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Pharmacological Research, Vol. 23, No. 1, 1991

PROTECTION AGAINST GASTRIC ULCER BY VERAPAMIL S. K. SRIVASTAVA, C. NATH?, M. B. GUPTAt, S. VRATt, J. N. SINHA, K. N. DHAWAN and G. E GUPTA*

Department of Pharmacology and Neuropharmacology Unit ( C.D.R.I.)t, King Georgds Medical College, Lucknow 226003, India Received in final form 4 May 1990

SUMMARY

The effect of verapamil, a calcium channel blocker, was studied against stress (cold restraint), aspirin and pylorus ligation induced gastric ulcers in rats. Verapamil inhibited ulcerogenic response and ulcer index in all the three types of ulcers. Verapamil also decreased total and free gastric acidity without changing gastric secretory volume. KzY WORDS:verapamil, gastric ulcer, stress, aspirin, pyloms ligation, gastric acidity.

INTRODUCTION

Gastric ulceration is a commonly encountered clinical problem and occurs due to a disturbance of the delicate balance between hydrochloric acid and mucosal resistance [1]. Alterations in the activity of central nervous system, peripheral neurotransmitters [2] and autacoids as well as several chemical substances can increase H + concentration resulting in ulcer formation [1]. Verapamil, a calcium channel blocker, has been found to inhibit the release of neurotransmitters in brain and gastric H + secretion in vitro [3]. Verapamil has also been found to inhibit gastric effects of stress in rats [4, 5]. To further explore the potentiality of verapamil as a protective agent against gastric ulcer we have evaluated it against gastric ulcer induced by different methods, viz. stress, aspirin and pyloric ligation in rats.

MATERIALS AND METHODS The study was conducted on adult albino rats (120-150 g) of either sex. Pregnancy was excluded. The animals were deprived of food "for 24 h prior to the commencement of the experiment and water was allowed ad libitum. For producing stress induced gastric ulcers, the animals were restrained by tying the hind and forelimbs together and kept for 2 h at 4°C [6]. The animals were sacrificed *To whom all correspondence should be addressed. 1043-6618/91/010081-06/S03.00/0

© 1991 The Italian Pharmacological Society

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immediately after the restraint period. For producing drug induced ulcers, aspirin (150 mg/kg) was administered intraperitoneally (i.p.) as a suspension in gum acacia and the animals were sacrificed 5 h after the aspirin treatment [7]. Pylorus ligation was carried out in rats according to the technique of Shay et al. [8]. The rats were sacrificed 6 h after pylorus ligation. The gastric juice was collected and centrifuged. Free and total acidity were estimated titrimetrically with 0.01 y NaOH using Toepfer's reagent and phenolphthalein as indicators. In all the animals the stomach was removed and examined under dissecting microscope for gastric lesions. The gastric lesions were scored as (1) shedding of epithelium = 10; (2) petechial and/or frank haemorrhage = 20; (3) one or two ulcers = 30; (4) multiple ulcers = 40 and (5) perforated ulcers = 50 [9]. The presence of any of these lesions was considered as a positive ulcerogenic response and has been expressed as percentage of rats showing gastric lesions. The severity of ulceration was expressed in terms of ulcer index which was the mean score of all the rats in a group. Verapamil was administered i.p. 30 min prior to restraint, aspirin injection or pylorus ligation in the test groups while control groups received identical volume of normal saline. The data concerning the acid secretions of gastric juice were analysed by Student t-test whereas the chi squared test was used for the data related to gastric ulceration. Drugs used were verapamil hydrochloride (Boehringer-Knoll) and aspirin (Boots). RESULTS In rats subjected to cold restraint, ulcerogenic response was 90% in the control group whereas in animals treated with 10, 20 and 40 mg/kg i.p. verapamil, the response was 80%, 30% and 20% respectively. The ulcer indices in this series were 30 in control group and 19, 6 and 4 respectively in verapamil treated groups (Table

I). The ulcerogenic response produced by aspirin was 90% in the control group and 60%, 40% and 30% in the 10, 20 and 40 mg/kg i.p. verapamil pretreated groups respectively. The ulcer indices in this series were 30 in the control group and 20, 12 and 6 in the respective verapamil treated groups (Table I). In pyloric ligation induced gastric ulcer, pretreatment with verapamil (40 mg/kg i.p.) lowered significantly ulcerogenic response (30%) and ulcer index (7) as compared to control (ulcer response 100% and index 27.5) (Table II). In the same experimental set-up the total and free acidity in verapamil treated rats were 255.0_+89.8 and 242.5 _+40 rnEq/1 respectively. These values are significantly less than control ones. There was no change in gastric acid secretory volume in control and verapamil treated rats (Table II).

