To study the control of histamine release, we developed techniques for culturing fundic mucosal mast cells. After enzyme dispersion, enrichment by elutriation, and overnight suspension culture, mast cells accounted for 30% of the cells present. Histamine release into the medium, measured by radioenzymatic assay, was stimulated by the lectin concanavalin A (Con A). Ragweed antigen released histamine in antisera-sensitized cultures. Con A-induced histamine release was enhanced by adenosine, but adenosine alone was inactive. The relative potency of adenosine analogues was consistent with interaction at an adenosine A1-receptor site. The calcium ionophore A23187 (0.1-1 microM) also induced histamine release. Phorbol esters that activate protein kinase C, such as phorbol 12-myristate 13-acetate, did not release histamine but enhanced release when added to low concentrations of A23187. In contrast, inactive phorbols, such as 4 alpha-phorbol 12,13-didecanoate, failed to enhance A23187-induced release. Parallel studies with canine hepatic mast cells yielded comparable results. We conclude that canine fundic mast cells possess receptors for immunoglobulin E and adenosine. Our data are consistent with increases in cytosolic calcium and protein kinase C activation working synergistically to stimulate fundic mast cells.
Pirenzepine, a newly described antagonist of selective muscarinic receptors (M1), has been shown to be a potent inhibitor of acid secretion. To determine whether this property of pirenzepine can be explained in part by its actions on hormones regulating acid secretion, we examined pirenzepine's effects on gastrin and somatostatinlike immunoreactivity (SLI) secretion from the isolated, perfused rat stomach. Carbachol at a dose of 10(-6) M inhibited SLI and stimulated gastrin secretion. Both atropine and pirenzepine reversed these effects in a dose-dependent fashion with D50 values of 1 X 10(-9) and 1 X 10(-7) M, respectively, against gastrin stimulation and 1 X 10(-8) and 1 X 10(-7) M, respectively, against SLI inhibition. Pirenzepine caused a progressive parallel rightward shift in the dose-response curves for SLI inhibition and gastrin stimulation by carbachol, suggesting competitive inhibition. The apparent inhibitory constant (ki) was calculated to be approximately 2 X 10(-9) M. These results indicate that gastrin and SLI release from the stomach is governed by high-affinity muscarinic receptors that are sensitive to pirenzepine. Pirenzepine's action as an acid secretory inhibitor, and possibly as an ulcer therapy drug, may be explained in part by these effects on gastric hormone regulation.
We examined regulation of histamine release from canine hepatic and fundic mucosal mast cells in short-term culture. We found that beta- but not alpha-adrenergic agonists markedly inhibited concanavalin A (ConA)-stimulated histamine release. Inhibition by epinephrine was reversed by the beta-antagonist propranolol, but not by the alpha-adrenergic antagonists phentolamine or yohimbine. The beta 2-selective antagonist ICI 115881 reversed the effects of epinephrine, whereas the beta 1-antagonists practolol and betaxolol had little effect. Prostaglandin E2 (PGE2), but not its analogue enprostil, inhibited ConA-stimulated histamine release. This difference may relate to the ability of PGE2, but not enprostil, to stimulate adenosine 3',5'-cyclic monophosphate (cAMP) production. Forskolin, cAMP analogues, and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also effectively inhibited ConA-stimulated histamine release. Neither adrenergic agonists nor PGE2 inhibited histamine release stimulated by the combination of phorbol 12-myristate-13-acetate plus the calcium ionophore A23187. These data suggest that inhibition was mediated via cAMP-dependent mechanisms and was exerted on primary cell activation, rather than on postreceptor activating events.
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