Abstract 13510: Discovery of Orally Active Transient Receptor Potential Vanilloid 4 (TRPV4) Blockers for the Treatment of Pulmonary Edema in Heart Failure
Pulmonary edema is a key determinant of symptoms, exercise capacity, and hospitalization in heart failure (HF) patients, and is associated with left ventricular dysfunction and elevated pulmonary venous pressure. We hypothesized that blockade of the Ca2+-permeable TRPV4 channel would reduce pulmonary edema and enhance respiratory function in HF, as recent evidence suggests that pulmonary venous pressure-induced edema is driven by endothelial TRPV4 activation that disrupts lung endothelial barrier integrity. We describe identification of GSK2193874 as the first orally active TRPV4 channel blocker, and demonstrate its efficacy in the treatment of HF-induced pulmonary edema. GSK2193874 selectively inhibits Ca2+ flux through recombinant TRPV4 channels (IC50=2 and 40 nM for rat and human TRPV4, respectively), and inhibits native human endothelial TRPV4 currents (n=9) while maintaining endothelial cell integrity during TRPV4 activation (n=3). Blockade of TRPV4 with GSK2193874 (30 nM) inhibits the increase in endothelial permeability and edema associated with elevation of pulmonary venous pressures in isolated perfused mouse (n=6), and canine (n=5) lungs. Acute aortic banding in the rat increases left ventricular end diastolic pressure (LVEDP), and induces pulmonary edema, reducing arterial oxygen tension. Pretreatment with a single oral dose of GSK2193874 (30 mg/kg, n=11) significantly inhibits the formation of pulmonary edema and restores arterial oxygen tension without affecting the increased LVEDP. In a 14 day HF model of myocardial infarction in mice TRPV4 blockade with GSK2193874 (60 mg/kg/day PO, n=40) prevents and resolves pulmonary edema, as assessed by magnetic resonance imaging and lung weight, leading to improved arterial oxygen tension and survival. TRPV4 immunolabeling of lung sections from congestive HF patients (n=12) demonstrates TRPV4 expression in the endothelium of small pulmonary vessels that is enhanced compared to controls (n=5). Taken together, these data support an important role for TRPV4 in the pathogenesis of high pulmonary capillary wedge pressure-induced pulmonary edema, and suggest that pharmacologic TRPV4 blockade may be a novel therapeutic approach to prevent and reduce pulmonary edema in HF patients.
- © 2011 by American Heart Association, Inc.