title: Excessive leukotriene B4 in nucleus tractus solitarii is prohypertensive in spontaneously hypertensive rats.
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.
authors.affiliation: School of Physiology and Pharmacology, Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol, United Kingdom.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Waki
authors.forename: Emma B
authors.initials: EB
authors.lastname: Hendy
authors.forename: Charles C T
authors.initials: CC
authors.lastname: Hindmarch
authors.forename: Sabine
authors.initials: S
authors.lastname: Gouraud
authors.forename: Marie
authors.initials: M
authors.lastname: Toward
authors.forename: Sergey
authors.initials: S
authors.lastname: Kasparov
authors.forename: David
authors.initials: D
authors.lastname: Murphy
authors.forename: Julian F R
authors.initials: JF
authors.lastname: Paton
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology; D007975:Leukotriene B4 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018077:Receptors, Leukotriene / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D020024:Leukotriene Antagonists; D018077:Receptors, Leukotriene; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase