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Objective:
To investigates the nitric oxide donating properties of furoxan moiety and validates its role in the gastroprotective effect of rabeprazole against indomethacin induced gastric mucosal Methods:
The study was performed between April and July 2010 in the Department of Pharmacology / College of Medicine /Baghdad University .The study was conducted on 72 adult male albino rats, divided into 6 groups, the first served as a control received the vehicle , the second received indomethacin orally of 60mg/kg. The third and fourth groups were pretreated orally 30 minute prior indomethacin with either rabeprazole or omeprazole. In order to study the possible role of nitric oxide (NO) in their gastroprotective effect ; intraperitoneal N - Arginine Methyl Ester (L-NAME) a nitric oxide synthase inhibitor was given 30 minutes prior to rabeprazole and omeprazole administration followed by indomethacin and this served as fifth and sixth group respectively .
The rats were then sacrificed after 4 hours and their stomachs were isolated and submitted to macroscopical assessment and for the measurement of the gastric prostaglandin E2 (PGE2), Results:
Rabeprazole and omeprazole produced significant gastroprotective effects. Their protective effects were associated with marked decrease in MPO activity. However, the protective effect of furoxan containing rabeprazole was significantly better than that of in omeprazole .On the other hand, L-NAME pretreatment decreased the effects of rabeprazole while L-NAME pretreatment don't decrease the protective effects of omeprazole.
Conclusions:
The prophylactic use of rabeprazole and omeprazole in this study prevented indomethacin induced gastropathy. However, significantly better than that of in omeprazole which indicates the important role of NO in the * MSc. Pharm.Al-Sadir general hospital**FICMS,Al-Sadir general hospital Introduction:
It was reported that incorporated of nitric oxide-releasing properties into a NSAIDs may minimize or protect against NSAIDs induced mg/kg was used for the induction of gastric gastropathy.(1)(2) .Nitric oxide (NO) is a crucial damage at a concentration of 15mg/ml.
mediator of gastrointestinal (GI) mucosal Indomethacin was dissolved in a vehicle of defense(3) , exerting many of the same actions as c arb ox y me th yl c e llu lo s e (C M C ).
addition it is capable of inhibiting neutrophil degranulation (5) , and has a number of effects concentrations were adjusted to 10mg/ml.
in the GI tract that could counteract the loss of saline (PH 7.2) at a concentration of 32.5 mucosa (6) , increases blood flow to the gastric m g / m l f o r i n t r a p e r i t o n e a l mucosa and maintain its integrity and defense administration according to the method of (7) , promoting repair and removal of toxins (8) , decreases interaction of neutrophils with the gastric microcirculation (1) , and may promote groups the first group served as a control newer proton pump inhibitor (PPI) provides reliable control of gastric acid secretion with more potent antisecretory activity than that of .The third and fourth groups were pretreated orally 30 minutes prior indomethacin with lansoprazole (10) .In addition to , rabeprazole contains a furoxan moiety (11 , 12 ) that has the omeprazole .In order to study the role of NO ability to release NO and reduces histamine in the protective effect, intraperitoneal L- secretion (1) .In addition , early reports showing that furoxan moiety can mimic some of the minutes before rabeprazole and omeprazole physiological actions of NO (13) . In this study the gastroprotective role of two different PPIs respectively . At the end of each experiment ( 4 h o u r s f o l l o w i n g in d o m e t h a c i n administration) the rats were sacrificed and gastropathy was investigated and their effects were opened along the greater curvature and Methods:
This study was conducted on 72 adult male stomach then quickly divided into two parts albino-Wister rats weighing (200-250 g) , divided into 6 groups, each group carried out with 12 rats per treatment. The study was initiated after seeking approval from the ethical Assessment of gastric mucosal damage:
and scientific committee in the Department of Gastric damage score was calculated by the Pharmacology / College of Medicine /Baghdad
University on April 2010 . Rats were starved for at least 24 hours before indomethacinadministration. During starvation , rats were Biological assays:
kept in cages provided with a wide wire - mesh floor to avoid coprophagy but allowed free each in specific buffer and stored in freeze until evaluation of biological parameters: m e a n s o f g a s t r i c d a m a g e s c o r e , A :prostaglandin E2 assay: The samples
used for assay of PGE2 were kept in sodium phosphate buffer (10 mmol/l ; pH 7.4).At the Scheffe test. All statistical tests were two- tailed with a p value of < 0.05 deemed with scissors, placed in a shaking water bath Results:
Gastric MPO activity
assay : The
indomethacin administration compared with a normal gastric mucosa in control group.
kept in phosphate buffer saline (50 mmol/l ; Indomethacin caused a significant (p< 0.05) tissue was homogenized in 2 ml of PBS (50 indomethacin caused significant suppression (p<0.05) of gastric PGE2 mean (57.92 + then centrifuged at 2000 x g for 5 min. at 4 C.
1.56ng/g) versus (222.08 + 2.92ng/g) in the MPO activity of supernatant was determined control group as shown in figure (2). Also by adding 0.1 ml of the supernatant to 2.9 ml there was significant increased (p<0.05) in of 50 mm phosphate buffer containing 0.167 control group as shown in figure (3 ).
