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 Ca2+ 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.
Willette
Robert N
RN
Investigative and Cardiac Biology, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, UW2510, King of Prussia, PA 19406, USA. robert.n.willette@gsk.com
Bao
Weike
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Nerurkar
Sandhya
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Yue
Tian-Li
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Doe
Chris P
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Stankus
Gerald
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Turner
Gregory H
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Haisong
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Thomas
Heath
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Fishman
Cindy E
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Sulpizio
Anthony
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Behm
David J
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Hoffman
Sandra
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Lin
Zuojun
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Lozinskaya
Irina
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Casillas
Linda N
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Trout
Robert E Lee
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Votta
Bartholomew J
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Thorneloe
Kevin
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Lashinger
Erin S R
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Figueroa
David J
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Marquis
Robert
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Xiaoping
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D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D007930:Leucine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000009:adverse effects* / Q000493:pharmacokinetics; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics; D014661:Vasoconstriction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects*
C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D013449:Sulfonamides; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486576:Trpv4 protein, mouse; C486577:Trpv4 protein, rat; D007930:Leucine