We herein investigated, using a
corticotropin-releasing factor (CRF) agonist and antagonists, whether CRF plays a role in the pathogenesis of
ischemia/reperfusion-induced small intestinal lesions in rats. Under
pentobarbital anesthesia, the superior mesenteric artery was clamped (
ischemia) for 75 min, followed by reperfusion with removal of the clamp. After a 24-h reperfusion, the area of hemorrhagic lesions that developed in the small intestine was measured.
Urocortin I (
CRF receptor 1/2 agonist),
astressin (
CRF receptor 1/2 antagonist),
NBI27914 (
CRF receptor 1 antagonist), or
astressin 2B (
CRF receptor 2 antagonist) was administered i.v. twice: 5 min before
ischemia and 6 hours after reperfusion.
Ischemia/reperfusion caused hemorrhagic lesions in the small intestine in
ampicillin- and
aminoguanidine-inhibitable manners, accompanied by enterobacterial invasion and the up-regulation of
inducible nitric oxide synthase expression and
myeloperoxidase activity. The severity of
ischemia/reperfusion-induced lesions was significantly reduced by
astressin and
astressin 2B, but not by
NBI27914, with the suppression of bacterial invasion,
myeloperoxidase activity, and
inducible nitric oxide synthase expression. In contrast,
urocortin I markedly aggravated these lesions, and this response was completely abrogated by the co-administration of
astressin 2B, but not
NBI27914. The gene expression of CRF,
CRF receptor 1, and
CRF receptor 2 was observed in the small intestine, and remained unchanged following
ischemia/reperfusion. These results suggest that
ischemia/reperfusion caused hemorrhagic lesions in the small intestine, the pathogenesis of which involved enterobacteria and
inducible nitric oxide synthase/
nitric oxide. These lesions were aggravated by
urocortin I in an
astressin 2B-inhibitable manner, but suppressed by
astressin in a
CRF receptor 2-dependent manner. Endogenous CRF may be involved in the pathogenesis of
ischemia/reperfusion-induced
enteritis, possibly via the activation of peripheral
CRF receptor 2.