Effect of the cholinergic system of the lateral periaqueductal gray (lPAG) on blood pressure and heart rate in normal and hydralazine hypotensive rats

Document Type : Original Article

Authors

1 Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Material Science and Metallurgy Engineering, Islamic Azad University-Karaj Branch

4 Division of Neurocognitive Sciences, Psychiatry, and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Due to the presence of the cholinergic system in the lateral periaqueductal gray (lPAG) column, the cardiovascular effects of Acetylcholine (ACH) and its receptors in normotensive and hydralazine (HYD) hypotensive rats in this area were evaluated.
Materials and Methods: After anesthesia, the femoral artery was cannulated and systolic blood pressure (SBP), mean arterial pressure (MAP), heart rate (HR), and also electrocardiogram for evaluation of low frequency (LF) and high frequency (HF) bands, important components of heart rate variability (HRV), were recorded. ACH, atropine (Atr, a muscarinic antagonist), and hexamethonium (Hex, an antagonist nicotinic) alone and together microinjected into lPAG, changes (Δ) of cardiovascular responses and normalized (n) LF, HF, and LF/HF ratio were analyzed.
Results: In normotensive rats, ACH decreased SBP and MAP, and enhanced HR while Atr and Hex did had no effects. In co-injection of Atr and Hex with ACH, only ACH+Atr significantly attenuated parameters. In HYD hypotension, ACH had no affect but Atr and Hex significantly improved the hypotensive effect. Co-injection of Atr and Hex with ACH decreased the hypotensive effect but the effect of Atr+ACH was higher. In normotensive rats, ACH decreased nLF, nHF, and nLF/nHF ratio. These parameters in the Atr +ACH group were significantly higher than in ACH group. In HYD hypotension nLF and nLF/nHF ratio increased which was attenuated by ACH. Also, Atr+ACH decreased nLF and nLF/nHF ratio and increased nHF.
Conclusion: The cholinergic system of lPAG mainly via muscarinic receptors has an inhibitory effect on the cardiovascular system. Based on HRV assessment, peripheral cardiovascular effects are mostly mediated by the parasympathetic system.

