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Stimulation of Epac/Rap1 pathway deactivates hyperpermeability after its onset in PAF‐induced acute inflammation in vivo
Author(s) -
Iwahashi Toru,
Kim David D,
Lal Brajesh K,
Durán Walter N
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.950.4
Subject(s) - cheek pouch , platelet activating factor , intravital microscopy , stimulation , cremaster muscle , inflammation , chemistry , in vivo , pharmacology , medicine , endocrinology , hamster , biology , microcirculation , microbiology and biotechnology
Epac (exchange protein activated by cAMP) regulates endothelial cell‐cell adhesion. We tested the hypothesis that stimulation of Epac can deactivate the inflammatory hyperpermeability caused by PAF (platelet‐activating factor). We used integrated optical intensity (IOI) as the index of microvascular permeability and examined tissues by intravital microscopy and image analysis. Two minutes after finishing the administration of 10 −7 M PAF, we applied the Epac‐specific cAMP analogue, 8‐(4‐chloro‐phenylthio)‐2′‐O‐Methyladenosine ‐3',5′‐cyclic monophosphate (8‐CPT) at 10 −5 M to stimulate Epac. PAF increased net IOI from baseline to a mean ± SEM value of 142.1 ± 5.3 in the mouse cremaster and from baseline to 70.7 ± 8.9 in hamster cheek pouch. 8‐CPT reduced these values to 68.5 ± 8.2 and 34.2 ± 9.7, respectively (P <0.05). Administration of 10 −5 M L‐NMMA or 10 −6 M ABT‐491 (PAF receptor blocker) after application of PAF did not inhibit PAF‐induced hyperpermeability. We conclude that stimulation of Epac deactivates PAF‐induced pro‐inflammatory hyperpermeability. (Supported by 5R01 HL070634 and 1RO1 HL088479).