Pathways involved in muscarinic M1 and M2 receptor stimulation in rabbit vas deferens.
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.
Eltze
M
M
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, Germany.
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D010277:Parasympathomimetics / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D005576:Colforsin; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; C073300:4-(4-chlorophenylcarbamoyloxy)-2-butynyl-trimethylammonium; D002217:Carbachol; D018021:Lithium Chloride; D013755:Tetradecanoylphorbol Acetate; C047983:1,9-dideoxyforskolin