Received for publication November 28, 2007.
Revised May 6, 2008.
Accepted for publication May 6, 2008.

Systemic Activation of the Transient Receptor Potential V4 Channel Causes Endothelial Failure and Circulatory Collapse: Part 2

Abstract

The transient receptor potential V4 (TRPV4) is a non-selective cation channel that exhibits polymodal activation and is expressed in 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 intravenous 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 analysis 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 produced potent endothelial-dependent relaxation of rodent isolated vascular ring segments that was abolished by NOS inhibition (L-NAME), ruthenium red and 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 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.

Key words: acute heart failure, endothelium, nitric oxide, permeability, pulmonary congestion, transient receptor potential V4

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