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Am J Physiol Lung Cell Mol Physiol 286: L445-L451, 2004. First published October 24, 2003; doi:10.1152/ajplung.00150.2003
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Role of EETs in regulation of endothelial permeability in rat lung

Diego F. Alvarez, Eli-Anne B. Gjerde, and Mary I. Townsley

Department of Physiology, University of South Alabama, Mobile, Alabama 36688

Submitted 13 May 2003 ; accepted in final form 17 October 2003

This study tested the hypothesis that epoxyeicosatrienoic acids (EETs) derived from arachidonic acid via P-450 epoxygenases are soluble factors linking depletion of endoplasmic reticulum Ca2+ stores and store-dependent regulation of endothelial cell (EC) permeability in rat lung. EC permeability was measured via the capillary filtration coefficient (Kf,c) in isolated, perfused rat lungs. 14,15-EET and 5,6-EET increased EC permeability, a response that was significantly different from that of 8,9-EET, 11,12-EET, and vehicle control. The permeability response to 14,15-EET was not significantly attenuated by the nonspecific Ca2+ channel blocker Gd3+ (P = 0.068). In lungs perfused with low [Ca2+], 14,15-EET tended to increase EC permeability, although a significant increase in Kf,c was observed only following Ca2+ add-back. As positive control, we showed that the 3.7-fold increase in Kf,c evoked by thapsigargin (TG), a known activator of store depletion-induced Ca2+ entry, was blocked by both Gd3+ and low [Ca2+] buffer. Nonetheless, the permeability response to TG could not be blocked by the phospholipase A2 inhibitors mepacrine or methyl arachidonyl fluorophosphonate or the P-450 epoxygenase inhibitors 17-octadecynoic acid or propargyloxyphenyl hexanoic acid. Similarly, combined pretreatment with ibuprofen and dicyclohexylurea to block EET metabolism had no effect on the permeability response to TG. We conclude that EETs have a heterogeneous impact on EC permeability. Despite a requirement for Ca2+ entry with both TG and 14,15-EET, our data suggest that distinct signaling pathways or heterogeneity in EC responsiveness is responsible for the observed EC injury evoked by EETs and store depletion in the isolated rat lung.

capillary filtration coefficient; store depletion; epoxyeicosatrienoic acid; cytochrome P-450


Address for reprint requests and other correspondence: M. I. Townsley, Dept. of Physiology, MSB 3074, Univ. of So. Alabama, Mobile, AL 36688 (E-mail: mtownsley{at}usouthal.edu).




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