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Abstract
Wilkes JM, Scott DR. Hersey SJ. Sachs G. Second messengers in the gastric gland: a focus on calcium. Scand J Gastroenterol 1991, 26(suppl 180), 70–84
The rabbit gastric gland model was used to study the nature of the muscarinic cholinergic and gastrin responses of parietal cells. Carbachol (100 μM) stimulation of acid secretion, as measured by the accumulation of aminopyrine. was inhibited hy the M1 antagonist pirenzepine with an IC50 of 13 μM: by the M2 antagonist 11.2–(diethylamino)methyl-l-piperidinyl acetyl-5,11-dihydro-6H-pyrido 2.343 1,4–benzo-diazepin-6–one (AF-DX 116) with an IC50 of 110μM: and by the M3 antagonist diphenylacetoxy-4–methylpiperidinemethiodide (4–DAMP) with an IC50 of 35 nM. The three antagonists displayed similar lC50 values for the inhibition of carbachol-stimulated production of 14CO2 from radiolabeled glucose. which is a measure of the turnover of the H–K–ATPase. Intracellular calcium levels were measured in gastric glands loaded with FURA2. Carbachol was shown both to release calcium from an intracellular pool and to promote calcium entry across the plasma membrane. The calcium entry was inhibitablc by 20 μM La34. The relative potency of the three muscarinic antagonists for inhibition of calcium entry was essentially the same as for inhibition of acid secretion or metabolism. However, the rise in cell calcium due to release of calcium from intracellular stores was inhibited by 4–DAMP with an IC50 of 1.7 nM. Image analysis confirmed that the effect of carbachol and of the antagonists on intracellular calcium was occurring in the parietal cell. In particular. the high-affinity inhibition of calcium release by 4–DAMP occurs in the parietal cell. Accordingly, it appears that the secretory receptor of the parietal cell is of the M3 type. and acid secretion depends on the entry of calcium rather than on calcium release from intracellular stores. In parallel experiments gastrin (G-17–sulfated) produced a dose-dependent increase in intracellular calcium (EC50. 0.14 ± 0.013 μM). No stimulation of acid secretion was observed. but pepsinogen secretion was stimulated dose-dependently (EC50 = 1.17 ± 0.21 μM).