Abstract

The mechanism of gastric antisecretory action for trifluoperazine, verapamil and 8-(N,N- diethylamino)octyl-3,4,5- trimethoxybenzoate (TMB-8) has been studied utilizing isolated hog gastric membranes enriched with ( H + + K +)- ATPase . The drugs inhibited the gastric ATPase due to their apparent competition with K + for the luminal high-affinity K +-site of the ATPase. The dose to inhibit 50% (ID 50) of the ATPase in the membranes rendered freely permeable to K + (20mM) was 50 μM for trifluoperazine and 1.5 mM for verapamil and TMB-8. In intact hog gastric membranes which develop a pH gradient in the presence of valinomycin, ATP and KCl, however, trifuoperazine at 4 μM, verapamil and TMB-8 at 15 μM inhibited 40 and 30% of the valinomycin-stimulated ATPase activity, respectively, and also blocked the ionophore-dependent intravesicular acidification as measured by aminopyrine accumulation. The enhanced potency of the drugs to inhibit the ATPase in the intact membrane vesicles may be attributed to the accumulation of the drugs as a weak base within the vesicles, where the luminal K +-site of the ATPase is accessible. Calmodulin and Ca 2+ had no effect on the extent of H +-accumulation as measured by aminopyrine accumulation in the membrane vesicles which were prepared in the presence of 1 mM EGTA. Since the drugs showed similar potency in interfering with H + movements either in the membrane vesicles or isolated rabbit gastric glands stimulated by dibutylryl cAMP, it is reasonable to suggest the inhibitory effect of the drugs on ( H + + K +)- ATPase as a primary cause for such interferences in both cases. A trifluoperazine analog and other lipophilic amine drugs similarly inhibited ( H + + K +- ATPase and H + accumulation in the membrane vesicles or in the glands. We have concluded that a tertiary amine, the only common functional group among these drugs, is primarily responsible for their ability to interact with the high-affinity K + site of the gastric ATPase.

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.