Abstract
The stimulation of the formation of inositol phosphate (IP) by (+-)-methyl-2,3,3a,4-tetrahydro-1H-indolo [3,2,1-de] [1,5] naphthyridine-6-carboxylate monohydrochloride (vinconate), a novel indolonaphthyridine derivative, was studied using both cerebral cortical slices and crude synaptic membranes prepared from the rat brain. Vinconate (10 mM-1 mM) inhibited the binding of [3H]quinuclidinyl benzilate to the muscarinic receptor in a dose-dependent manner and the IC50 value for [3H]quinuclidinyl benzilate binding was found to be 17 microM. The rightward shift of the inhibition curve of [3H]quinuclidinyl benzilate binding by carbachol in the presence of GTP (100 microM) was abolished by vinconate (100 microM). Carbachol (10 nM-10 mM) significantly increased [3H]IP formation in a dose-dependent manner and the rate of [3H]IP formation mediated by carbachol stimulation was significantly accentuated in the presence of 10 microM vinconate. The enhancement of [3H]IP accumulation by vinconate was inhibited by approximately 50% in the presence of atropine (1-1000 microM), although up to 1 mM of phentolamine and ketanserin had no effect on the vinconate-induced increase of phosphatidylinositol turnover. Moreover, vinconate significantly accentuated 20 mM KCl-evoked stimulation of [3H]IP formation. Vinconate had no differential effect on the ratio of IP or inositol 1,4-biphosphate and inositol 1,4,5-triphosphate formations. These results suggest that vinconate may induce a facilitation of phosphatidylinositol turnover via the stimulation of muscarinic receptors and a facilitation of coupling between muscarinic receptors and GTP-binding protein. The presence of a direct stimulatory effect of vinconate on phosphatidylinositol turnover has also been suggested.
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|