“Gastrin” and “CCK” receptors on histamine-and somatostatin-containing cells from rabbit fundic mucosa—II: Characterization by means of selective antagonists (L-364, 718 and L-365, 260)

Abstract

In the preceding paper, by means of selective agonists to gastrin (HG-17) and cholecystokinin (CCK-39), we evidenced the existence of “gastrin-type” receptors that could regulate histamine release and “CCK-type” receptors that could stimulate somatostatin release in isolated rabbit fundic nonparietal cells (F1 cells). Furthermore, these receptors could induce phosphoinositide breakdown. To confirm the involvement of these receptor types in these biological and biochemical processes, we used selective antagonists, L-364,718 (3-(benzoylamino)-benzodiazepine) specific to “CCK-A-type” receptor and L-365,260 (3-(acylamino)-benzodiazepine) specific to “gastrin/CCK-B-type” receptor. Neither L-364,718 nor L-365,260 alone caused any significant stimulation of [ 3H]inositol phosphate ([ 3H] InsP) production and release of histamine or somatostatin-like immunoreactivity (SLI). Each analogue inhibited in a dose-dependent manner [ 125I] HG-17 or [ 125I]CCK-39 binding to F1 cells, [ 3H]InsP accumulation and histamine and SLI release stimulated by HG-17 or CCK-39. L-365, 260 appeared to be 30–70 times more potent than L-364,718 in inhibiting [ 125I]HG-17 binding to F1 cells, as well as HG-17-induced [ 3H]InsP accumulation and HG-17- or CCK-39-enhanced histamine release ( ic 50 values: ≈5–20 nM for L-365,260 and ≈200–1500 nM for L-364,718 ). In contrast, L-364,718 was 200 to 400 times more potent than L-365,260 in inhibiting [ 125I]CCK-39 binding to F1 cells, CCK-39-induced [ 3H]-InsP accumulation and SLI release stimulated by CCK-39 or HG-17 ( ic 50 values: ≈0.3–1 nM for L-364, 718 and 100–200 nM for L-365,260 ). These results led to conclude: (i) the existence of a “gastrintype” receptor related to histamine release; (ii) the existence of a “CCK-A-type” receptor related to somatostatin release; (iii) the existence of “gastrin type” and “CCK-A-type” receptors linked to the phosphoinositide breakdown pathway.