Excessive Leukotriene B4 in Nucleus Tractus Solitarii is Prohypertensive in Spontaneously Hypertensive Rats

Overview

Journal Hypertension

Date 2012 Nov 23

PMID 23172924

Citations 26

Authors

Hidefumi Waki

Emma B Hendy

Charles C T Hindmarch

Sabine Gouraud

Marie Toward

Sergey Kasparov

David Murphy

Julian F R Paton

Affiliations

Soon will be listed here.

Abstract

Inflammation within the brain stem microvasculature has been associated with chronic cardiovascular diseases. We found that the expression of several enzymes involved in arachidonic acid-leukotriene B4 (LTB4) production was altered in nucleus tractus solitarii (NTS) of spontaneously hypertensive rat (SHR). LTB4 produced from arachidonic acid by 5-lipoxygenase is a potent chemoattractant of leukocytes. Leukotriene B4-12-hydroxydehydrogenase (LTB4-12-HD), which degrades LTB4, was downregulated in SHR rats compared with that in Wistar-Kyoto rats. Quantitative real-time PCR revealed that LTB4-12-HD was reduced by 63% and 58% in the NTS of adult SHR and prehypertensive SHR, respectively, compared with that in age-matched Wistar-Kyoto rats (n=6). 5-lipoxygenase gene expression was upregulated in the NTS of SHR (≈50%; n=6). LTB4 levels were increased in the NTS of the SHR, (17%; n=10, P<0.05). LTB4 receptors BLT1 (but not BLT2) were expressed on astroglia in the NTS but not neurons or vessels. Microinjection of LTB4 into the NTS of Wistar-Kyoto rats increased both leukocyte adherence and arterial pressure for over 4 days (peak: +15 mm Hg; P<0.01). In contrast, blockade of NTS BLT1 receptors lowered blood pressure in the SHR (peak: -13 mm Hg; P<0.05) but not in Wistar-Kyoto rats. Thus, excessive amounts of LTB4 in NTS of SHR, possibly as a result of upregulation of 5-lipoxygenase and downregulation of LTB4-12-HD, can induce inflammation. Because blockade of NTS BLT1 receptors lowered arterial pressure in the SHR, their endogenous activity may contribute to the hypertensive state of this rodent model. Thus, inflammatory reactions in the brain stem are causally associated with neurogenic hypertension.

Citing Articles

Dynamic dysregulation of transcriptomic networks in brainstem autonomic nuclei during hypertension development in the female spontaneously hypertensive rat.

Moss A, Kuttippurathu L, Srivastava A, Schwaber J, Vadigepalli R Physiol Genomics. 2023; 56(3):283-300.

PMID: 38145287 PMC: 11283910. DOI: 10.1152/physiolgenomics.00073.2023.

Renal denervation based on experimental rationale.

Katsurada K, Ogoyama Y, Imai Y, Patel K, Kario K Hypertens Res. 2021; 44(11):1385-1394.

PMID: 34518650 PMC: 9577563. DOI: 10.1038/s41440-021-00746-7.

Vasculo-Neuronal Coupling and Neurovascular Coupling at the Neurovascular Unit: Impact of Hypertension.

Presa J, Saravia F, Bagi Z, Filosa J Front Physiol. 2020; 11:584135.

PMID: 33101063 PMC: 7546852. DOI: 10.3389/fphys.2020.584135.

New progress on the study of aortic stiffness in age-related hypertension.

Onuh J, Qiu H J Hypertens. 2020; 38(10):1871-1877.

PMID: 32890259 PMC: 7647939. DOI: 10.1097/HJH.0000000000002452.

CX3CR1-microglia mediates neuroinflammation and blood pressure regulation in the nucleus tractus solitarii of fructose-induced hypertensive rats.

Ho C, Lin Y, Chen H, Ho W, Sun G, Hsiao M J Neuroinflammation. 2020; 17(1):185.

PMID: 32532282 PMC: 7291459. DOI: 10.1186/s12974-020-01857-7.

References

Nohgawa M, Sasada M, Maeda A, Asagoe K, Harakawa N, Takano K . Leukotriene B4-activated human endothelial cells promote transendothelial neutrophil migration. J Leukoc Biol. 1997; 62(2):203-9. DOI: 10.1002/jlb.62.2.203. View

Zhang M, Mao Y, Ramirez S, Tuma R, Chabrashvili T . Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience. 2010; 171(3):852-8. DOI: 10.1016/j.neuroscience.2010.09.029. View

Takagishi M, Waki H, Bhuiyan M, Gouraud S, Kohsaka A, Cui H . IL-6 microinjected in the nucleus tractus solitarii attenuates cardiac baroreceptor reflex function in rats. Am J Physiol Regul Integr Comp Physiol. 2009; 298(1):R183-90. DOI: 10.1152/ajpregu.00176.2009. View

Gouraud S, Waki H, Bhuiyan M, Takagishi M, Cui H, Kohsaka A . Down-regulation of chemokine Ccl5 gene expression in the NTS of SHR may be pro-hypertensive. J Hypertens. 2011; 29(4):732-40. DOI: 10.1097/HJH.0b013e328344224d. View

Banisadr G, Gosselin R, Mechighel P, Rostene W, Kitabgi P, Melik Parsadaniantz S . Constitutive neuronal expression of CCR2 chemokine receptor and its colocalization with neurotransmitters in normal rat brain: functional effect of MCP-1/CCL2 on calcium mobilization in primary cultured neurons. J Comp Neurol. 2005; 492(2):178-92. DOI: 10.1002/cne.20729. View

Tager A, Luster A . BLT1 and BLT2: the leukotriene B(4) receptors. Prostaglandins Leukot Essent Fatty Acids. 2003; 69(2-3):123-34. DOI: 10.1016/s0952-3278(03)00073-5. View

Yokomizo T, Izumi T, Shimizu T . Leukotriene B4: metabolism and signal transduction. Arch Biochem Biophys. 2001; 385(2):231-41. DOI: 10.1006/abbi.2000.2168. View

Ando H, Zhou J, Macova M, Imboden H, Saavedra J . Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats. Stroke. 2004; 35(7):1726-31. DOI: 10.1161/01.STR.0000129788.26346.18. View

Waki H, Liu B, Miyake M, Katahira K, Murphy D, Kasparov S . Junctional adhesion molecule-1 is upregulated in spontaneously hypertensive rats: evidence for a prohypertensive role within the brain stem. Hypertension. 2007; 49(6):1321-7. DOI: 10.1161/HYPERTENSIONAHA.106.085589. View

10.

Waki H, Katahira K, Polson J, Kasparov S, Murphy D, Paton J . Automation of analysis of cardiovascular autonomic function from chronic measurements of arterial pressure in conscious rats. Exp Physiol. 2005; 91(1):201-13. DOI: 10.1113/expphysiol.2005.031716. View

11.

Rosas-Ballina M, Olofsson P, Ochani M, Valdes-Ferrer S, Levine Y, Reardon C . Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011; 334(6052):98-101. PMC: 4548937. DOI: 10.1126/science.1209985. View

12.

Fukuda S, Yasu T, Kobayashi N, Ikeda N, Schmid-Schonbein G . Contribution of fluid shear response in leukocytes to hemodynamic resistance in the spontaneously hypertensive rat. Circ Res. 2004; 95(1):100-8. DOI: 10.1161/01.RES.0000133677.77465.38. View

13.

Johnstone M, Gearing A, Miller K . A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J Neuroimmunol. 1999; 93(1-2):182-93. DOI: 10.1016/s0165-5728(98)00226-4. View

14.

Manev H, Uz T, Sugaya K, Qu T . Putative role of neuronal 5-lipoxygenase in an aging brain. FASEB J. 2000; 14(10):1464-9. DOI: 10.1096/fj.14.10.1464. View

15.

Mayorov D, Head G, de Matteo R . Tempol attenuates excitatory actions of angiotensin II in the rostral ventrolateral medulla during emotional stress. Hypertension. 2004; 44(1):101-6. DOI: 10.1161/01.HYP.0000131290.12255.04. View

16.

Ostermann G, Weber K, Zernecke A, Schroder A, Weber C . JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002; 3(2):151-8. DOI: 10.1038/ni755. View

17.

Schmid-Schonbein G, Seiffge D, DeLano F, Shen K, ZWEIFACH B . Leukocyte counts and activation in spontaneously hypertensive and normotensive rats. Hypertension. 1991; 17(3):323-30. DOI: 10.1161/01.hyp.17.3.323. View

18.

Shanmugham L, Petrarca C, Castellani M, Frydas S, Vecchiet J, Conti P . Rantes potentiates human macrophage aggregation and activation responses to calcium ionophore (A23187) and activates arachidonic acid pathways. J Biol Regul Homeost Agents. 2007; 20(1-2):15-23. View

19.

Huang L, Zhao A, Wong F, Ayala J, Struthers M, Ujjainwalla F . Leukotriene B4 strongly increases monocyte chemoattractant protein-1 in human monocytes. Arterioscler Thromb Vasc Biol. 2004; 24(10):1783-8. DOI: 10.1161/01.ATV.0000140063.06341.09. View

20.

Zubcevic J, Waki H, Raizada M, Paton J . Autonomic-immune-vascular interaction: an emerging concept for neurogenic hypertension. Hypertension. 2011; 57(6):1026-33. PMC: 3105900. DOI: 10.1161/HYPERTENSIONAHA.111.169748. View