title: Inhibitory effect of diazepam on muscarinic receptor-stimulated inositol 1,4,5-trisphosphate production in rat parotid acinar cells.
abstract: 1. This study examined the effect of diazepam (DZP) on phosphoinositide turnover, which plays an important role in the regulation of salivary secretion, in rat parotid acinar cells. 2. DZP (10(-9) M to 10(-5) M), a potent agonist of both central- and peripheral-type benzodiazepine receptors, dose-dependently decreased inositol 1,4,5-trisphosphate IP3 production stimulated by carbachol, a muscarinic receptor agonist, in the cells. 3. DZP produced a maximum inhibitory response at a concentration of 10(-5) M, with IP3 production decreased to 63% of maximal levels. The concentration inducing half maximal inhibition of IP3 production was approximately 3.5 x 10 (-8) M. 4. An inhibitory response to DZP was produced by a short-term pretreatment (<3 min) of the cells and prevented by antagonist and competing ligand for the central- and peripheral-type benzodiazepine receptors, flumazenil and PK 11195, respectively. 5. DZP showed a non-competitive inhibition of carbachol-stimulated IP3 production. It did not directly inhibit the activities of GTP-binding regulatory proteins and phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PLC) in the parotid gland membranes, though choline chloride inhibited PLC activity. 6. DZP (10(-5) M) attenuated the increase in the intracellular Ca2+ concentration ([Ca(2+)](i)) in the cells following stimulation of the muscarinic and alpha(1)-adrenoceptors. 7. These results suggest that in the parotid acinar cells, DZP inhibits muscarinic receptor-stimulated IP3 production through benzodiazepine receptors and that PLC activity which produces IP3 is inhibited by chloride. The decreases in IP3 and [Ca(2+)](i) in the cells may be connected with the suppression of salivary secretion induced by DZP.
authors.affiliation: Department of Pharmacology, Tokyo Dental College, 1-2-2 Masago, Mihama-ku, Chiba 261-8502, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kujirai
authors.forename: Kohei
authors.initials: K
authors.lastname: Sawaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D019204:GTP-Binding Proteins / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D010306:Parotid Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D054801:Phosphoinositide Phospholipase C; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D002712:Chlorides; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D011963:Receptors, GABA-A; D011976:Receptors, Muscarinic; D010656:Phenylephrine; D005442:Flumazenil; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C; D019204:GTP-Binding Proteins; D003975:Diazepam; D002118:Calcium; C037850:PK 11195