Nitric oxide releasing aspirin protects the gastric mucosa against stress and promotes healing of stress-induced gastric mucosal damage: role of heat shock protein 70.
OBJECTIVE
Nitric oxide (NO) releasing nonsteroidal anti-inflammatory drugs do not cause gastric mucosal damage, despite inhibition of the cyclooxygenase activity to a similar extent as conventional nonsteroidal anti-inflammatory drugs that induce such damage. We compared the effects of native aspirin (ASA) with those of NO-releasing ASA (NO-ASA) on the development and healing of acute gastric lesions induced by water immersion and restraint stress (WRS) and the mucosal expression of heat shock protein 70 (HSP70).


METHODS
Wistar rats received: (1). vehicle; (2). ASA (40 mg/kg i.g), and (3). NO-ASA (2.5-40 mg/kg i.g.), followed 0.5 h later by 3.5 h of WRS with or without glyceryl trinitrate, the donor of NO, and carboxy-PTIO, a NO scavenger. Healing of WRS lesions was assessed 0-24 h after termination of WRS. Number of gastric lesions, gastric mucosal blood flow (GBF), malondialdehyde (MDA) content, and RT-PCR expression of HSP70 mRNA were determined.


RESULTS
WRS caused typical bleeding erosions that were aggravated by aspirin and this was accompanied by a fall in the GBF and a significant rise in the mucosal MDA concentrations. In contrast, NO-ASA, which raised significantly the luminal content of NO(x), reduced number of WRS lesions and mucosal MDA levels while increasing significantly the GBF. These protective and hyperemic effects of NO-ASA against WRS lesions were mimicked by addition of glyceryl trinitrate to native ASA and significantly attenuated by carboxy-PTIO added to NO-ASA. HSP70 mRNA was significantly upregulated by WRS, and this was significantly attenuated by ASA, but not by NO-ASA. NO-ASA decreased significantly the MDA content and induced overexpression of HSP70 mRNA during healing of WRS lesions.


CONCLUSIONS
NO-ASA exhibits mucosal protective and healing effects against WRS-induced gastric lesions due to the release of NO, which induces gastric hyperemia, and the attenuation of lipid peroxidation and counteracts the inhibition of HSP70 expression induced by native ASA.
Konturek
Peter C
PC
First Department of Medicine I, University Erlangen-Nürnberg, Erlangen, Germany. pkonturek@aol.com
Brzozowski
Thomas
T
Ptak
Agata
A
Kania
Joanna
J
Kwiecień
Sławomir
S
Hahn
Eckhart G
EG
Konturek
Stanisław J
SJ
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000502:physiology*; D015227:Lipid Peroxidation; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000503:physiopathology*
D018840:HSP70 Heat-Shock Proteins; D012333:RNA, Messenger; C098312:nitroxy-butyl-acetylsalicylic acid; D001241:Aspirin