Role of calcitonin gene-related peptide in the postischemic anti-inflammatory effects of antecedent ethanol ingestion.
The aim of this study was to determine the role of calcitonin gene-related peptide (CGRP) in the postischemic anti-inflammatory effects of antecedent ethanol ingestion. Ethanol was administered to wild-type C57BL/6 mice on day 1 as a bolus by gavage at a dose that produces a peak plasma ethanol of 45 mg/dl 30 min after administration. Twenty-four hours later (day 2), the superior mesenteric artery was occluded for 45 min followed by 70 min of reperfusion (I/R). Intravital fluorescence microscopy was used to quantify the numbers of rolling (LR) and adherent (LA) leukocytes labeled with carboxyfluorescein diacetate succinimidyl ester in postcapillary venules of the small intestine. I/R increased LR and LA, effects that were prevented by antecedent ethanol. The postischemic anti-inflammatory effects of ethanol consumption were abolished by administration of a specific CGRP receptor antagonist [CGRP-(8-37)] or after sensory nerve neurotransmitter depletion using capsaicin administered 4 days before ethanol ingestion, which initially induces rapid release of CGRP from sensory nerves, thereby depleting stored neuropeptide. Administration of exogenous CGRP or induction of endogenous CGRP release by treatment with capsaicin 24 h before I/R mimicked the postischemic anti-inflammatory effects of antecedent ethanol ingestion. Preconditioning with capsaicin 24 h before I/R was prevented by coincident treatment with CGRP-(8-37), while exogenous CGRP induced an anti-inflammatory phenotype in mice depleted of CGRP by capsaicin administration 4 days earlier. Our results indicate that the effect of antecedent ethanol ingestion to prevent postischemic LR and LA is initiated by a CGRP-dependent mechanism.
Kamada
Kazuhiro
K
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, USA.
Gaskin
F Spencer
FS
Yamaguchi
Taiji
T
Carter
Patsy
P
Yoshikawa
Toshikazu
T
Yusof
Mozow
M
Korthuis
Ronald J
RJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D004334:Drug Administration Schedule; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology; D005452:Fluoresceins; D007511:Ischemia / Q000097:blood / Q000378:metabolism*; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D017538:Mesenteric Artery, Superior; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000097:blood; D013388:Succinimides
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D000893:Anti-Inflammatory Agents; D005452:Fluoresceins; D013388:Succinimides; D000431:Ethanol; D015740:Calcitonin Gene-Related Peptide