Nitric oxide-releasing aspirin protects gastric mucosa against ethanol damage in rats with functional ablation of sensory nerves.
OBJECTIVE
The aim of the present study was to investigate, whether sensory nerves are involved in the gastroprotection induced by NO releasing non-steroidal anti-inflammatory drugs (NO-NSAID).


METHODS
Studies were performed in Wistar rats with intact or inactivated sensory nerves by pretreatment with large dose of capsaicin (125 mg/kg sc).


METHODS
Acute gastric lesions were induced by 100% ethanol (100% EtOH). 1 h before exposure to 100% EtOH, rats received vehicle, aspirin (ASA) or NO-releasing aspirin (NO-ASA) in the same dose (50 mg/kg). The animals were killed 1 h after exposure to 100% EtOH.


METHODS
Determinations were made of gastric mucosal injury, mucosal gastric blood flow, mucosal mRNA expression of glutathione peroxidase (GPx), zinc copper superoxide dismutase (SOD) and heat shock protein (HSP70) by RT-PCR and protein expression for HSP70 by Western blotting.


RESULTS
Pretreatment with ASA aggravated the acute gastric injury induced by 100% EtOH, whereas pretreatment with NO-ASA led to a significant reduction in this injury. Administration of 100% EtOH was accompanied by a pronounced upregulation of HSP70, which was reduced by ASA, but enhanced by NO-ASA application. Sensory deactivation with capsaicin enhanced acute ethanol lesions and led to a significant attenuation in HSP70 expression. In contrast to ASA, NO-ASA attenuated gastric mucosal lesions and significantly upregulated HSP70 expression despite blockade of sensory nerves. NO-ASA, but not ASA, caused an upregulation of SOD and GPx mRNA in gastric mucosa with or without sensory denervation.


CONCLUSIONS
NO-ASA protects gastric mucosa even after blockade of sensory nerves due to the upregulation of HSP70 expression and attenuation of the oxidative injury resulting from strong upregulation of genes for antioxidant enzymes.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D015153:Blotting, Western; D002211:Capsaicin / Q000494:pharmacology; D000431:Ethanol / Q000009:adverse effects*; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000294:innervation* / Q000473:pathology; D005979:Glutathione Peroxidase / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000502:physiology*; D013276:Stomach Ulcer / Q000473:pathology / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018840:HSP70 Heat-Shock Proteins; D012333:RNA, Messenger; D009569:Nitric Oxide; D000431:Ethanol; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C102148:nitroaspirin; D001241:Aspirin; D002211:Capsaicin