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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Isorhynchophylline Regulates the Circadian Rhythm of the Hypothalamus in Spontaneously Hypertensive Rats to Treat Hypertension

Author(s): Danyang Wang, Mengjia Sun, Yuecheng Liu, Lihua Wang, Chao Li, Yunlun Li* and Haiqiang Jiang*

Volume 29, Issue 2, 2023

Published on: 03 January, 2023

Page: [139 - 148] Pages: 10

DOI: 10.2174/1381612829666221222115134

Price: $65

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Abstract

Background: The neurotransmitter metabolism in spontaneously hypertensive rats (SHR) is disordered, and these disturbances in neurotransmitter levels can further exacerbate the development of hypertension. Neurotransmitters can affect the expression of circadian clock genes.

Objective: To clarify the time-dependent internal mechanism of the imbalance of the target neurotransmitter metabolic rhythm of spontaneously hypertensive rats, the circadian research was carried out by the method of targeted metabolomics and molecular biology technology.

Methods: We have explored the mechanism of isorhynchophylline regulating the circadian rhythm through the ERK signaling pathway and thus treating hypertension by detecting the changes of central hypothalamic biological clock rhythm genes after isorhynchophylline intervention, from hypothalamic neurotransmitter rhythmicity.

Results: The expression of rhythm genes in normal rats showed a certain rhythm at 6 time points, while the expression of rhythm genes in model rats decreased, and the gene rhythm returned to normal after isorhynchophylline treatment. Cosine analysis of 12 neurotransmitters in hypothalamus showed that there were 6 rhythmic neurotransmitters in the normal group, while in the model group, 4 of the 6 neurotransmitters lost their rhythmicity, and the rhythmicity returned to normal after isorhynchophylline intervention. Compared with the normal group, the expression of ERK protein in the model group increased significantly and decreased after isorhynchophylline treatment.

Conclusion: The mechanism of isorhynchophylline treating hypertension is not only the regulation of serum neurotransmitters rhythm, but also acting on rhythm genes in the feedback loop of the central biological clock.

Keywords: Hypertension, isorhynchophylline, circadian rhythm, biological clock, feedback regulation, neurotransmitter.

