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Effects of verapamil on gastric acid secretion in vitro and in vivo
1Department of Pharmacology, Hoechst AG, Frankfurt, F.R.G.
Abstract:
The activity of H,K-ATPase, the gastric acid producing enzyme, was concentration dependently inhibited by verapamil in the mM range. Verapamil concentration dependently inhibited acid formation in gastric glands, measured as [14C]aminopyrine accumulation or oxygen consumption. The IC50 values were in the microM range. No inhibition of acid secretion by verapamil was observed in Heidenhain-pouch dogs and stomach-lumen-perfused rats. However, in pylorus-ligated rats an inhibition was observed, this effect is related to its cardiovascular effectiveness. To understand the action of verapamil, its physicochemical properties were considered. Verapamil is a highly lipophilic base with a pKa of 8.7. It accumulates in membranes and in the acidic spaces of the parietal cell. We suggest that the inhibition of vesicular bound H,K-ATPase is dependent on a non-specific accumulation of verapamil in the membrane (detergent effect) and that inhibition of acid production in vitro is due to an additional accumulation of the drug in acidic compartments, leading to an impaired function of the proton pump. Verapamil does not decrease acid secretion in vivo by this mechanism as the required dose would be higher than the dose that causes a strong depression of the cardiovascular system.
Insights
Verapamil inhibits gastric acid production in vitro by affecting the H,K-ATPase proton pump. In vivo, this effect is limited due to cardiovascular side effects at higher doses.
Area of Science:
- Pharmacology
- Gastroenterology
- Cell Biology
Background:
- H,K-ATPase is the primary enzyme responsible for gastric acid production.
- Verapamil, a known cardiovascular drug, was investigated for its effects on gastric acid secretion.
Purpose of the Study:
- To investigate the inhibitory effects of verapamil on gastric acid production.
- To elucidate the mechanism of action of verapamil on the H,K-ATPase enzyme.
Main Methods:
- In vitro studies using gastric glands and H,K-ATPase activity assays.
- Measurement of [14C]aminopyrine accumulation and oxygen consumption.
- In vivo studies in Heidenhain-pouch dogs and pylorus-ligated rats.
Main Results:
- Verapamil inhibited H,K-ATPase activity and acid formation in gastric glands in vitro (IC50 in microM range).
- No significant inhibition of gastric acid secretion was observed in Heidenhain-pouch dogs and stomach-lumen-perfused rats in vivo.
- Inhibition was observed in pylorus-ligated rats, likely linked to cardiovascular effects.
Conclusions:
- Verapamil's in vitro inhibition of gastric acid production is attributed to its lipophilicity and accumulation in parietal cell membranes and acidic compartments, affecting proton pump function.
- The mechanism of inhibition in vivo is limited because effective doses would exceed cardiovascular safety limits.