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Beneficial effects of 5-aminoisoquinolinone, a novel, potent, water-soluble, inhibitor of poly (ADP-ribose) polymerase, in a rat model of splanchnic artery occlusion and reperfusion.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2004 May 25; Vol. 492 (2-3), pp. 203-10. - Publication Year :
- 2004
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Abstract
- Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with ischemia-reperfusion and inflammation. Splanchnic artery occlusion and reperfusion causes an enhanced formation of reactive oxygen species which contribute to the pathophysiology of shock. The aim of the present study was to investigate the effects of 5-aminoisoquinolinone (5-AIQ), a potent water-soluble inhibitor of poly(ADP-ribose) polymerase (PARP), in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion shock was induced in rats by clamping both the superior mesenteric artery and the celiac artery for 45 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, all animals were sacrificed for histological examination and biochemical studies. Treatment of rats with 5-AIQ (3 mg/kg i.v.), attenuated the fall of mean arterial blood pressure caused by splanchnic artery occlusion shock. 5-AIQ also attenuated the ileum injury as well as the increase in the tissue levels of myeloperoxidase and malondialdehyde caused by splanchnic artery occlusion shock in the ileum. The immunohistochemical examination also demonstrated a marked increase in the immunoreactivity to PAR, nitrotyrosine, and intercellular adhesion molecule (ICAM-1) in the necrotic ileum from splanchnic artery occlusion-shocked rats. 5-AIQ treatment significantly reduced the increase of positive staining for PAR, nitrotyrosine and ICAM-I. In conclusion, these results show that 5-AIQ, a new water-soluble potent inhibitor of poly(ADP-ribose) polymerase, exerts multiple protective effects in splanchnic artery occlusion/reperfusion shock.
- Subjects :
- Animals
Celiac Artery
Disease Models, Animal
Intercellular Adhesion Molecule-1 drug effects
Intercellular Adhesion Molecule-1 metabolism
Ischemia etiology
Ischemia pathology
Lipid Peroxidation drug effects
Male
Malondialdehyde metabolism
Mesenteric Artery, Superior
Peroxidase metabolism
Rats
Rats, Sprague-Dawley
Reperfusion
Reperfusion Injury etiology
Reperfusion Injury pathology
Solubility
Tyrosine antagonists & inhibitors
Water
Intestine, Small blood supply
Ischemia metabolism
Isoquinolines pharmacology
Mesenteric Vascular Occlusion complications
Poly(ADP-ribose) Polymerase Inhibitors
Reperfusion Injury metabolism
Tyrosine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0014-2999
- Volume :
- 492
- Issue :
- 2-3
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 15178366
- Full Text :
- https://doi.org/10.1016/j.ejphar.2004.03.033