| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1996: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Stimulation of the m_3-muscarinic cholinergic and alpha_1-adrenergic receptors in the rat parotid gland leads to increased inositol 1,4,5-trisphosphate (IP_3) generation through a GTP-binding regulatory protein (G-protein) and phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PLC) and intracellular^1 Ca^<2+> release. The resulting elevation in cytosolic Ca^<2+> concentration triggers the process of fluid secretion in parotid acinar cells. Benzodiazepine compounds such as diazepam and clonazepam induce the inhibition of salivary secretion as a side effect. This study was examined the effect of diazepam on phosphoinositide metabolism, which plays an important process of salivary secretion, in rat parotid glands. In rat parotid acinar cells, diazepam (10^<-9>-10^<-5>M), which is a potent agonist of both central-and peripheral-type benzodiazepine receptors, dose-dependently decreased carbachol-stimulated IP_3 generation. The maximum decrease was approximately 40%. The inhibit
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ory response of diazepam was completely blocked in combination with the central-and peripheral-type benzodiazepine receptor antagonists, flumazenil and PK 11195, respectively. Diazepam produced a noncompetitive inhibition on the dose-dependence curves of carbachol-stimulated IP_3 generation. In rat parotid plasma membranes, diazepam (10^<-8>-10^<-5>M) decreased PLC activity induced by sodium fluoride, which directly activates the alpha subunit of G-protein. However, the maximum decrease was approximately 10%. Diazepam had no effect on the 1% sodium cholate extracted PLC activity from the membranes. These results strongly indicate that diazepam inhibit phosphoinositide metabolism in rat parotid gland through the benzodiazepine receptors in the membranes, but not act on the muscarinic receptor, G-protein, and PLC.These results also indicate that the reduction of IP_3 levels in the parotid acinar cells may be concerned in the inhibition of salivary secretion induced by benzodiazepine compounds. Less
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