Interaction of calcium channel antagonists with parietal cell acid production, adenylate cyclase, intracellular-free Ca2+ and H+/K+-ATPase.
The calcium channel antagonists verapamil, gallopamil and nifedipine were tested for their effects on acid secretion stimulated by histamine and dibutyryl-cyclic AMP in isolated and enriched guinea pig parietal cells, on adenylate cyclase activity mediated by histamine H2 receptors, on histamine-stimulated increase in cytosolic-free Ca2+ concentration [Ca2+], on gastric H+/K(+)-ATPase activity and on H+/K(+)-ATPase-mediated proton uptake in intact gastric membrane vesicles. Verapamil and gallopamil impaired all cellular and enzymatic test systems studied. Both drugs affected with highest potency the acid secretion in the parietal cell preparation (IC50: 1-2 mumol/l) and the H+/K(+)-ATPase-mediated H+ uptake in gastric membrane vesicles, whereas their inhibitory action was less pronounced on adenylate cyclase and on histamine-induced increase in cytosolic-free [Ca2+]. The type of interaction found in the gastric membrane vesicle preparation indicates that both drugs act as protonophores. Nifedipine was less effective as an inhibitor of acid secretion in the parietal cell preparation and in reducing proton concentration in isolated gastric membrane vesicles. The drug failed to block adenylate cyclase and H+/K+-ATPase activity. Since nifedipine is a more effective calcium channel blocking agent but a less lipophilic drug than verapamil and gallopamil, we conclude that the antisecretory activity of calcium channel antagonists in vitro is mediated by a nonspecific, i.e. a protonophoric, action. We suggest that verapamil exhibits its antisecretory activity in vivo partially by its protonophoric action at the secretory membrane of the parietal cell, whereas the decrease in acid secretion by nifedipine is not mediated by this mechanism.
Beil
W
W
Abteilung Allgemeine Pharmakologie, Medizinische Hochschule Hannover, BRD.
Bersimbaev
R J
RJ
Hannemann
H
H
Sewing
K F
KF
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D005711:Gallopamil / Q000494:pharmacology; D006168:Guinea Pigs; D017506:H(+)-K(+)-Exchanging ATPase; D006632:Histamine / Q000494:pharmacology; D006851:Hydrochloric Acid / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000201:enzymology*; D011522:Protons; D013270:Stomach / Q000648:ultrastructure; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D011522:Protons; D005711:Gallopamil; D006632:Histamine; D002217:Carbachol; D014700:Verapamil; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D000262:Adenylyl Cyclases; D009543:Nifedipine; D006851:Hydrochloric Acid; D002118:Calcium