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November 1990, Volume 40, Issue 11

Original Article

A COMPARATIVE STUDY OF THE EFFECTS OF VERAPAMIL AND CIMETIDINE ON ISOLATED RAT STOMACH STRIP

Talat Ahmed Nishat  ( Department of Pharmacology, Rawalpindi Medical College, Rawalpindi. )

ABSTRACT

Effects of verapamil and cimetidine were studied on smooth muscle of rat stomach by using an isolated fundus strip preparation. Verapamil 0.5 ug/ml significantly (P< 0.001) reduced acetylchollne (Ach) induced contractions of rat stomach fundus strip. The inhibition was very prolong and dose dependent. On the other hand cimetidine 60 ug/mI significantly (P c 0.00 1) potentiated the Ach-induced contractions, potentiation was dose related. The spontaneous contractions of stomach strip were completely abolished by 8 ug/mI verapamil, whereas 1000ug/ml cimetidine had no effect. It was concluded that verapamil given for cardiovascular disorders would also supplement relief of pain from peptic ulcer and might prevent stress ulcer formation (JPMA 40 : 263 , 1990).

INTRODUCTION

In the stomach, motility and acid secretion have been shown to be dependent to some extent on calcium ions and are likely to be modified by calcium channel blockers.1 Verapamil inhibits motility in rat isolatedcolonby acting on calcium channels in the smooth muscle cell membrane2. Gastrointestinal smooth muscle contains both his­tamine Hi and H2 receptors. Stimulation of Hi receptors leads to contraction and stimulation of H2 receptors to relaxation of gastrointestinal smooth muscle cells. His­tamine3 H2 blockers may constitute molecular dependent side effects of gastrointestinal tract4. If calcium channel blockers are proved to be effective in reducing peptic ulceration, the undesirable effects of histamine H2 antagonists may be avoided. The effects of stress which are exerted mostly on cardiovascular5 and gastrointestinal systems6 may also be ameliorated with drugs like calcium antagonists which have proved very useful for most of cardiovascular disorders. 7 Verapamil and nifedipine were shown to inhibit gastric acidity in conscious rats8. ­Present study was undertaken to compare the effects of verapamil and cimetidine on smooth muscle of rat stomach.

MATERIALS AND METHODS

A fundus strip of rat stomach 3-4 cms in length was mounted in an organ bath containing physiological solu­don, aerated with 100% oxygen flowing at moderate speed with the temperature maintained at 37°C. The composition of solution in mM/L was : Na C1 (110) ; NaHCO3 (24); KC1 (5.0); Na2 HPO4 7H20 (1.1); CaCl2 (2.2); Mg SO4 (1.2) and glucose (5 5) 9,10. One end of strip was attached to 02 delivery tube and other to a simple heavy lever writing sideways with ink on a kymograph. An initial resting tension of  was applied to each muscle strip and the tissues were allowed to equi­librate for 30 min. 11 In response to the administration of acetylcholine, intensity of each contraction was recorded on kymograph and its amplitude was measured in mil­limeters. Ach 8 ug/ml, producing submaximal response, was used to test the sensitivity of tissue to verapamil and cimetidine. After instillation of verapamil the tissue recove­red slowly, therefore a long duration time cycle of 30 minutes was followed. When antagonist was used it was allowed to act for 5 minutes before the addition of agonist. Effects of verapamil and cimetidine on Ach induced contractions were studied at 3 and 4 dose levels respective­ly.Effects of verapamil (8ug/ml) and cimetidine (1000 ug/ml) on spontaneous contractions of rat stomach strip were also observed. A short duration time cycle of 4 mm. was followed. The drugs were allowed to°act for 3 mm. before taking the record of tracings on kymograph.
Statistical analysis
Seven samples of size six each were taken as a self-control to see the effects of three doses of verapamil and four doses of cimetidine. The mean difference before and after the treatment in self-control group were tested using the paired students \'t\' test for correlated means. The ED50 i.e., medium effective dose (concentration/mi producing 50% change in anjplitude of Ach induced response) was calculated from a graph plotted by taking log doses as independent variable and mean percent change as dependent variable.

RESULTS

(a) Induced contractions
When allowed to act for 5 minutes verapamil in concentrations of 0.5,2 and 8ygfml significantly (P <0.001) reduced the Ach (8 ug/ml)-induced contractions (Figure 1).

The intensity of inhibition was concentration dependent (Table 1 and Figure 2).


Recovery from inhibition was only with very low concentrations. In concentrations producing significant inhibition (P <0.001) recovery was very slow and usually incomplete. Cimetidine in 60,125,500 and 1000 ug/ml concentra­tion significantly (P <0.001) potentiated Ach (8 ug/ml) induced contractions (Figure 3).

Intensity of potentiation was concentration related (Table II and Figure 2).

Recovery was moderately slow but complete. The ED50 of verapamil was about 40 times lower than that of cimetidine. Dose response curve had shown that both drugs will produce ceiling effect with increase in dose (Figure 4).


(b) Spontaneous contractions
Verapamil (8 ug/ml) completely abolished the spon­taneous contractions of stomach strip. Cimetidine (1000 ug/ml) had no effect.

DISCUSSION

Increase in gastric motility during stress appears to cause ulcers in stressed pylorus occluded rats12. . In the present work verapamil inhibited acetylcholine induced contractions of rat stomach in a dose dependent manner. In the past verapamil was shown to prevent acetylcholine induced contractions in guinea pig stomach strip. 13 In another study it prevented stress produced increase in gastric motility in a dose dependent manner in intact rats. 14 Presently 1.76 x 10-4 mol/L verapamil completely abolished the spontaneous contractions of isolated fundus strip of rat stomach. Other investigators found that verapamil 10-3 mol/L entirely inhibited isolated toad gastric muscle con­tractions. 15 Cimetidine 1 mgfml had no effect on spontaneous contractions of rat stomach strip. Previously 0.3mg cimetidine in 50ml bath was shown to have no effect on spontaneous contractions of rat stomach tissue9. Cime­tidine 9.3 x 10-4 mol/L produced 50% potentiation (EDso) of Ach induced contractions in isolated stomach strip (P <0.001). Previously 1.2 x io-4 mol/L and 4.0 x 10-4mol/L cimetidine had no significant effect on histamine or bethanechol induced contractions of guinea pig isolated ileum. Recently one case of stomach and three cases of esophagus have been reported showing stimulatory res­ponse to cimetidine in human. Present work has shown that cimetidine had no effect on spontaneous contractions but potentiates Ach induced contractions. Verapamil inhibits spontaneous as well as acetylcholine induced contractions of rat stomach strip. A physical rubbing of the gastric mucosa after its vitality has been reduced by stress may trigger the formation of stress ulcers in intact rats. 17 Therefore, it is likely that verapamil used for cardiovascular disorderswould also have addition­al benefit of preventing stress ulcer formation.

ACKNOWLEDGEMENT

This work was supported by a grant from Post­graduate Medical Institute, Lahore.

REFERENCES

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