« Previous Next »
[1]
Doyle AE. Hypertension and vascular disease. Am J Hypertens 1991; 4(2_Pt_2): 103S-6S.
[http://dx.doi.org/10.1093/ajh/4.2.103S] [PMID: 2021454]
[2]
Rust P, Ekmekcioglu C. Impact of salt intake on the pathogenesis and treatment of hypertension. Adv Exp Med Biol 2016; 956: 61-84.
[http://dx.doi.org/10.1007/5584_2016_147] [PMID: 27757935]
[3]
Gao Q, Xu L, Cai J. New drug targets for hypertension: A literature review. Biochim Biophys Acta Mol Basis Dis 2021; 1867(3): 166037.
[http://dx.doi.org/10.1016/j.bbadis.2020.166037] [PMID: 33309796]
[4]
Ge J, He ML, Tang Y, Liu YM, Jin J, Zhang D. Relationship between circadian rhythm disorder of blood pressure and ischemic stroke. Acta Academiae Medicinae Sinicae 2020; 42(6): 831-5.
[5]
Douma LG, Gumz ML. Circadian clock-mediated regulation of blood pressure. Free Radic Biol Med 2018; 119: 108-14.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.11.024] [PMID: 29198725]
[6]
Smolensky MH, Hermida RC, Portaluppi F. Circadian mechanisms of 24-hour blood pressure regulation and patterning. Sleep Med Rev 2017; 33: 4-16.
[http://dx.doi.org/10.1016/j.smrv.2016.02.003] [PMID: 27076261]
[7]
Lei Y, Jin J, Ban H, Du Y. Effects of acupuncture on circadian rhythm of blood pressure in patients with essential hypertension. Zhongguo Zhenjiu 2017; 37(11): 1157-61.
[http://dx.doi.org/10.13703/j.0255-2930.2017.11.005] [PMID: 29354950]
[8]
Zhang J, Sun R, Jiang T, Yang G, Chen L. Circadian blood pressure rhythm in cardiovascular and renal health and disease. Biomolecules 2021; 11(6): 868.
[http://dx.doi.org/10.3390/biom11060868] [PMID: 34207942]
[9]
Ingelsson E, Björklund-Bodegård K, Lind L, Ärnlöv J, Sundström J. Diurnal blood pressure pattern and risk of congestive heart failure. JAMA 2006; 295(24): 2859-66.
[http://dx.doi.org/10.1001/jama.295.24.2859] [PMID: 16804152]
[10]
Rey G, Reddy AB. Connecting cellular metabolism to circadian clocks. Trends Cell Biol 2013; 23(5): 234-41.
[http://dx.doi.org/10.1016/j.tcb.2013.01.003] [PMID: 23391694]
[11]
Koronowski KB, Kinouchi K, Welz PS, et al. Defining the independence of the liver circadian clock. Cell 2019; 177(6): 1448-1462.e14.
[http://dx.doi.org/10.1016/j.cell.2019.04.025] [PMID: 31150621]
[12]
Pan X, Mota S, Zhang B. Circadian clock regulation on lipid metabolism and metabolic diseases. Adv Exp Med Biol 2020; 1276: 53-66.
[http://dx.doi.org/10.1007/978-981-15-6082-8_5] [PMID: 32705594]
[13]
Skene DJ, Skornyakov E, Chowdhury NR, Gajula RP. Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism. 2018; 115(30): 7825-30.
[http://dx.doi.org/10.1073/pnas.1801183115]
[14]
Ding G, Gong Y, Eckel-Mahan KL, Sun Z. Central circadian clock regulates energy metabolism. Adv Exp Med Biol 2018; 1090: 79-103.
[http://dx.doi.org/10.1007/978-981-13-1286-1_5] [PMID: 30390286]
[15]
Tahara Y, Aoyama S, Shibata S. The mammalian circadian clock and its entrainment by stress and exercise. J Physiol Sci 2017; 67(1): 1-10.
[http://dx.doi.org/10.1007/s12576-016-0450-7] [PMID: 27084533]
[16]
Panda S. Circadian physiology of metabolism. Science 2016; 354(6315): 1008-15.
[http://dx.doi.org/10.1126/science.aah4967] [PMID: 27885007]
[17]
Ikegami K, Refetoff S. Interconnection between circadian clocks and thyroid function. Nat Rev Endocrinol 2019; 15(10): 590-600.
[http://dx.doi.org/10.1038/s41574-019-0237-z]
[18]
Scala M, Amadori E, Fusco L, Marchese F, Capra V, Minetti C, et al. Abnormal circadian rhythm in patients with GRIN1-related developmental epileptic encephalopathy. Eur J Paediatr Neurol 2019; 23(4): 657-1.
