lithium-chloride and 1-9-dideoxyforskolin

Pretreatment of the field-stimulated rabbit isolated vas deferens for 30 min with LiCl (2 x 10(-2) and 4 x 10(-2) M) attenuated the inhibition of neurogenic twitch contractions due to muscarinic M1 receptor stimulation by 4-(4-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343), and enhanced the muscarinic M2 receptor-mediated potentiation of contractions evoked by carbachol. When the tissues were preincubated for 5 min with the adenylate cyclase activator, forskolin (3 x 10(-8)-3 x 10(-7) M), the response to carbachol was attenuated whereas that to 4-Cl-McN-A-343 remained unchanged. 1,9-Dideoxy-forskolin (3 x 10(-7) and 10(-6) M), which fails to activate cyclase, did not abolish the carbachol effect. In addition, desensitization of the response to 4-Cl-McN-A-343 but not to carbachol occurred in preparations incubated for 90 min with the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA, 3 x 10(-8)-3 x 10(-7) M), whereas its inactive 4 alpha-stereoisomer (4 alpha-PMA, 3 x 10(-7) M) was without effect. In unstimulated preparations, LiCl, forskolin and PMA did not impair contractions due to exogenous ATP (10(-3) M). These findings are consistent with the hypothesis that, in rabbit vas deferens, inhibitory muscarinic M1 receptors stimulate LiCl-sensitive phosphatidylinositol turnover (IP3 pathway) involving protein kinase C, whilst excitatory muscarinic M2 receptors are coupled to inhibition of adenylate cyclase, resulting in reduced levels of cyclic AMP.

Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; Adenylyl Cyclase Inhibitors; Animals; Carbachol; Colforsin; Dose-Response Relationship, Drug; Electric Stimulation; In Vitro Techniques; Lithium Chloride; Male; Muscle Contraction; Muscle, Smooth; Parasympathomimetics; Phosphatidylinositols; Rabbits; Receptors, Muscarinic; Signal Transduction; Stereoisomerism; Tetradecanoylphorbol Acetate; Vas Deferens