The widespread presence of the Na-K-2Cl (NKCC) cotransporter protein suggests that chronic administration of inhibitors may result in adverse effects. Inhibition of the NKCC cotransporter by loop diuretics is felt to underlie the diuretic and the pulmonary smooth muscle relaxant effects of this drug class. However, the fundamental regulation of salt and water movement by this cotransporter suggests that it may also mediate cell volume changes occurring during cell cycle progression. Thus we hypothesized that NKCC cotransporter inhibition by loop diuretics would decrease cellular proliferation. Normal human bronchial smooth muscle cells (BSMC) showed a significant concentration-dependent decrease in cell counts after 7 days of exposure to both bumetanide (n=5-10) and furosemide (n=6-16) compared with controls. Proliferation was similarly inhibited in normal human lung fibroblasts (n=5-9). To determine whether this was due to loss of cells, we performed apoptosis assays on BSMC. Both annexin V-propidium iodide staining (n=5-10) and single cell gel electrophoresis assays (n=4) were negative for necrosis and apoptosis in BSMC exposed to 10 microM bumetanide. Subsequent analysis of the cell cycle by flow cytometry showed that bumetanide-exposed BSMC were delayed in G1 phase compared with controls (n=4-8). This is the first evidence for loop diuretic inhibition of airway smooth muscle cell proliferation. NKCC cotransporter inhibition impeded G1-S phase transition without facilitating cell death. Thus although inhibition by loop diuretics relaxes airway smooth muscle, the NKCC cotransporter may have a more important role in cell proliferation regulation.

Purpose:To compare the sensitivity of contrast-enhanced magnetic resonance imaging (MRI) and arterial spin labeling to perfusion deficits in the lung. Materials and Methods:A rabbit model of pulmonary embolism was imaged with both flow-sensitive alternating inversion recovery with an extra radiofrequency pulse (FAIRER) arterial spin labeling and Gd-DOTA enhanced MRI. The signal-to-noise ratio (SNR) was measured in the area of the perfusion deficit and the normal lung for both techniques. Results:The defect was readily visible in all images. The normal lung had an average of 3.8 Ϯ 1.2 times the SNR of the unperfused lung with the arterial spin labeling technique, and approximately 13.7 Ϯ 3.3 times the SNR with the contrast-enhanced technique. Conclusion:Gd-DOTA enhanced MRI provides higher SNR in pulmonary perfusion imaging; however, arterial spin labeling is also adequate and may be used when repeated studies are indicated.

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ObjectiveTo compare P792 (gadomelitol, a rapid clearance blood pool MR contrast agent) with gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA), a standard extracellular agent, for their suitability to diagnose a pulmonary embolism (PE) during a first-pass perfusion MRI and 3D contrast-enhanced (CE) MR angiography (MRA).Materials and MethodsA perfusion MRI or CE-MRA was performed in a rabbit PE model following the intravenous injection of a single dose of contrast agent. The time course of the pulmonary vascular and parenchymal enhancement was assessed by measuring the signal in the aorta, pulmonary artery, and lung parenchyma as a function of time to determine whether there is a significant difference between the techniques. CE-MRA studies were evaluated by their ability to depict the pulmonary vasculature and following defects between 3 seconds and 15 minutes after a triple dose intravenous injection of the contrast agents.ResultsThe P792 and Gd-DOTA were equivalent in their ability to demonstrate PE as perfusion defects on first pass imaging. The signal from P792 was significantly higher in vasculature than that from Gd-DOTA between the first and the tenth minutes after injection. The results suggest that a CE-MRA PE could be reliably diagnosed up to 15 minutes after injection.ConclusionP792 is superior to Gd-DOTA for the MR diagnosis of PE.