|Year : 2012 | Volume
| Issue : 3 | Page : 387-389
Evaluation of anti-ulcer effect of amlodipine in gastric ulcer models in rats
Amol N Patil, Manjari G Advani, SN Mali, Sudhir Pawar, Sanket B Raut
Department of Pharmacology, L.T.M. Medical College, and L.T.M.G. Hospital, Sion, Mumbai, India
|Date of Submission||06-Aug-2011|
|Date of Decision||26-Dec-2011|
|Date of Acceptance||28-Feb-2012|
|Date of Web Publication||17-May-2012|
Amol N Patil
Department of Pharmacology, L.T.M. Medical College, and L.T.M.G. Hospital, Sion, Mumbai
Aims: To study anti-ulcer effect of Amlodipine and compared it with ranitidine in indomethacin, alcohol and pyloric ligation-induced gastric ulcers in wistar rats.
Materials and Methods: Gastric ulcers were induced in Wistar albino rats by oral administration of indomethacin (200 mg/kg), alcohol (80%, 1 ml/100 gm) and by pyloric ligation. Antiulcer activity of amlodipine (0.5 mg/kg, i.p.) was observed either alone or in combination with ranitidine (15 mg/kg, i.p.), on ulcer index, gastric pH and gastric volume. Statistical analysis was done by ANOVA and unpaired one tailed 't ' test. P<0.05 was considered statistically significant.
Results: Amlodipine produced significant (P<0.05) decrease in ulcer index and gastric pH as compared to control. It also produced significant (P<0.05) increase in gastric volume as compared to ranitidine. The anti-ulcer effects of ranitidine were significantly higher than that of amlodipine. Combination of amlodipine and ranitidine did not show significant increase in anti-ulcer activity as compared with ranitidine alone.
Conclusions: Amlodipine produced significant anti-ulcer effects in all 3 experimental models. Amlodipine increased the volume of gastric secretions as compared to ranitidine.
Keywords: Amlodipine, ranitidine, ulcer index
|How to cite this article:|
Patil AN, Advani MG, Mali S N, Pawar S, Raut SB. Evaluation of anti-ulcer effect of amlodipine in gastric ulcer models in rats. Indian J Pharmacol 2012;44:387-9
|How to cite this URL:|
Patil AN, Advani MG, Mali S N, Pawar S, Raut SB. Evaluation of anti-ulcer effect of amlodipine in gastric ulcer models in rats. Indian J Pharmacol [serial online] 2012 [cited 2013 Jun 18];44:387-9. Available from: http://www.ijp-online.com/text.asp?2012/44/3/387/96344
| » Introduction|| |
It has been estimated that 50% of healthy individuals experience heartburns on a daily basis.  The major causes of peptic ulcer disease are - stress, chronic use of non-steroidal anti-inflammatory drugs (NSAID S ), alcohol, cigarette smoking, genetic predisposition, diet, and Helicobacter pylori on.  Amongst the most frequently implicated associations are NSAIDs, alcohol and stress. 
Calcium influx plays an important role in stimulation-secretion coupling in mammalian oxyntic cells, an effect that can possibly be inhibited by calcium channel blockers. Moreover, calcium channel blockers exert an inhibitory effect on histamine, gastrin, carbachol and cyclic-AMP induced stimulation of gastric acid secretion. Hence, it is possible that calcium channel blockers may have a protective effect against gastric ulcers. 
The anti-ulcer effects of calcium channel blockers, viz., verapamil, nifedipine and diltiazem have been reported. , All these drugs have been reported to potentiate the anti-ulcer and anti-secretory effects of famotidine at low doses. Amlodipine is currently one of the most widely prescribed calcium channel blocker (CCB) for various cardiovascular disorders. A recent study reported that amlodipine demonstrated a significant anti-ulcer effect when used in combination with omeprazole and famotidine in pyloric ligated rats.  However, for a multi-etiological disease like peptic ulcer, further study on the different models would be necessary to establish its anti-ulcer activity.
