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 L(p) was measured. Second, after systemic LPS injection, L(p) was measured after subsequent perfusion with GLP-1. Thirdly, L(p) was measured after LPS injection and perfusion with GLP-1+GLP-1 receptor antagonist. Lastly, L(p) was measured after LPS injection and perfusion with GLP-1+inhibitors of the cAMP/PKA pathway. Results are presented as mean area under the curve (AUC)+/-SEM. GLP-1 had no effect on L(p) (AUC: baseline=27+/-1.4, GLP-1=1+/-0.4, p=0.08). LPS increased L(p) two-fold (AUC: LPS=54+/-1.7, p<0.0001). GLP-1 reduced the LPS increase in L(p) by 75% (AUC: LPS+GLP-1=34+/-1.5, p<0.0001). GLP-1 antagonism reduced the effects of GLP-1 by 60% (AUC: LPS+GLP-1+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.
Dozier
Kristopher C
KC
Department of Surgery, University of California, San Francisco-East Bay, Alameda County Medical Center, Oakland, CA, USA.
Cureton
Elizabeth L
EL
Kwan
Rita O
RO
Curran
Brian
B
Sadjadi
Javid
J
Victorino
Gregory P
GP
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D007249:Inflammation / Q000503:physiopathology*; D007546:Isoquinolines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008643:Mesentery / Q000098:blood supply*; D010446:Peptide Fragments / Q000494:pharmacology; D010477:Perfusion; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors; D020889:Rolipram / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014699:Venules / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*
D004791:Enzyme Inhibitors; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007546:Isoquinolines; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D018027:Receptors, Glucagon; D013449:Sulfonamides; D016048:Dideoxyadenosine; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; C021008:2',5'-dideoxyadenosine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020889:Rolipram; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide