Proton pump inhibition--the ultimate control of acid secretion?
The cellular mechanisms of acid secretion by the parietal cell (PC) include stimulation of membrane receptors, increases in cytosolic cyclic AMP levels, and activation of protein kinase systems. These events culminate in stimulation of a membrane-based proton pump. This consists of a non-electrogenic H+-K+-ATPase which transports H+ ions into the secretory canaliculus of the PC in exchange for the cation K+. It has been proposed that blockade of this proton pump would result in inhibition of acid secretion by all classes of acid secretagogues. Thus, the effects of membrane receptor agonists as well as any agents which augment cellular cAMP levels should be inhibited. Substituted benzimidazoles are weak bases which prevent acid secretion by blocking the H+-K+-ATPase system. In order to test the above hypothesis, we investigated the effects of the substituted benzimidazole H168/68 and cimetidine (C) on histamine (H) and 8B-stimulated acid secretion. The rabbit isolated gastric gland (IGG) model was used and acid secretion assessed by the accumulation of 14C-labeled weak base aminopyrine (AP) within the IGG in response to secretagogue stimulation. H168/68 and C both inhibited H (5 X 10(-5) M)-stimulated [14C]AP accumulation in a concentration-dependent manner (P less than 0.05). H168/68 inhibited both H- and 8B-stimulated [14C]AP accumulation (P less than 0.05), while C inhibited only H-stimulated [14C]AP accumulation (P less than 0.05). H168/68 suppressed [14C]AP below even unstimulated levels of [14C]AP accumulation. These results support the hypothesis that H168/68 inhibits the PC distal to cAMP stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Zdon
M J
MJ
Ballantyne
G H
GH
Schafer
D E
DE
Tyshkov
M
M
Cambria
R P
RP
Modlin
I M
IM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D009853:Omeprazole; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000378:metabolism; D011522:Protons; D011817:Rabbits
D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D007473:Ion Channels; D011522:Protons; D000632:Aminopyrine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D002927:Cimetidine; D006632:Histamine; D009853:Omeprazole