Journal
JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE
Volume 59, Issue 2, Pages 302-306Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.ta.0000180385.23675.98
Keywords
microvascular permeability; hydraulic permeability; second messenger; signal transduction; cAMP; cGMP
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Background: Endothelial cell receptors involved in post-injury/sepsis fluid extravasation are coupled to G-proteins that stimulate production of cGMP and cAMP. We hypothesize that cGMP and cAMP are endothelial second messengers that control microvascular permeability. The purposes of this series of experiments are to determine microvascular permeability under the following conditions: 1) reduced cGMP levels, 2) elevated cGMP levels, 3) reduced cAMP levels, and 4) elevated cAMP levels. Methods. Rat mesenteric venules were cannulated and hydraulic permeability (L.) was measured at 3- to 5-minute intervals during 1) cGMP synthesis inhibition, 2) inhibition of cGMP degradation, 3) cAMP synthesis inhibition, and 4) inhibition of cAMP degradation (n = 6 in each study group). LP units are x 10(-7) cm/sec/cm H2O and represented as mean +/- SEM. Results. Compared with baseline LP (1.10 +/- 0.06), reduced cGMP levels by inhibiting its synthesis decreased L-p by over 50% (0.50 +/- 0.02, p < 0.001), while elevated cGMP levels by preventing its degradation increased L-p by more than 2-fold (0.91 +/- 0.10 to 2.26 +/- 0.15, p < 0.001). The reduction of cAMP levels by synthesis inhibition elevated LP over 400% from 0.92 +/- 0.04 to 4.11 +/- 0.54 (p < 0.001), and elevation of cAMP level by blocking its degradation reduced L-p almost 50 % from 1.11 +/- 0.04 to 0.59 +/- 0.06 (P < 0.001). Conclusions: The second messengers, cGMP and cAMP, contribute to the control mechanisms that govern fluid leak across the endothelial barrier: cGMP increases microvascular permeability, while cAMP decreases microvascular permeability. Endothelial cell cyclic nucleotide second messengers are pharmacologically accessible and may be targeted during post-injury/sepsis-associated microvascular fluid leak.
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