 4543311; PMCID: PMC1904064.
Desiderato O, Testa M. Shock-stress, gastric secretion and habituation in the chronic gastric fistula rat. Physiol Behav. 1976;16(1):67-73. doi: 10.1016/0031-9384(76)90194-3.
Marrone GC, Silen W. Pathogenesis, diagnosis and treatment of acute gastric mucosal lesions. Clin Gastroenterol. 1984;13(2):635-650. PMID: 6430609.
Meerson FZ. Adaptation, Stress and Prophylaxis [in Russian]. Moskva: Nauka;1981:279.
Peskar BM. Neural aspects of prostaglandin involvement in gastric mucosal defense. J Physiol Pharmacol. 2001;52(4 Pt 1):555-568. PMID: 11787758.
Taché Y. Brainstem neuropeptides and vagal protection of the gastric mucosal against injury: role of prostaglandins, nitric oxide and calcitonin-gene related peptide in capsaicin afferents. Curr Med Chem. 2012;19(1):35-42. doi: 10.2174/092986712803414097.
Zhao DQ, Xue H, Sun HJ. Nervous mechanisms of restraint water-immersion stress-induced gastric mucosal lesion. World J Gastroenterology. 2020;26(20):2533–2549. doi.org/10.3748/wjg.v26.i20.2533
Lee TJ, Liu J, Evans MS. Cholinergic-nitrergic transmitter mechanisms in the cerebral circulation. Microsc Res Tech. 2001;53(2):119-128. doi: 10.1002/jemt.1076.
Lee TJ, Chang HH, Lee HC, Chen PY, Lee YC, Kuo JS, Chen MF. Axo-axonal interaction in autonomic regulation of the cerebral circulation. Acta Physiol (Oxf). 2011;203(1):25-35. doi: 10.1111/j.1748-1716.2010.02231.x.
Kim MH, Lee SH, Hwang DY, Park YB, Ham SH, Yang WM. Protective effects of Banhasasim-tang, a herbal medicine, against cold restraint stress-induced gastric ulcers. Pak J Pharm Sci. 2022;35(1):9-13. PMID: 35221266.
Filaretova LP, Filaretov AA, Makara GB. Corticosterone increase inhibits stress-induced gastric erosions in rats. Am J Physiology. 1998;274(6):G1024–G1030. doi.org/10.1152/ajpgi.1998.274.6.G1024
Filaretova LP. The hypothalamic-pituitary-adrenocortical system: Hormonal brain-gut interaction and gastroprotection. Auton Neurosci. 2006;125(1-2):86-93. doi: 10.1016/j.autneu.2006.01.005.
Filaretova LP, Bagaeva TR, Amagase K, Takeuchi K. Contribution of glucocorticoids to protective influence of preconditioning mild stress against stress-induced gastric erosions. ANYAS. 2008;1148:209–212. doi.org/10.1196/annals.1410.005
Filaretova L, Makara G. The surprising dual action of glucocorticoids. Ideggyogy Sz. 2014;67(3-4):121-123. PMID: 26118254.
Filaretova L, Podvigina T, Bagaeva T, Morozova O. From gastroprotective to ulcerogenic effects of glucocorticoids: role of long-term glucocorticoid action. Curr Pharm Des. 2014;20(7):1045-1050. doi: 10.2174/13816128113199990419.
Filaretova L, Komkova O, Sudalina M, Yarushkina N. Non-Invasive Remote Ischemic Preconditioning May Protect the Gastric Mucosa Against Ischemia-Reperfusion-Induced Injury Through Involvement of Glucocorticoids. Front Pharmacol. 2021;12:682643. doi: 10.3389/fphar.2021.682643.
Selye H. Stress and inflammation. Am J Proctol. 1953;4(3):229-230. PMID: 13080458.
Dajani EZ, Bianchi RG, Casler JJ, Weet JF. Gastric antiulcer and antisecretory effects of carbenoxolone, aldosterone and desoxycorticosterone in rats. Arch Int Pharmacodyn Ther. 1979;242(1):128-138. PMID: 543742.
Clavenna G, Musci R, Dorigotti L. Antiulcer and mineralocorticoid activities of carbenoxolone and desoxycorticosterone in rats. J Pharm Pharmacol. 1982;34(8):517-519. doi: 10.1111/j.2042-7158.1982.tb04777.x.
