Glucagon-like peptide-1 protects mesenteric endothelium from injury during inflammation

Glucagon-like peptide-1 (GLP-1) is a proglucagon-derived hormone with cellular protective actions. We hypothesized that GLP-1 would protect the endothelium from injury during inflammation. Our aims were to determine the: (1) effect of GLP-1 on basal microvascular permeability, (2) effect of GLP-1 on increased microvascular permeability induced by lipopolysaccaride (LPS), (3) involvement of the GLP-1 receptor in GLP-1 activity. and (4) involvement of the cAMP/PKA pathway in GLP-1 activity. Microvascular permeability (L-p) of rat mesenteric post-capillary venules was measured in vivo. First, the effect of GLP-1 on basal LP was measured. Second, after systemic LPS injection, LP was measured after subsequent perfusion with GLP-1. Thirdly, Lp was measured after LPS injection and perfusion with GLP1 + GLP-1 receptor antagonist. Lastly, Lp was measured after LPS injection and perfusion with GLP1 + inhibitors of the cAMP/PKA pathway. Results are presented as mean area under the curve (AUC) +/- SEM. GLP-1 had no effect on Lp (AUC: baseline = 27 +/- 1.4, GLP-1 = 1 +/- 0.4. p = 0.08). LPS increased Lp two-fold (AUC: LPS = 54 +/- 1.7, p < 0.0001). GLP-1 reduced the LPS increase in L-p by 75% (AUC: LPS + GLP1 - 34 1.5, p < 0.0001). GLP-1 antagonism reduced the effects of GLP-1 by 60% (AUC: LPS + GLP1 + antagonist = 46 +/- 2.0, p < 0.001). The cAMP synthesis inhibitor reduced the effects of GLP-1 by 60% (AUC: LPS + GLP-1 + cAMP inhibitor = 46 +/- 1.5, p < 0.0001). The PKA inhibitor reduced the effects of GLP-1 by 100% (AUC: LPS + GLP-1 + PKA inhibitor = 56 1.5, p < 0.0001). GLP-1 attenuates the increase in microvascular permeability induced by LPS. GLP-1 may protect the endothelium during inflammation, thus decreasing third-space fluid loss. (C) 2009 Elsevier Inc. All rights reserved.