Role of endothelin-1 and cyclic nucleotides in ischemia/reperfusion- mediated microvascular leak

René Ramirez, Terry Chong, Brian Curran, Gregory P. Victorino, John J. Ferrara, Homar M. Smathers, Richard J. Mullins

    Research output: Contribution to journalArticle

    4 Scopus citations

    Abstract

    Background: A consequence of ischemia/reperfusion (IR) is endothelial barrier dysfunction and intravascular volume loss. The purposes of our study are to explore the impact of: 1) cyclic guanosine monophosphate (cGMP) synthesis inhibition, 2) cyclic adenosine monophosphate (cAMP) synthesis inhibition, 3) treatment with endothelin-1, and 4) endothelin-1 (ET-1)-mediated cAMP changes on IR-induced fluid leak. We hypothesize that IR-mediated microvascular fluid leak results from increased cGMP activity and ET-1 decreases IR-induced fluid leak via cAMP. Methods: A micro-cannulation technique was used to determine fluid leak or hydraulic permeability (Lp) in rat mesenteric venules. L p was measured during IR and after treatment with 1) cGMP synthesis inhibitor (LY83583,10 μmol/L) 2) cAMP synthesis inhibitor (2′,5′dideoxyadenosine,10 μmol/L), 3) ET-1 (80 pM), and 4) cAMP synthesis inhibitor plus ET-1 (n = 6 in each group; Lp represented as mean ± standard error of the mean; units 10-7cm/sec/cmH 2O). Results: IR resulted in an increase in Lp (L p = 7.07 ± 0.20) sevenfold above baseline (1.05 ± 0.31) (p ≤ 0.001). Compared with IR alone, 1) pretreatment with cGMP synthesis inhibitor completely blocked IR-induced fluid leak (Lp = 1.08 ± 0.18) (p ≤ 0.001), 2) pretreatment with cAMP synthesis inhibitor attenuated fluid leak (Lp = 3.92 ± 0.20) (p ≤ 0.005), 3) treatment with ET-1 decreased fluid leak (Lp = 5.38 ± 0.28) (p ≤ 0.005), and 4) pretreatment with a cAMP inhibitor plus treatment with ET-1 reduced fluid leak nearly 50% compared with ET-1 alone (Lp = 2.95 ± 0.12) (p ≤ 0.005). Conclusion: cGMP inhibition completely blocks fluid leak, pointing toward a central role as a mediator of IR-induced postcapillary venular leak. ET-1 mildly decreased leak. Furthermore, ET-1 may not exert its effects on microvascular fluid leak during IR via cAMP.

    Original languageEnglish (US)
    Pages (from-to)515-522
    Number of pages8
    JournalJournal of Trauma - Injury, Infection and Critical Care
    Volume60
    Issue number3
    DOIs
    StatePublished - Mar 1 2006

    Keywords

    • Endothelin-1
    • Hydraulic permeability
    • Ischemia reperfusion
    • Microvascular permeability
    • cAMP
    • cGMP

    ASJC Scopus subject areas

    • Surgery
    • Critical Care and Intensive Care Medicine

    Fingerprint Dive into the research topics of 'Role of endothelin-1 and cyclic nucleotides in ischemia/reperfusion- mediated microvascular leak'. Together they form a unique fingerprint.

  • Cite this