Abstract
We have established earlier that PAF causes hyperpermeability via eNOS‐derived NO. We investigate here the alternative hypothesis that PAF and BK diminish cAMP levels and Epac activity and thus reduce the barrier properties of the endothelium. We studied the hamster cheek pouch microcirculation by intravital microscopy and measured FITC‐Dx clearance (Cl‐FITC‐Dx) as an index of macromolecular transport. We homogenized the pouches and determined cAMP content (ELISA kit) at defined intervals related to changes in Cl‐FITC‐Dx. We applied 8‐CPT‐2′‐O‐Me‐cAMP (8‐CPT) topically 2 min after PAF application to stimulate Epac activity. PAF (10−7M) and BK (10−6M) elevated Cl‐FITC‐Dx from 2.66 + 0.4 and 2.21 + 0.76 to 112.28 + 43.02 and 67.76 + 10.03 nl/min, respectively. Application of 8‐CPT reduced the PAF and BK‐induced elevation in Cl‐FITC‐Dx by 50%. cAMP levels in tissues collected at 5 min, 15 min and 30 min after PAF application were both reduced by 30% compared to baseline (Basal; 29.5 ± 4.5, PAF 30 min; 18.7 ± 1.3 pmol cAMP/g). We speculate that PAF and BK stimulate hyperpermeability via two complementary mechanisms: a) eNOS‐derived NO and b) reduction of cAMP levels and Epac activity. We demonstrate that the PAF‐ and BK‐induced hyperpermeability can be deactivated by increasing Epac activity. (Supported by Fondecyt 1040816, Proyecto puente VRAID y NIH 5RO1 HL070634‐06).
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