Keywords

Main Subjects

References

1. Lefler Y, Campagner D, Branco T. The role of the periaqueductal gray in escape behavior. Curr Opin Neurobiol 2020;60:115-21.
2. Behbehani MM. Functional characteristics of the midbrain periaqueductal gray. Prog Neurobiol 1995;46:575-605.
3. Dampney RA. Central neural control of the cardiovascular system: Current perspectives. Adv Physiol Educ 2016;40:283-296.
4. Bandler R, Shipley MT. Columnar organization in the midbrain periaqueductal gray: Modules for emotional expression? Trends Neurosci 1994;17:379-389.
5. Gerrits P, Krukerink M, Veening J. Columnar organization of estrogen receptor-α immunoreactive neurons in the periaqueductal gray projecting to the nucleus para-retroambiguus in the caudal brainstem of the female golden hamster. Neuroscience 2009;161:459-474.
6. da Silva Jr LG, Menezes R, Villela DC, Fontes M. Excitatory amino acid receptors in the periaqueductal gray mediate the cardiovascular response evoked by activation of dorsomedial hypothalamic neurons. Neuroscience 2006;139:1129-1139.
7. Di Pinto G, Di Bari M, Martin‐Alvarez R, Sperduti S, Serrano‐Acedo S, Gatta V, et al. Comparative study of the expression of cholinergic system components in the CNS of experimental autoimmune encephalomyelitis mice: Acute vs remitting phase. Eur J Neurosci 2018;48:2165-2181.
8. Deng J, Jiang H. Role of nicotinic acetylcholine receptors in cardiovascular physiology and pathophysiology: Current trends and perspectives. Curr Vasc Pharmacol 2021;19:370-378.
9. Kubo T, Taguchi K, Sawai N, Ozaki S, Hagiwara Y. Cholinergic mechanisms responsible for blood pressure regulation on sympathoexcitatory neurons in the rostral ventrolateral medulla of the rat. Brain Res Bull 1997;42:199-204.
10. Shafei MN, Niazmand S, Hosseini M, Daloee MH. Pharmacological study of cholinergic system on cardiovascular regulation in the cuneiform nucleus of rat. Neurosci Lett 2013;549:12-7.
11. Mohebbati R, Abbassian H, Shafei MN, Gorji A, Negah SS. The alteration of neuronal activities of the cuneiform nucleus in non-hypovolemic and hypovolemic hypotensive conditions. Arq Neuropsiquiatr 2021;79:871-878.
12. Curtis KS, Cunningham JT, Heesch CM. Fos expression in brain stem nuclei of pregnant rats after hydralazine-induced hypotension. Am J Physiol Regul Integr Comp Physiol 1999;277:R532-R540.
13. Rodrigues SF, de Oliveira MA, dos Santos RA, Soares AG, de Cássia Tostes R, Carvalho MH, et al. Hydralazine reduces leukocyte migration through different mechanisms in spontaneously hypertensive and normotensive rats. Eur J Pharmacol 2008;589:206-214.
14. Yalım Z, Demir ME, Yalım SA, Alp Ç. Investigation of heart rate variability and heart rate turbulence in chronic hypotensive hemodialysis patients. Int Urol Nephrol 2020;52:775-782.
15. Wu L-L, Bo J-H, Zheng F, Zhang F, Chen Q, Li Y-H, et al. Salusin-β in intermediate dorsal motor nucleus of the vagus regulates sympathetic-parasympathetic balance and blood pressure. Biomedicines 2021;9:1118-1131.
16. Ye T, Zhang C, Wu G, Wan W, Liang J, Liu X, et al. Pinocembrin attenuates autonomic dysfunction and atrial fibrillation susceptibility via inhibition of the NF-κB/TNF-α pathway in a rat model of myocardial infarction. Int Immunopharmacol 2019;77:105926.
17. Deolindo Mv, Pelosi G, Correa FMdA. Cardiovascular effects of acetylcholine microinjected into the lateral periaqueductal gray area of rats. FASEB J 2009;23:1019.
18. Monassi CR, Hoffmann A, Menescal-de-Oliveira L. Involvement of the cholinergic system and periaqueductal gray matter in the modulation of tonic immobility in the guinea pig. Physiol Behav 1997;62:53-59.
19. Deolindo MV, Pelosi GG, Busnardo C, Resstel LBM, Corrêa FMA. Cardiovascular effects of acetylcholine microinjection into the ventrolateral and dorsal periaqueductal gray of rats. Brain Res 2011;1371:74-81.
20. George Zaki Ghali M. Retracted: Midbrain control of breathing and blood pressure: The role of periaqueductal gray matter and mesencephalic collicular neuronal microcircuit oscillators. Eur J Neurosci 2020;52:3879-3902.
21. Alikhani V, Nikyar T, Mohebbati R, Shafei MN, Ghorbani A. Cardiovascular responses induced by the activation of muscarinic receptors of the pedunculopontine tegmental nucleus in anesthetized rats. Clin Exp Hypertens 2022;44:297-305.
22. Yuan Y, Naito H, Kitamori K, Hashimoto S, Asano T, Nakajima T. The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension. PloS One 2020;15:e0243846-e0243864.
23. Hosseiniravesh MR, Hojati V, Mohebbati R, Khajavirad A, Shajiee H, Shafei MN. Effect of MK-801, an antagonist of NMDA receptor in the pedunculopontine tegmental nucleus, on cardiovascular parameters in normotensive and hydralazine hypotensive rats. Iran J Basic Med Sci 2022;25:569-576.
24. Nikyar T, Hosseini M, Niazmand S, Shafei MN. Evaluation of nicotinic receptor of pedunculopontine tegmental nucleus in central cardiovascular regulation in anesthetized rat. Iran J Basic Med Sci 2018;21:376-381.
25. Pasandi H, Abbaspoor S, Shafei MN, Hosseini M, Khajavirad A. GABA A receptor in the Pedunculopontine tegmental (PPT) nucleus: Effects on cardiovascular system. Pharmacol Rep 2018;70:1001-1009.
26. Nasimi A, Shafei M, Alaei H. Glutamate injection into the cuneiform nucleus in rat, produces correlated single unit activities in the Kolliker-Fuse nucleus and cardiovascular responses. Neuroscience 2012;223:439-446.
