Cyclic nucleotide second messengers (cAMP and cGMP) play a central role in signal transduction and regulation of mesenteric postcapillary fluid leak.
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 (Lp) 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 x10 cm(-7)/sec/cmH2O and represented as mean +/- SEM.


RESULTS
Compared with baseline Lp (1.10 +/- 0.06), reduced cGMP levels by inhibiting its synthesis decreased Lp by over 50% (0.50 +/- 0.02, p < 0.001), while elevated cGMP levels by preventing its degradation increased Lp 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 Lp 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.
Chong
Terry J
TJ
UCSF East Bay Surgery Department, Alameda Country Medical Center, Oakland, CA 94602, USA. chongt@surgery.ucsf.edu
Victorino
Gregory P
GP
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D008643:Mesentery / Q000098:blood supply; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014699:Venules / Q000502:physiology
D000634:Aminoquinolines; D010726:Phosphodiesterase Inhibitors; C041715:6-anilino-5,8-quinolinedione; D000242:Cyclic AMP; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D020889:Rolipram