Isoflurane, but not sevoflurane, increases transendothelial albumin permeability in the isolated rat lung: role for enhanced phosphorylation of caveolin-1.

BACKGROUND Caveolae mediated transendothelial transport of albumin has recently been shown to be the primary mechanism regulating microvascular endothelial albumin permeability. The authors investigated the effects of isoflurane and sevoflurane on pulmonary endothelial albumin permeability and assessed the potential role of the caveolae scaffold protein, caveolin-1, in these effects. METHODS Isolated rat lungs and cultured rat lung microvessel endothelial cells (RLMVECs) were exposed to 1.0 or 2.0 minimum alveolar concentration (MAC) isoflurane or sevoflurane for 30 min. I-albumin permeability-surface area product and capillary filtration coefficient were determined in the isolated lungs. In RLMVECs, uptake and transendothelial transport of I-albumin were measured in the absence and presence of pretreatment with 2 mm methyl-beta-cyclodextrin, a caveolae-disrupting agent. Uptake of fluorescent-labeled albumin, as well as phosphorylation of Src kinase and caveolin-1, was also determined. In Y14F-caveolin-1 mutant (nonphosphorylatable) expressing RLMVECs, uptake of I-albumin and phosphorylation of caveolin-1 were evaluated. RESULTS In the isolated lungs, 2.0 MAC isoflurane increased I-albumin permeability-surface area product by 48% without affecting capillary filtration coefficient. In RLMVECs, isoflurane more than doubled the uptake of I-albumin and caused a 54% increase in the transendothelial transport of I-albumin. These effects were blocked by pretreatment with methyl-beta-cyclodextrin. The isoflurane-induced increase in uptake of I-albumin in wild-type RLMVECs was abolished in the Y14F-caveolin-1 mutant expressing cells. Isoflurane also caused a twofold increase in Src and caveolin-1 phosphorylation. Neither 1.0 MAC isoflurane nor 1.0 or 2.0 MAC sevoflurane affected any index of albumin transport or phosphorylation of caveolin-1. CONCLUSION Isoflurane, but not sevoflurane, increased lung transendothelial albumin permeability through enhancement of caveolae-mediated albumin uptake and transport in the isolated lung. This effect may involve an enhanced phosphorylation of caveolin-1.