27. Alikhani V, Mohebbati R, Hosseini M, Khajavirad A, Shafei MN. Role of the glutamatergic system of ventrolateral periaqueductal gray (vlPAG) in the cardiovascular responses in normal and hemorrhagic conditions in rats. Iran J Basic Med Sci 2021; 24:586-594.
28. Mohebbati R, Hosseini M, Khazaei M, Rad AK, Shafei MN. Involvement of the 5-HT1A receptor of the cuneiform nucleus in the regulation of cardiovascular responses during normal and hemorrhagic conditions. Iran J Basic Med Sci 2020;23:858-864.
29. Park J, Zheng L, Marquis A, Walls M, Duerstock B, Pond A, et al. Neuroprotective role of hydralazine in rat spinal cord injury‐attenuation of acrolein‐mediated damage. J Neurochem 2014;129:339-349.
30. Dai C, Wang Z, Wei L, Chen G, Chen B, Zuo F, et al. Combining early post-resuscitation EEG and HRV features improves the prognostic performance in cardiac arrest model of rats. Am J Emerg Med 2018;36:2242-2248.
31. Paxinos G, Watson C. The rat brain in stereotaxic coordinates: compact sixth edition. New York: Academic Press; 2009; 143-149.
32. Dampney RA, Furlong TM, Horiuchi J, Iigaya K. Role of dorsolateral periaqueductal grey in the coordinated regulation of cardiovascular and respiratory function. Auton Neurosci 2013;175:17-25.
33. Depaulis A, Keay KA, Bandler R. Longitudinal neuronal organization of defensive reactions in the midbrain periaqueductal gray region of the rat. Exp Brain Res 1992;90:307-318.
34. Subramanian HH, Balnave RJ, Holstege G. The midbrain periaqueductal gray control of respiration. J Neurosci 2008;28: 12274-12283.
35. Renno WM, Mullett MA, Beitz AJ. Systemic morphine reduces GABA release in the lateral but not the medial portion of the midbrain periaqueductal gray of the rat. Brain Res 1992;594:221-232.
36. Islas ÁA, Scior T, Torres-Ramirez O, Salinas-Stefanon EM, Lopez-Lopez G, Flores-Hernandez J. Computational molecular characterization of the interaction of acetylcholine and the NMDA receptor to explain the direct glycine-competitive potentiation of NMDA-mediated neuronal currents. ACS Chem Neurosci 2022;13:229-244.
37. Bandler R, Keay KA, Floyd N, Price J. Central circuits mediating patterned autonomic activity during active vs passive emotional coping. Brain Res Bull 2000;53:95-104.
38. Hudson PM, Lumb BM. Neurones in the midbrain periaqueductal grey send collateral projections to nucleus raphe magnus and the rostral ventrolateral medulla in the rat. Brain Res 1996;733:138-141.
39. Farkas E, Jansen AS, Loewy AD. Periaqueductal gray matter projection to vagal preganglionic neurons and the nucleus tractus solitarius. Brain Res 1997;764:257-261.
40. Soltis RP, DiMicco JA. GABAA and excitatory amino acid receptors in dorsomedial hypothalamus and heart rate in rats. Am J Physiol 1991;260:R13-R20.
41. Soltis RP, DiMicco JA. Interaction of hypothalamic GABAA and excitatory amino acid receptors controlling heart rate in rats. Am J Physiol Regul Integr Comp Physiol 1991;261:R427-R433.
42. Monassi CR, Leite-Panissi CRA, Menescal-de-Oliveira L. Ventrolateral periaqueductal gray matter and the control of tonic immobility. Brain Res Bull 1999;50:201-208.
43. Moraes G, Mendonça M, Mourão A, Graziani D, Pinto M, Ferreira P, et al. Ventromedial medullary pathway mediating cardiac responses evoked from periaqueductal gray. Auton Neurosci 2020;228:102716-102724.
44. Zhang C, Sun T, Zhou P, Zhu Q, Zhang L. Role of muscarinic acetylcholine receptor-2 in the cerebellar cortex in cardiovascular modulation in anaesthetized rats. Neurochem Res 2016;41:804-812.
45. Knowles HJ, Tian Y-M, Mole DR, Harris AL. Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor-1 α, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases. Circul Res 2004;95:162-169.
46. Liu X, Qu C, Yang H, Shi S, Zhang C, Zhang Y, et al. Chronic stimulation of the sigma-1 receptor ameliorates autonomic nerve dysfunction and atrial fibrillation susceptibility in a rat model of depression. Am J Physiol Heart Circ Physiol 2018;315:H1521-H1531.
47. Souza HC, Ballejo G, Salgado MCO, Dias Da Silva VJ, Salgado HC. Cardiac sympathetic overactivity and decreased baroreflex sensitivity in L-NAME hypertensive rats. Am J Physiol Heart Circ Physiol 2001;280:H844-H850.
48. Scrogin KE, Hatton DC, Chi Y, Luft FC. Chronic nitric oxide inhibition with L-NAME: effects on autonomic control of the cardiovascular system. Am J Physiol Regul Integr Comp Physiol 1998;274:R367-R374.
49. Moreira E, Ida F, Oliveira V, Krieger E. Early depression of the baroreceptor sensitivity during onset of hypertension. Hypertension 1992;19:II198-II201.
50. Linhares RR. Arrhythmia detection from heart rate variability by SDFA method. Int J Cardiol 2016;224:27-32.
51. Arai Y, Saul JP, Albrecht P, Hartley LH, Lilly LS, Cohen RJ, et al. Modulation of cardiac autonomic activity during and immediately after exercise. Am J Physiol Regul Integr Comp Physiol 1989;256:H132-H141.
52. Van De Borne P, Montano N, Pagani M, Oren R, Somers VK. Absence of low-frequency variability of sympathetic nerve activity in severe heart failure. Circulation 1997;95:1449-1454.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 8
August 2023
Pages 891-898

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