title: Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat.
abstract: Systemic arterial hypertension has been previously suggested to develop as a compensatory condition when central nervous perfusion/oxygenation is compromised. Principal sympathoexcitatory C1 neurons of the rostral ventrolateral medulla oblongata (whose activation increases sympathetic drive and the arterial blood pressure) are highly sensitive to hypoxia, but the mechanisms of this O2 sensitivity remain unknown. Here, we investigated potential mechanisms linking brainstem hypoxia and high systemic arterial blood pressure in the spontaneously hypertensive rat. Brainstem parenchymal PO2 in the spontaneously hypertensive rat was found to be ≈15 mm Hg lower than in the normotensive Wistar rat at the same level of arterial oxygenation and systemic arterial blood pressure. Hypoxia-induced activation of rostral ventrolateral medulla oblongata neurons was suppressed in the presence of either an ATP receptor antagonist MRS2179 or a glycogenolysis inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol, suggesting that sensitivity of these neurons to low PO2 is mediated by actions of extracellular ATP and lactate. Brainstem hypoxia triggers release of lactate and ATP which produce excitation of C1 neurons in vitro and increases sympathetic nerve activity and arterial blood pressure in vivo. Facilitated breakdown of extracellular ATP in the rostral ventrolateral medulla oblongata by virally-driven overexpression of a potent ectonucleotidase transmembrane prostatic acid phosphatase results in a significant reduction in the arterial blood pressure in the spontaneously hypertensive rats (but not in normotensive animals). These results suggest that in the spontaneously hypertensive rat, lower PO2 of brainstem parenchyma may be associated with higher levels of ambient ATP and l-lactate within the presympathetic circuits, leading to increased central sympathetic drive and concomitant sustained increases in systemic arterial blood pressure.
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.). n.marina@ucl.ac.uk a.gourine@ucl.ac.uk.
authors.forename: Nephtali
authors.initials: N
authors.lastname: Marina
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Richard
authors.initials: R
authors.lastname: Ang
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Asif
authors.initials: A
authors.lastname: Machhada
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Kasymov
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Anastassios
authors.initials: A
authors.lastname: Karagiannis
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Hosford
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Valentina
authors.initials: V
authors.lastname: Mosienko
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Anja G
authors.initials: AG
authors.lastname: Teschemacher
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Pirkko
authors.initials: P
authors.lastname: Vihko
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Julian F R
authors.initials: JF
authors.lastname: Paton
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.).
authors.forename: Sergey
authors.initials: S
authors.lastname: Kasparov
authors.affiliation: From the Centre for Cardiovascular and Metabolic Neuroscience (N.M., R.A., A.M., V.K., A.K., P.S.H., A.V.G.), Department of Clinical Pharmacology and Experimental Therapeutics (N.M., P.S.H.), and Neuroscience, Physiology and Pharmacology (R.A., A.M., V.K., A.K., A.V.G.), University College London, London, United Kingdom; School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (V.M., A.G.T., J.F.R.P., S.K.); and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland (P.V.). n.marina@ucl.ac.uk a.gourine@ucl.ac.uk.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
mesh_terms: D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001933:Brain Stem / Q000098:blood supply* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology
chemical_list: D019344:Lactic Acid; D000255:Adenosine Triphosphate
keywords: adenosine triphosphate; hypertension; hypoxia; lactic acid; sympathetic nervous system