Characterization of the human monocyte endothelin B (ETB) receptor: Functional coupling of ETB receptor to nitric oxide synthase activation.
Item
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Title
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Characterization of the human monocyte endothelin B (ETB) receptor: Functional coupling of ETB receptor to nitric oxide synthase activation.
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Identifier
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AAI9732936
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identifier
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9732936
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Creator
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King, Jonathan M.
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Contributor
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Adviser: Harold I. Magazine
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Date
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1997
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Cell | Biology, Molecular | Chemistry, Biochemistry
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Abstract
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Endothelin-1 (ET-1) is a peptide hormone which exerts diverse actions over numerous physiological mechanisms including cardiovascular hemodynamics; neurotransmission or neuromodulation; muscle contractility; and control of cell proliferation. Human monocytes have the capacity to produce both endothelin-1 (ET-1) and nitric oxide (NO), yet the role of these mediators in monocyte function remains unclear.;Employing a molecular and pharmacological approach we have provided direct evidence that human peripheral blood monocytes (PBM) and the human monocytic cell line THP-1, bind ET-1 and express ET{dollar}\sb{lcub}\rm B{rcub}{dollar} receptors. Utilizing an NO selective amperometric probe we have provided the first direct demonstration of NO release in human PBM in response to ET-1 stimulation. This coupled to immunocytochemical analysis of NO synthase (NOS) isoforms in THP-1 cells we have determined that the monocyte ET{dollar}\sb{lcub}\rm B{rcub}{dollar} receptor is functionally coupled to activation of constitutive NOS (ecNOS).;Exposure of PBM to ET-1 markedly reduced adhesion of these cells to human saphenous vein whereas PBM adhesion in the presence of BQ-788, an ET{dollar}\sb{lcub}\rm B{rcub}{dollar} selective antagonist, was restored to that of control levels. These data demonstrate that PBM interactions with the vascular wall can be reduced by autocrine production of NO and suggest that PBM ET{dollar}\sb{lcub}\rm B{rcub}{dollar} receptors may attenuate monocyte activity at sites of inflammation.;Accumulation of monocytes at sites of vascular injury may have profound hemodynamic effects. We have demonstrated that adherent monocytes augment the vascular contractile potency of ET-1. Increased ET-1 induced vascular tone in the presence of adherent monocytes may contribute to elevated blood pressure in patients suffering from hypertension. Activation of monocytes with proinflammatory cytokines resulted in expression of inducible NOS (iNOS) and enhanced monocyte adhesion to the vascular wall. ET-1 stimulation of activated monocytes did not attenuate their adhesion indicating that the monocyte ET{dollar}\sb{lcub}\rm B{rcub}{dollar} receptor is functionally coupled to ecNOS but not iNOS activation. Monocyte ET{dollar}\sb{lcub}\rm B{rcub}{dollar} receptor-coupled NO is likely to modulate their adhesion and activity at sites of vascular injury. The inability of ET-1 stimulation to modulate adhesion of activated monocytes may be detrimental and contribute to the progression of vascular disease.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
