(+-)-Methyl-2,3,3a,4-tetrahydro-1H-indolo [3,2,1-de] [1,5] naphthyridine-6-carboxylate monohydrochloride facilitates phosphatidylinositol hydrolysis: possible involvement of muscarinic and nonmuscarinic mechanisms.
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.
Katsura
M
M
Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
Iino
T
T
Kuriyama
K
K
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D010646:Phentolamine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism; D014748:Vinca Alkaloids / Q000494:pharmacology*
D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D014748:Vinca Alkaloids; D011813:Quinuclidinyl Benzilate; D001285:Atropine; C038627:vinconate; D006160:Guanosine Triphosphate; D002217:Carbachol; D007650:Ketanserin; D011188:Potassium; D010646:Phentolamine