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1 Department of Physiology, University of South Alabama, Mobile, AL, USA
* To whom correspondence should be addressed. E-mail: mtownsley{at}usouthal.edu.
This study tested the hypothesis that epoxyeicosatrienoic acids (EETs), derived from arachidonic acid via P450 epoxygenases, are soluble factors linking depletion of endoplasmic reticulum calcium (Ca++) 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. Lung injury elicited by 14,15-EET appeared to involve both Ca++ entry and Ca++- independent mechanisms in rat lung. The non-specific Ca++ channel blocker Gd+++ did not significantly attenuate the response to 14,15-EET (p=0.068) and 14,15-EET tended to increase EC permeability in lungs perfused with low [Ca++]. However, significant increase in Kf,c due to 14,15-EET was observed following Ca++ add-back. As positive control, we showed that thapsigargin (TG) increased EC permeability, an effect that was blocked by both Gd+++ and low [Ca++] buffer. Nonetheless, the 3.7 fold increase in EC permeability evoked by TG, a known activator of store-depletion induced Ca++ entry, could not be blocked by the phospholipase A2 inhibitors, mepacrine or methyl arachidonyl fluorophosphonate, or the P450 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 induced by TG. We conclude that EETs are eicosanoids with a heterogeneous ability to increase EC permeability. Despite a requirement for Ca++ entry with both TG and 14,15-EET, our data suggest that distinct signaling pathways or heterogeneity in EC responsiveness are responsible for the observed injury evoked by EETs and store depletion in the isolated rat lung.
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