[http://dx.doi.org/10.1016/j.ejpn.2019.05.011]
[19]
Kondratova AA, Kondratov RV. The circadian clock and pathology of the ageing brain. Nat Rev Neurosci 2012; 13(5): 325-35.
[http://dx.doi.org/10.1038/nrn3208] [PMID: 22395806]
[20]
Sollars PJ, Pickard GE. The neurobiology of circadian rhythms. Psychiatr Clin North Am 2015; 38(4): 645-65.
[http://dx.doi.org/10.1016/j.psc.2015.07.003] [PMID: 26600101]
[21]
De Lazzari F, Bisaglia M, Zordan M, Sandrelli F. Circadian rhythm abnormalities in Parkinson’s disease from humans to flies and back. Int J Mol Sci 2018; 19(12): 3911.
[http://dx.doi.org/10.3390/ijms19123911] [PMID: 30563246]
[22]
Barbato E, Mianzo H, Litman P, Darrah R. Dysregulation of circadian rhythm gene expression in cystic fibrosis mice. J Circadian Rhythms 2019; 17(1): 2.
[http://dx.doi.org/10.5334/jcr.175] [PMID: 31065288]
[23]
Freeman SL, Kwon H. Heme binding to human CLOCK affects interactions with the E-box. Proc Natl Acad Sci U S A 2019; 116(40): 19911-6.
[http://dx.doi.org/10.1073/pnas.1905216116]
[24]
Wu D, Su X, Potluri N, Kim Y, Rastinejad F. NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors. Elife 2016; 5: e18790.
[http://dx.doi.org/10.7554/eLife.18790]
[25]
Wu D, Rastinejad F. Structural characterization of mammalian bHLH-PAS transcription factors. Curr Opin Struct Biol 2017; 43: 1-9.
[http://dx.doi.org/10.1016/j.sbi.2016.09.011] [PMID: 27721191]
[26]
St John PC, Hirota T, Kay SA, Doyle FJ III. Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock. Proc Natl Acad Sci USA 2014; 111(5): 2040-5.
[http://dx.doi.org/10.1073/pnas.1323618111] [PMID: 24449901]
[27]
Lee Y, Jang AR. KPNB1 mediates PER/CRY nuclear translocation and circadian clock function. Elife 2015; 4: e08647.
[http://dx.doi.org/10.7554/eLife.08647]
[28]
Cao X, Yang Y. Molecular mechanism of the repressive phase of the mammalian circadian clock. Proc Natl Acad Sci U S A 2021; 118(2)
[http://dx.doi.org/10.1073/pnas.2021174118]
[29]
Shi JS, Yu JX, Chen XP, Xu RX. Pharmacological actions of Uncaria alkaloids, rhynchophylline and isorhynchophylline. Acta Pharmacol Sin 2003; 24(2): 97-101.
[PMID: 12546715]
[30]
Tian Z, Zhang S, Wang H, et al. Intervention of Uncaria and its components on liver lipid metabolism in spontaneously hypertensive rats. Front Pharmacol 2020; 11: 910.
[http://dx.doi.org/10.3389/fphar.2020.00910] [PMID: 32765256]
[31]
Li Y, Yu R, Zhang D, et al. Deciphering the mechanism of the anti-hypertensive effect of isorhynchophylline by targeting neurotransmitters metabolism of hypothalamus in spontaneously hypertensive rats. ACS Chem Neurosci 2020; 11(11): 1563-72.
[http://dx.doi.org/10.1021/acschemneuro.9b00699] [PMID: 32356970]
[32]
Hou Q, Zhang S, Li Y, et al. New insights on association between circadian rhythm and lipid metabolism in spontaneously hypertensive rats. Life Sci 2021; 271: 119145.
[http://dx.doi.org/10.1016/j.lfs.2021.119145] [PMID: 33548288]
[33]
Sun M, Wang H, Gong L, Qi D, Wang X, Li Y, et al. A novel time-dimension and circadian rhythm-dependent strategy for pharmacodynamic evaluation of Uncaria in the regulation of neurotransmitter circadian metabolic homeostasis in spontaneously hypertensive rats. Biomed Pharmacother 2020; 131: 110704.
[http://dx.doi.org/10.1016/j.biopha.2020.110704]
[34]
Davies SK, Ang JE, Revell VL, et al. Effect of sleep deprivation on the human metabolome. Proc Natl Acad Sci USA 2014; 111(29): 10761-6.
[http://dx.doi.org/10.1073/pnas.1402663111] [PMID: 25002497]
[35]
Isherwood CM, Van der Veen DR, Johnston JD, Skene DJ. Twenty-four-hour rhythmicity of circulating metabolites: Effect of body mass and type 2 diabetes. FASEB J 2017; 31(12): 5557-67.
