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Systemic Activation of the Transient Receptor Potential Vanilloid Subtype 4 Channel Causes Endothelial Failure and Circulatory Collapse: Part 2

The transient receptor potential (TRP) vanilloid subtype 4 (V4) is a nonselective cation channel that exhibits polymodal activation and is expressed in the endothelium, where it contributes to intracellular Ca 2+ homeostasis and regulation of cell volume. The purpose of the present study was to eval...

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Published in:The Journal of pharmacology and experimental therapeutics 2008-08, Vol.326 (2), p.443-452
Main Authors: Willette, Robert N, Bao, Weike, Nerurkar, Sandhya, Yue, Tian-Li, Doe, Chris P, Stankus, Gerald, Turner, Gregory H, Ju, Haisong, Thomas, Heath, Fishman, Cindy E, Sulpizio, Anthony, Behm, David J, Hoffman, Sandra, Lin, Zuojun, Lozinskaya, Irina, Casillas, Linda N, Lin, Min, Trout, Robert E Lee, Votta, Bartholomew J, Thorneloe, Kevin, Lashinger, Erin S R, Figueroa, David J, Marquis, Robert, Xu, Xiaoping
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cited_by cdi_FETCH-LOGICAL-c392t-873fcdedbb4571509b259494cc7e50c286207b51b8e45411bae7bba2280566113
cites cdi_FETCH-LOGICAL-c392t-873fcdedbb4571509b259494cc7e50c286207b51b8e45411bae7bba2280566113
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container_issue 2
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container_title The Journal of pharmacology and experimental therapeutics
container_volume 326
creator Willette, Robert N
Bao, Weike
Nerurkar, Sandhya
Yue, Tian-Li
Doe, Chris P
Stankus, Gerald
Turner, Gregory H
Ju, Haisong
Thomas, Heath
Fishman, Cindy E
Sulpizio, Anthony
Behm, David J
Hoffman, Sandra
Lin, Zuojun
Lozinskaya, Irina
Casillas, Linda N
Lin, Min
Trout, Robert E Lee
Votta, Bartholomew J
Thorneloe, Kevin
Lashinger, Erin S R
Figueroa, David J
Marquis, Robert
Xu, Xiaoping
description The transient receptor potential (TRP) vanilloid subtype 4 (V4) is a nonselective cation channel that exhibits polymodal activation and is expressed in the endothelium, where it contributes to intracellular Ca 2+ homeostasis and regulation of cell volume. The purpose of the present study was to evaluate the systemic cardiovascular effects of GSK1016790A, a novel TRPV4 activator, and to examine its mechanism of action. In three species (mouse, rat, and dog), the i.v. administration of GSK1016790A induced a dose-dependent reduction in blood pressure, followed by profound circulatory collapse. In contrast, GSK1016790A had no acute cardiovascular effects in the TRPV4 –/– null mouse. Hemodynamic analyses in the dog and rat demonstrate a profound reduction in cardiac output. However, GSK1016790A had no effect on rate or contractility in the isolated, buffer-perfused rat heart, and it produced potent endothelial-dependent relaxation of rodent-isolated vascular ring segments that were abolished by nitric-oxide synthase (NOS) inhibition ( N -nitro- l -arginine methyl ester; l -NAME), ruthenium red, and endothelial NOS (eNOS) gene deletion. However, the in vivo circulatory collapse was not altered by NOS inhibition ( l -NAME) or eNOS gene deletion but was associated with (concentration and time appropriate) profound vascular leakage and tissue hemorrhage in the lung, intestine, and kidney. TRPV4 immunoreactivity was localized in the endothelium and epithelium in the affected organs. GSK1016790A potently induced rapid electrophysiological and morphological changes (retraction/condensation) in cultured endothelial cells. In summary, inappropriate activation of TRPV4 produces acute circulatory collapse associated with endothelial activation/injury and failure of the pulmonary microvascular permeability barrier. It will be important to determine the role of TRPV4 in disorders associated with edema and microvascular congestion.
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The purpose of the present study was to evaluate the systemic cardiovascular effects of GSK1016790A, a novel TRPV4 activator, and to examine its mechanism of action. In three species (mouse, rat, and dog), the i.v. administration of GSK1016790A induced a dose-dependent reduction in blood pressure, followed by profound circulatory collapse. In contrast, GSK1016790A had no acute cardiovascular effects in the TRPV4 –/– null mouse. Hemodynamic analyses in the dog and rat demonstrate a profound reduction in cardiac output. However, GSK1016790A had no effect on rate or contractility in the isolated, buffer-perfused rat heart, and it produced potent endothelial-dependent relaxation of rodent-isolated vascular ring segments that were abolished by nitric-oxide synthase (NOS) inhibition ( N -nitro- l -arginine methyl ester; l -NAME), ruthenium red, and endothelial NOS (eNOS) gene deletion. 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ispartof The Journal of pharmacology and experimental therapeutics, 2008-08, Vol.326 (2), p.443-452
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source Medical Journals (Open access)
subjects Animals
Aorta, Thoracic - drug effects
Aorta, Thoracic - metabolism
Capillary Permeability - drug effects
Cell Adhesion - drug effects
Cell Line
Dogs
Dose-Response Relationship, Drug
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Female
Hemodynamics - drug effects
Humans
Immunohistochemistry
Leucine - adverse effects
Leucine - analogs & derivatives
Leucine - pharmacokinetics
Male
Mice
Mice, Knockout
Molecular Structure
Patch-Clamp Techniques
Rats
Rats, Sprague-Dawley
Sulfonamides - adverse effects
Sulfonamides - pharmacokinetics
TRPV Cation Channels - agonists
TRPV Cation Channels - genetics
Vasoconstriction - drug effects
Ventricular Function, Left - drug effects
title Systemic Activation of the Transient Receptor Potential Vanilloid Subtype 4 Channel Causes Endothelial Failure and Circulatory Collapse: Part 2
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