title: Systemic leukotriene B4receptor antagonism lowers arterial blood pressure and improves autonomic function in the spontaneously hypertensive rat.
abstract: Evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4(LTB4), a potent chemoattractant involved in the inflammatory response, but its mode of action is poorly understood. In the SHR, we observed an increase in T cells and macrophages in the brainstem; in addition, gene expression profiling data showed that LTB4production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. When LTB4receptor 1 (BLT1) receptors were blocked with CP-105,696, arterial pressure was reduced in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in systolic blood pressure (BP) indicators. These data provide new evidence for the role of LTB4as an important neuro-immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension.
  
  
  
  Accumulating evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4(LTB4), a potent chemoattractant involved in the inflammatory response. However, the mechanism for LTB4-mediated inflammation in hypertension is poorly understood. Here we report in the SHR, increased brainstem infiltration of T cells and macrophages plus gene expression profiling data showing that LTB4production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. Chronic blockade of the LTB4receptor 1 (BLT1) receptor with CP-105,696, reduced arterial pressure in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in low and high frequency spectra of systolic blood pressure, and an increase in spontaneous baroreceptor reflex gain (sBRG). These data provide new evidence for the role of LTB4as an important neuro-immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension.
authors.affiliation: Department of Pharmacology and Physiology Washington, The George Washington University School of Medical and Health Sciences, Washington, DC, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Marvar
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Emma B
authors.initials: EB
authors.lastname: Hendy
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Cruise
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Dawid
authors.initials: D
authors.lastname: Walas
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: DeCicco
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Rajanikanth
authors.identifier: 0000-0002-8405-1037
authors.initials: R
authors.lastname: Vadigepalli
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Schwaber
authors.affiliation: Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Waki
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, University of Bristol, Whitson Street, Bristol, BS1 3NY, UK.
authors.forename: David
authors.initials: D
authors.lastname: Murphy
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK. julian.f.r.paton@bristol.ac.uk.
authors.forename: Julian F R
authors.initials: JF
authors.lastname: Paton
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects* / Q000502:physiology; D017704:Baroreflex / Q000187:drug effects / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007975:Leukotriene B4 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*
chemical_list: D001578:Benzopyrans; D002264:Carboxylic Acids; C513241:Ltb4r protein, rat; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; C089698:CP 105696