DISCUSSION It is evident from the results that verapamil significantly decreases the incidence (per cent ulcerogenic response) and severity (ulcer index) of ulcers induced by stress, aspirin or pyloric ligation. It is almost equieffective in all three models.

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It is well known that both the neurogenic influences and local gastric factors play an important role in gastric ulcerogenesis. Verapamil has been found to interfere with both the factors. It inhibits in vitro release of catecholamines and acetylcholine from brain preparations [3] and activation of these neurotransmitter systems at the central and peripheral sites is facilitatory to stress ulcers [9] as well as to aspirin ulcers [7]. Excessive acid secretion from parietal cell is one of the most important local gastric factors in ulcerogenesis. Kirkegaard et al. [10] have reported the inhibitory effect of verapamil on acid secretion evoked by histamine or gastrin in guinea-pig isolated gastric fundic mucosa. Verapamil has also been reported to suppress carbachol induced acid secretion in rabbit isolated gastric glands [11]. Im et al. [12] reported that verapamil inhibits the parietal cell proton pump (H + + K +) ATPase by competing with K +. In the present study verapamil decreased total and free acidity without affecting gastric secretory volume. In view of these observations, the protective effects of verapamil against gastric ulcer can be ascribed to the suppression of neurotransmitter systems (adrenergic and cholinergic) and/or gastric acidity. In conclusion, this study has revealed the protective activity of verapamil against gastric ulcer. Verapamil has also been found to be effective in inhibiting the gastrin induced acid secretion in healthy human subjects [10]: Therefore verapamil may be worth evaluating clinically in gastric ulcers.

ACKNOWLEDGEMENT The authors are grateful to Mr D. N. Bhalla for his technical assistance.

REFERENCES 1. McGuigan JE. Peptic ulcer. In: Braunwald E, Isselbacher KJ, Petersdoff RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison principles of internal medicine. Hamburg: McGraw Hill Company GmbH, 1987: 1239-53. 2. Bhargava KP, Gupta GP, Gupta MB. Central neurotransmitter and stress ulcerogenesis. In: Dhawan BN, Agarwal KK, Arora RB, Parmar SS, eds. Pharmacology for health in Asia. New Delhi: Allied Publishers Pvt Ltd, 1980: 179-91. 3. Godfraind T, Miller R, Wibo M. Calcium antagonism and calcium entry blockade. PharmacolRev 1986; 38: 321-416. 4. Ogle CW, Cho Men Chi H, Tang C, Koo Marcel WL. The influence of verapamil on gastric effects of stress in rats. EurJPharmaco11985; 112: 399-404. 5. Glavin B. Calcium channel modulators: effects on gastric function. Eur J Pharmacol 1989; 160: 323-30. 6. Senay EC, Lavine RJ. Synergism between cold and restraint for rapid production of stress ulcers in rats. Proc Soc Exp Biol Med 1967; 124: 1221-3. 7. Dass M, Gupta MB, Gupta GP, Bhargava KE Biogenic amines in the pathogenesis of gastric ulceration induced by aspirin in rats. Ind J Med Res 1977; 62: 273-8. 8. Shay H, Kamarow SA, Fele SS, Meranze D, Gruenstein H, Siplet H. A simple method for uniform production of gastric ulceration in rats. Gastroenterology 1945; 5: 43-5. 9. Bhargava KP, Dass M, Gupta GP, Gupta MB. Study of central neurotransmitters in stress induced gastric ulceration in albino rats. Br J Pharmaco11980; 68: 769-72. 10. Kirkegaard P, Christiansen J, Petersen B, Skovolesan P. Calcium and stimulus-secretion

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coupling in gastric fundic mucosa. Effect of inhibition of calcium transport by verapamil on gastric acid secretion in the isolated guinea pig fundic mucosa and in healthy subjects. ScandJ Gastroentero11982; 17: 533-8. 11. Chew CS. Differential effects of extra-cellular calcium removal and nonspecific effects of Ca + + antagonists on acid secretory activity in isolated gastric glands. Biochim Biophys Acta 1985; 846: 370-8. 12. Im WB, Blackeman DP, Mendalin J, Sachs G. Inhibition of H *, K + ATPase and H + accumulation in dog gastric membranes by trifluoperazine, verapamil and 8-(N,Ndiethylamino)acetyl-3,4,5-methoxybenzoate. Biochim BiophysActa 1984; 770: 65-72.

Protection against gastric ulcer by verapamil.

The effect of verapamil, a calcium channel blocker, was studied against stress (cold restraint), aspirin and pylorus ligation induced gastric ulcers i...
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