Rabeprazole pretreated group: rabeprazole measured spectrophotometrically. One unit pretreatment caused significant reduction of MPO activity was defined as that which (p< 0.05) of GDS , mean (0.52+ 0.03mm ) would convert 1 Mmol of H2O2 to water in 1 figure ( 1 ) . Gastric PGE2 level was not mean ( 64.17+ 2.2
Statistical analysis:
ng/g) versus (57.92 + 1.56ng/g) in the
using SPSS version 11 (SPSS, Inc, Chicago, figure ( 2 ) .By evaluating the effect of activity mean ( 6.27+ 0.28 u/mg ) compared descriptive statistics. One way ANOVA test was used for comparison between groups of treated group as shown in figure ( 3 ) . When control, indomethacin, rabeprazole with and rabeprazole in order to validate any role of N O ,L-N AM E pr et re at me n t c a us e s significant decrease in the gastroprotective failed to decrease the cytoprotective effect of omeprazole; where it is shown that there pretreated group: Omeprazole pretreatment is no significant effect on GDS as shown in also demonstrate significant gastroprotective cytoprotective action between rabeprazole and omeprazole ; reveals that rabeprazole was more effective in prevent ulcerogenic treated group as shown in figure (1).This effect action of indomethacin , where rabeprazole was correlated with the inability of omeprazole to up regulates gastric PGE2 level mean (
59.58+ 1.44 ng/g ) versus (57.92 + 1.56ng/g)
in the indomethacin treated group as shown in shown in figure (1), and its suppression of MPO activity was significantly greater than that of in omeprazole as shown in figure (3) significant change in gastric MPO activity mean (10.46+ 0.34 u/mg) compared to (35.08+0.83u/mg)) in the indomethacin treated groupas shown in figure (3) .
Fig(1) : The effect of rabeprazole versus omeprazole pretreatment on the gastric
damage score induced by indomethacin. The results are expressed as the mean +
* P < 0.05 when compared with indomethacin group.
†
P < 0.05 when compared with omeprazole pretreated group.
Fig.(2) : The effect of rabeprazole versus omeprazole pretreatment on the gastric PGE2
levels inhibited by indomethacin. The results are expressed as the mean +
Fig.(3) : The effect of rabeprazole versus omeprazole pretreatment on the increased
gastric MPO activity induced by indomethacin .The results are expressed as the mean +
* P < 0.01 when compared with indomethacin group.
† < 0.01 when compared with omeprazole pretreated group.
Fig(4) : The effect of L-NAME pretreatment on the cytoprotective effect of rabeprazole
and omeprazole on the gastric damage score induced by indomethacin . The results are
expressed as the mean +
* P < 0.05 when compared with rabeprazole pretreated group without L-NAME.
Discussion:
significant decrease in the extent of the gastric damage caused by indomethacin.
did not seem to be related to gastric PGs continue NSAIDs use (18) . This therapeutic effect of PPIs is generally attributed to their study were not able to alter the gastric PGE2 level which was significantly suppressed by through inhibition of the gastric H,K-ATPase (19 However ,in this study the significant reduction in the gastric damage score obtained could not inhibition of MPO activity, a specific marker be explained on this bases alone . This is because in present study only one single dose infiltration in tissues and adherence to the vascular endothelium, which are the early events of gastric damage associated with the secretion requires several doses of PPIs (18 .) Moreover the time allowed of PPIs to produce its effects on acid secretion in this study was of the cytoprotective effects of omeprazole relatively short (4.5 hrs) , where more than 5 hrs are needed before any significant increment in the gastric acid PH could be detected (20) omeprazole is similar to that of rabeprazole rabeprazole in this study was significantly 5. Carmelo Scarpignato and Richard H Hunt
omeprazole in their extent of protection the the end or the end of the beginning ?.
gastric mucosa in this experiment could be current opinion in pharmacology .2008 ; 8: moiety that has the ability to release NO , a 6. Brown JF , Keates AC , Hanson PJ ,
mediator that involved in the cytoprotection gastric mucosal cells . Am J Physiol.1993 ; mechanisms of rabeprazole , this is because 7.Full Young Chang , Chih Yen Chen , Ching
significantly decrease the protective effects pretreatment did not seem to decrease the endothelin-1 and nitric oxide activity in gastric damage score and therefore any role Helicobacter Pylori eradication. World be excluded .Another possible explanation is 8. Hallas J , Dall M , Andries A , Andersen BS
these two PPIs, where the bioavailability of Aalykke C , Hansen JM , et al.Use of single multiple dosing , rising from 35% for a first dose to 60% after repeated dosing (23 , 24 ) in contrast bioavailability of rabeprazole does 9. Ma L ,Wallace JL .Endothelial nitric oxide
multiple dosing (19) , this can result in greater synthase modulates gastric ulcer healing in antisecretory effects of rabeprazole during 10. Yuji Mizokami. Efficacy and safety of
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