Sabbadin C, Bordin L, Donà G, Manso J, Avruscio G, Armanini D. Licorice: From Pseudohyperaldosteronism to Therapeutic Uses. Front Endocrinol (Lausanne). 2019;10:484. doi: 10.3389/fendo.2019.00484.
Koo MW, Ogle CW, Cho CH. Effects of verapamil, carbenoxolone and N-acetylcysteine on gastric wall mucus and ulceration in stressed rats. Pharmacology. 1986;32(6):326-34. doi: 10.1159/000138188.
Stewart PM, Wallace AM, Atherden SM, Shearing CH, Edwards CR. Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11 beta-hydroxysteroid dehydrogenase activity in man. Clin Sci (Lond). 1990;78(1):49-54. doi: 10.1042/cs0780049.
Kawashima D, Asai M, Katagiri K, Takeuchi R, Ohtsuka K. Reinvestigation of the effect of carbenoxolone on the induction of heat shock proteins. Cell Stress Chaperones. 2009;14(5):535-543. doi: 10.1007/s12192-009-0106-0.
Suleyman H, Halici Z, Cadirci E, Hacimuftuoglu A, Keles S, & Gocer F. Indirect role of α2-adrenoreceptors in anti-ulcer effect mechanism of nimesulide in rats. Naunyn-Schmiedeberg's archives of pharmacology. 2007;375:189-198.
Pawlik MW, Kwiecien S, Ptak-Belowska A, Pajdo R, Olszanecki R, Suski M, Madej J, Targosz A, Konturek SJ, Korbut R, Brzozowski T. The renin-angiotensin system and its vasoactive metabolite angiotensin-(1-7) in the mechanism of the healing of preexisting gastric ulcers. The involvement of Mas receptors, nitric oxide, prostaglandins and proinflammatory cytokines. J Physiol Pharmacol. 2016;67(1):75-91. PMID: 27010897.
Selye H. Forty years of stress research: principal remaining problems and misconceptions. Can Med Assoc J. 1976;115(1):53-56. PMID: 1277062; PMCID: PMC1878603.
Rao SS, Saifi AQ. Relevance of male hormonal status with antiulcer effect of cimetidine in pylorus ligated rats. Indian J Physiol Pharmacol. 1987;31(4):263-266. PMID: 3450632.
László F, Varga C, Montoneri C, Drago F. Damaging actions of testosterone on cysteamine-induced gastroduodenal ulceration and vascular leakage in the rat. Eur J Pharmacol. 1997;337(2-3):275-278. doi: 10.1016/s0014-2999(97)01265-x.
Loginov AS, Arbuzova VG, Amirov NSh, Astaf'eva OV, Zvenigorodskaia LA. The hormonal characteristics of the pathogenesis of gastric peptic ulcer and duodenal peptic ulcer [in Russian]. Ter Arkh. 1995;67(10):19-23. PMID: 8779096.
Aguwa CN. Effects of exogenous administration of female sex hormones on gastric secretion and ulcer formation in the rat. Eur J Pharmacol. 1984 Sep 3;104(1-2):79-84. doi: 10.1016/0014-2999(84)90371-6.
Kurt D, Saruhan BG, Kanay Z, Yokus B, Kanay BE, Unver O, Hatipoglu S. Effect of ovariectomy and female sex hormones administration upon gastric ulceration induced by cold and immobility restraint stress. Saudi Med J. 2007;28(7):1021-1027. PMID: 17603703.
Ribeiro Júnior RF, Ronconi KS, Jesus ICG, Almeida PWM, Forechi L, Vassallo DV, Guatimosim S, Stefanon I, Fernandes AA. Testosterone deficiency prevents left ventricular contractility dysfunction after myocardial infarction. Mol Cell Endocrinol. 2018;460:14-23. doi: 10.1016/j.mce.2017.06.011.
Elsenbruch S, Enck P. The stress concept in gastroenterology: from Selye to today. F1000Res. 2017;6:2149. doi: 10.12688/f1000research.12435.1.
Kozyavkina NV, Popovych IL, Popovych DV, Zukow W, Bombushkar IS. Sexual dimorphism in some psycho-neuro-endocrine parameters at human. JEHS. 2021;11(5):370-391.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Oksana Fihura, Oksana Melnyk, Sofiya Ruzhylo, Nataliya Zakalyak, Halyna Kondratska, Walery Zukow, Igor Popovych
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 189
Number of citations: 0