GLP-1-(7-36) amide, -(1-37), and -(1-36) amide: Potent cAMP-dependent stimuli of rat parietal cell function

We investigated the effect of glucagon-like peptide 1 (GLP-1)-(7-36) amide and its molecular variants GLP-1-(1-37) and GLP-1-(1-36) amide on enzymatically dispersed enriched rat parietal cells using [¹⁴C]aminopyrine accumulation as a measure of H⁺ production. GLP-1-(7-36) amide was 100 times more potent than GLP-1-(1-37) and GLP-1-(1-36) amide in stimulating [¹⁴C]aminopyrine accumulation. At their maximally effective concentrations, GLP-1-(7-36) amide (10^-8 M), GLP-1-(1-37) (10^-6 M), and GLP-1-(1-36) amide (10^-6 M) reached 80-90% of the response to 10^-4 M histamine. However, the peptides were 100-10,000 times more potent than histamine, which induced maximal [¹⁴C]aminopyrine accumulation at 10^-4 M. Stimulation by GLP-1 was dependent on the presence of a phosphodiesterase inhibitor and was not altered by pertussis toxin. Ranitidine failed to affect the response to the GLP-1 variants. Stimulation of H⁺ production by GLP-1 was accompanied by an increase in the formation of adenosine 3',5'-cyclic monophosphate (cAMP) but not by changes in phosphoinositol breakdown. In stimulating [¹⁴C]aminopyrine accumulation, the GLP-1 variants acted additively to threshold but not to maximal concentrations of histamine, suggesting that histamine and GLP-1 activate the same cAMP pool. In contrast, in anesthetized rats GLP-1-(7-36) amide (10-500 ng·kg^-1·h^-1) had no effect on basal and pentagastrin-stimulated acid secretion in vivo. We conclude that GLP-1 exerts a direct stimulatory effect on rat parietal cells. This potent effect is mediated by cAMP and is independent of H₂ receptors. In vivo direct stimulation by GLP-1 of the parietal cells might be counterbalanced by indirect inhibitory mechanisms that are excluded in the in vitro cell system.