Referenced in: none

Automatically associated channels: SK2 , TRP , TRPV , TRPV4

Title: An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure.

Authors: Kevin S Thorneloe, Mui Cheung, Weike Bao, Hasan Alsaid, Stephen Lenhard, Ming-Yuan Jian, Melissa Costell, Kristeen Maniscalco-Hauk, John A Krawiec, Alan Olzinski, Earl Gordon, Irina Lozinskaya, Lou Elefante, Pu Qin, Daniel S Matasic, Chris James, James Tunstead, Brian Donovan, Lorena Kallal, Anna Waszkiewicz, Kalindi Vaidya, Elizabeth A Davenport, Jonathan Larkin, Mark Burgert, Linda N Casillas, Robert W Marquis, Guosen Ye, Hilary S Eidam, Krista B Goodman, John R Toomey, Theresa J Roethke, Beat M Jucker, Christine G Schnackenberg, Mary I Townsley, John J Lepore, Robert N Willette

Journal, date & volume: Sci Transl Med, 2012 Nov 7 , 4, 159ra148

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23136043

Abstract
Pulmonary edema resulting from high pulmonary venous pressure (PVP) is a major cause of morbidity and mortality in heart failure (HF) patients, but current treatment options demonstrate substantial limitations. Recent evidence from rodent lungs suggests that PVP-induced edema is driven by activation of pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channels. To examine the therapeutic potential of this mechanism, we evaluated TRPV4 expression in human congestive HF lungs and developed small-molecule TRPV4 channel blockers for testing in animal models of HF. TRPV4 immunolabeling of human lung sections demonstrated expression of TRPV4 in the pulmonary vasculature that was enhanced in sections from HF patients compared to controls. GSK2193874 was identified as a selective, orally active TRPV4 blocker that inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents. In isolated rodent and canine lungs, TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP. Furthermore, in both acute and chronic HF models, GSK2193874 pretreatment inhibited the formation of pulmonary edema and enhanced arterial oxygenation. Finally, GSK2193874 treatment resolved pulmonary edema already established by myocardial infarction in mice. These findings identify a crucial role for TRPV4 in the formation of HF-induced pulmonary edema and suggest that TRPV4 blockade is a potential therapeutic strategy for HF patients.