Hence, the present study was undertaken to evaluate the anti-ulcer effect of amlodipine and compare it with ranitidine in alcohol and indomethacin-induced gastric ulcers in rats, in addition to the pyloric ligation model. It was also decided to observe an interaction between amlodipine and ranitidine in these animal models.
| » Materials and Methods|| |
The study was conducted after obtaining permission from the Institutional Animal Ethics Committee.
Fresh solution of amlodipine (TAKA Pharmaceuticals Ltd.) in 0.01% DMSO solvent and indomethacin (National Pharmaceuticals) in distilled water were prepared daily.
Ranitidine ampoules (Daffodills Pharma Ltd.), ethanol 80% and DMSO solvent (Rajesh Chemicals) were the other drugs used. Ether was obtained from hospital supply.
72 Wistar rats of either sex weighing between 150 g - 250 g were used for the study. Prior to the experiments, the rats were kept in the central animal house in rat cages and were given standard rat feed with water ad libitum. Cages were fitted with wire mesh floor to avoid coprophagy.
Rats were divided into 3 groups of 24 each, for ethanol, indomethacin and pyloric ligation-induced gastric ulcers. Each group was further divided into 4 subgroups ensuring at least 2 female rats in each group.
Group I: Control (0.5 ml DMSO solvent intra-peritoneally)
Group II: Amlodipine (0.5 mg/kg intra-peritoneally in 0.01% DMSO solvent)
Group III: Amlodipine (0.5 mg/kg intra-peritoneally in 0.01% DMSO solvent) + Ranitidine (15 mg/kg intra-peritoneally)
Group IV: Ranitidine (15 mg/kg intra-peritoneally)
Rats were kept fasting for 24 hours for alcohol, indomethacin-induced ulcers and 36 hours for pyloric ligation-induced ulcer. The rats were sacrificed by cervical dislocation 1, 6 and 19 hours after alcohol, indomethacin administration and pyloric ligation, respectively. The abdomen was dissected to retrieve stomach, analyzed for volume of gastric secretion, pH and ulcer index.
Alcohol-induced gastric ulcer: The study medications were administered 1 hour prior to induction of ulcer with ethanol (80%, 1 ml/100 gm) orally. 
Indomethacin-induced gastric ulcer: The study medications were administered 1 hour prior to giving indomethacin (20 mg/ kg was administered in distilled water solution by gavage feeding). 
Pylorus ligation-induced gastric ulcer: Under inhalational ether anesthesia, the abdomen was opened by a small midline incision below the xiphoid process. The pyloric portion of the stomach was identified, slightly lifted out and ligated, avoiding traction to the pylorus or damage to the blood supply. The stomach was then replaced carefully, and the abdominal wall closed by interrupted sutures. Amlodipine was given 4 hour prior, and ranitidine, normal saline were given 1 hour prior the ligation procedure to obtain best results.  Animals were deprived of both food and water during the postoperative period. 
Gastric mucosal injury was assessed by Volume of Gastric secretion (in ml), pH of gastric secretion and ulcer index (UI). Ulcer index was calculated by following formula 
With small nick, fundus of stomach was perforated on greater curvature of stomach. After ligation of cardiac and pyloric end, the greater curvature of stomach was opened. The accumulated gastric secretion fluid was collected, and volume and pH was measured. Gastric mucosa was observed under magnifying glass to calculate the ulcer index. 
All the data are expressed as mean ± standard error of mean. One-way ANOVA test [SPSS Version no. 15] unpaired one tailed 't' test was also used considering P<0.05 to be statistically significant.
| » Results|| |
Amlodipine (0.5 mg/kg) produced significant (P<0.01) increase in the gastric pH as compared to the control in all 3 models of gastric ulcer. A significant (P<0.05) reduction in ulcer index was also observed in indomethacin and pylorus ligation-induced ulcers. However, these effects were less than as compared to ranitidine. Ranitidine significantly (P<0.05) increased the gastric pH and decreased the gastric volume secretion and ulcer index in all the 3 models. A significant (P<0.05) increase in the volume of gastric secretion was observed in amlodipine-treated rats as compared to ranitidine groups [Table 1].
|Table 1: Effects of amlodipine, ranitidine and amlodipine + Ranitidine on gastric pH, volume of gastric secretion and ulcer index in alcohol, indomethacin and pylorus ligation induced gastric ulcers in rats (N = 6)|
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| » Discussion|| |
Peptic ulcer disease results from imbalance between aggressive factors and the maintenance of the mucosal integrity through endogenous defense mechanism.  CCBs have demonstrated not only reduction in gastric acid secretion but also increasing mucus production and rise in the TC/ PR ratio (TC=total carbohydrate content of gastric juice, PR=total protein content of gastric juice), thus boosting the mucosal defense mechanisms.  They have also demonstrated additional actions like inhibition of mast-cell degranulation  and up-regulation of the nitric oxide (NO) system, which further provides protection to gastric mucosa. 
Hypertension and peptic ulcer disease can often co-exist in adult population particularly, 4 th decade onwards as both are aggravated by stress, diet and personality type. , There is high probability that a patient of hypertension may be receiving concomitant treatment for peptic ulcer disease.  In such situations, amlodipine could prove to be a suitable antihypertensive and ulcer protective agent. In our study, we selected lowest effective dose of 0.5 mg/kg in all the 3 gastric ulcer models. Ranitidine is one of the safest, efficacious and cheaper antiulcer agents, which is an ideal active comparator to study the ulceroprotective effect of an experimental drug.  The 3 ulcer models selected by us represent the most common etiologies of peptic ulcers, i.e. drugs, stress and alcohol. 
The results of this study shows that amlodipine in dose of 0.5 mg/kg demonstrates anti-ulcer action in different etiologies of peptic ulcers. Similar observations were reported by Kilic et al.,  with verapamil in ethanol-induced gastric ulcer model and Jain et al.,  with verapamil and diltiazem. One previous study has demonstrated ulcer protective efficacy of amlodipine in doses 0.5 mg/kg and 1 mg/kg in pylorus ligation model in rats.  Such similar studies have been conducted on nifedipine,  verapamil,  and other CCBs in past and have demonstrated ulcer protective action. Bhave et al., showed significant dose-dependent decrease in ulcer index and rise in pH with amlodipine (0.5 mg/kg and 1 mg/ kg).  They also reported a decrease in volume of gastric secretion with amlodipine, which is contrary to our findings. In our study, amlodipine showed significant increase in the volume of gastric secretion as compared to ranitidine in all the 3 experimental models. Previous studies, like Kilic et al., found dose-dependent increase in gastric mucus quantity with an increasing concentration of verapamil in alcohol-induced ulcers. 
We directly compared the anti-ulcer effect of amlodipine with ranitidine and observed that though the effect of amlodipine on gastric pH was less than ranitidine, there was no significant difference in the values of ulcer index. Highest anti-ulcer action of amlodipine was demonstrated with 1 mg/kg dose when studied previously by Bhave et al. in pylorus ligation model.  However, since this study also included other models, we selected the low dose of 0.5 mg/kg to see if the least effective dose could produce desired anti-ulcer effect.
In this study, we also evaluated the combination of amlodipine and ranitidine for its anti-ulcer action and observed that although the difference was not statistically significant, there was a minor improvement in the parameters studied. Potentiation of anti-ulcer effect has been demonstrated in studies by Bhave et al., and Mandal et al. when they studied combination of CCBs and anti-ulcer drugs. ,
Thus, the present study demonstrates the ulceroprotective effects of amlodipine in 3 different experimental models in rats. A rise in the volume of gastric secretion and pH is observed, which can be due to an increase in mucus, bicarbonate ions or by secretion other than hydrochloric acid. This could either be a direct action of amlodipine or by increase in gastric mucosal blood flow.  It would be interesting to study the patients on amlodipine therapy and observe if they are less prone to develop peptic ulcers.
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