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.

Purpose:To compare atherosclerotic plaque uptake of a first (ferumoxtran-10) and second generation (ferumoxytol) ultrasmall superparamagnetic iron oxide (USPIO) contrast agent with different pharmacokinetic/pharmacodynamic properties. Materials and Methods:New Zealand White rabbits maintained on a high cholesterol/fat diet were subjected to balloon injury to the abdominal aorta. Ferumoxtran-10 or ferumoxytol (500 mol/kg) was administered at 2, 4, and 8 weeks following injury. In vivo magnetic resonance imaging (MRI) was performed immediately prior to, immediately after, and 6 days post-contrast administration. Ex vivo MRI, histologic, and inductively coupled plasma-mass spectrometry (ICP-MS) iron analyses were performed on the excised vessels. Results:The blood pool clearance of ferumoxytol (t 1 ⁄2 Յ 6 hours) was more rapid than that of ferumoxtran-10 (t 1 ⁄2 Յ 48 hours). Decreased in vivo MRI signal intensity in the abdominal aorta was observed at 2, 4, and 8 weeks following injury with ferumoxtran-10, but not with ferumoxytol. Consistent with these observations, ex vivo MRI signal intensity was decreased in the ferumoxtran-10 vessels, and to a lesser degree in the ferumoxytol vs. control vessels (-contrast agent). In contrast, in vitro macrophage phagocytosis of USPIO was four to six fold greater with ferumoxytol than with ferumoxtran-10. Additionally, the absolute iron content correlated with ex vivo MRI signal intensity in all vessels (r ϭ -0.86, P Ͻ 0.0001).

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Owing to its signal-enhancing characteristics in viable well-perfused tissue, divalent manganese (Mn 2þ ) has been used as a myocardial imaging contrast agent. Because Mn 2þ can enter excitable cells through the voltage-gated L-type calcium channels, manganese-enhanced MRI (MEMRI) has been used to determine the viability and the inotropic state of the heart. In this study, we examined the correlation between left ventricular infarction zone as assessed by cardiac MEMRI and function in mice with permanent coronary artery occlusion. At an Mn 2þ infusion dose of 1.72 AE 0.47 nmol/min/g body weight, the steady-state signal intensity (SI) enhancement 20-26 min post-Mn 2þ infusion of the normal septum and leftventricular wall during diastole was 128.2 AE 14.4 and 127.9 AE 26.5%, respectively, whereas the infarction zone was 56.0 AE 7.1%. During systole, the SI enhancement was 144.6 AE 33.0, 116.0 AE 18.7 and 48.3 AE 20.0% for the normal septum, left-ventricular wall and infarction zone, respectively. A good correlation was obtained between the MEMRI determined infarction volume and conventional histological TTC staining (r ¼ 0.9582, p < 0.01). There was also a strong negative correlation between MEMRI determined infarction percentage (compared with whole left ventricle) and ejection fraction (r ¼ À0.94, p < 0.05). These data suggest that the Mn 2þ concentration at steady state in the heart may reflect altered tissue viability in the infarcted tissue as well as surrounding region following myocardial infarction. In conclusion, in vivo cardiac MEMRI offers a manner in which functional, pathologic and viability data may be obtained simultaneously in myocardial tissue.