[http://dx.doi.org/10.1096/fj.201700323R] [PMID: 28821636]
[36]
Razavi P, Devore EE, Bajaj A, et al. Shift work, chronotype, and melatonin rhythm in nurses. Cancer Epidemiol Biomarkers Prev 2019; 28(7): 1177-86.
[http://dx.doi.org/10.1158/1055-9965.EPI-18-1018] [PMID: 31142495]
[37]
Kervezee L, Cermakian N. Individual metabolomic signatures of circadian misalignment during simulated night shifts in humans. PLoS Biol 2019; 17(6): e3000303.
[http://dx.doi.org/10.1371/journal.pbio.3000303]
[38]
Tognini P, Murakami M, Liu Y, et al. Distinct circadian signatures in liver and gut clocks revealed by ketogenic diet. Cell Metab 2017; 26(3): 523-538.e5.
[http://dx.doi.org/10.1016/j.cmet.2017.08.015] [PMID: 28877456]
[39]
Milanova IV, Kalsbeek MJT, Wang XL, et al. Diet-induced obesity disturbs microglial immunometabolism in a time-of-day manner. Front Endocrinol 2019; 10: 424.
[http://dx.doi.org/10.3389/fendo.2019.00424] [PMID: 31316470]
[40]
Khalaf D, Krüger M. The effects of oral l-Arginine and l-Citrulline supplementation on blood pressure. Nutrients 2019; 11(7): 1679.
[http://dx.doi.org/10.3390/nu11071679]
[41]
Prado NJ, Ferder L, Manucha W, Diez ER. Anti-inflammatory effects of melatonin in obesity and hypertension. Curr Hypertens Rep 2018; 20(5): 45.
[http://dx.doi.org/10.1007/s11906-018-0842-6] [PMID: 29744660]
[42]
Trott AJ, Menet JS. Regulation of circadian clock transcriptional output by CLOCK: BMAL1. PLoS Genet 2018; 14(1): e1007156.
[http://dx.doi.org/10.1371/journal.pgen.1007156]
[43]
Parico GCG, Perez I. The human CRY1 tail controls circadian timing by regulating its association with CLOCK: BMAL1. Proc Natl Acad Sci U S A 2020; 117(45): 27971-9.
[http://dx.doi.org/10.1073/pnas.1920653117]
[44]
Wu X, Chen L, Zeb F, Li C, Jiang P, Chen A, et al. Clock-bmal1 mediates MMP9 induction in acrolein-promoted atherosclerosis associated with gut microbiota regulation. Environ Pollut 2019; 252(Pt B): 1455-63.
[http://dx.doi.org/10.1016/j.envpol.2019.06.042]
[45]
Morioka N, Sugimoto T, Sato K, et al. The induction of Per1 expression by the combined treatment with glutamate, 5-hydroxytriptamine and dopamine initiates a ripple effect on Bmal1 and Cry1 mRNA expression via the ERK signaling pathway in cultured rat spinal astrocytes. Neurochem Int 2015; 90: 9-19.
[http://dx.doi.org/10.1016/j.neuint.2015.06.013] [PMID: 26151099]
[46]
Wang WY, Wang W, Wu H. Microdialysis sampling combined with ultra-high-performance liquid chromatography-tandem mass spectrometry for the determination of geniposide in dialysate of joint cavities in adjuvant arthritis rats. Rapid Commun Mass Spectrom 2018.
[http://dx.doi.org/10.1002/rcm.8056]
[47]
Liu LL, Lin Y, Chen W, et al. Metabolite profiles of the cerebrospinal fluid in neurosyphilis patients determined by untargeted metabolomics analysis. Front Neurosci 2019; 13: 150.
[http://dx.doi.org/10.3389/fnins.2019.00150] [PMID: 30863278]
[48]
Stoessel D, Schulte C, Teixeira dos Santos MC, et al. Promising metabolite profiles in the plasma and CSF of early clinical Parkinson’s disease. Front Aging Neurosci 2018; 10: 51.
[http://dx.doi.org/10.3389/fnagi.2018.00051] [PMID: 29556190]
[49]
Song Z, Tang G, Zhuang C, Wang Y, Wang M, Lv D, et al. Metabolomic profiling of cerebrospinal fluid reveals an early diagnostic model for central nervous system involvement in acute lymphoblastic leukaemia. Br J Haematol 2022; 198(6): 994-1010.
[http://dx.doi.org/10.1111/bjh.18307]

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