GASTRIN AND CCK RECEPTORS ON HISTAMINE-CONTAINING AND SOMATOSTATIN-CONTAINING CELLS FROM RABBIT FUNDIC MUCOSA .2. CHARACTERIZATION BY MEANS OF SELECTIVE ANTAGONISTS (L-364,718 AND L-365,260)

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 non-parietal 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 [H-3]inositol phosphate ([H-3]InsP) production and release of histamine or somatostatin-like immunoreactivity (SLI). Each analogue inhibited in a dose-dependent manner [I-125]HG-17 or [I-125]CCK-39 binding to F1 cells, [H-3]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 [I-125]HG-17 binding to F1 cells, as well as HG-17-induced [H-3]InsP accumulation and HG-17- or CCK-39-enhanced histamine release (IC50 values: almost-equal-to 5-20 nM for L-365,260 and almost-equal-to 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 [I-125]CCK-39 binding to F1 cells, CCK-39-induced [H-3]InsP accumulation and SLI release stimulated by CCK-39 or HG-17 (IC50 values: almost-equal-to 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 "gastrin-type" 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.