Abstract
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.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.107.134551.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
-
ABBREVIATIONS:
- TRP
- transient receptor potential
- V4
- vanilloid subtype 4
- NO
- nitric oxide
- EET
- epoxyeicosatrienoic acid
- HR
- heart rate
- WT
- wild type
- eNOS
- endothelial NO synthase
- DMSO
- dimethyl sulfoxide
- BP
- blood pressure
- l-NAME
- N-nitro-l-arginine methyl ester
- HUVEC
- human umbilical vein endothelial cell
- AoSMC
- human aortic smooth muscle cell
- HAEC
- human aortic endothelial cell
- V1
- vanilloid subtype 1
- RuR
- ruthenium red
- MAP
- mean arterial pressure
- SVR
- systemic vascular resistance
- MRI
- magnetic resonance imaging
- 4α-PDD
- 4α-phorbol 12,13-didecanoate.
- Received November 20, 2007.
- Accepted May 6, 2008.
- Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics