Carbachol but not acetylcholine inhibits contraction by the protein kinase C-dependent and -independent pathways in the smooth muscle of guinea pig taenia caeci.
In the intestinal smooth muscle of guinea pig taenia caeci, acetylcholine and carbachol induced a transient contraction followed by a sustained contraction. The magnitudes of the transient and sustained contractions were similar when muscle was stimulated with acetylcholine (0.1 microM-1 mM) or a lower concentration (0.1 microM) of carbachol. However, higher concentrations of carbachol (1 - 100 microM) induced significantly smaller sustained contraction than the transient contraction. In the 45 mM KCI-stimulated strips, addition of 100 microM carbachol induced a transient increase followed by a sustained decrease in the contractile tension. In contrast, acetylcholine (0.1 microM-1 mM) showed only weak inhibitory effect on the high K(+)-induced contraction either in the absence or presence of a cholinesterase inhibitor, 0.5 microM diisopropylfluorophosphate. The same concentration of diisopropylfluorophosphate shifted the concentration-response curve for acetylcholine to lower concentrations. In the muscles pretreated with 3 microM phorbol 12-myristate 13-acetate for 24 hr to desensitize protein kinase C, sustained contractions induced by higher concentrations of carbachol (1-100 microM) were significantly greater than those in the strips without the treatment with phorbol ester. However, the transient contraction and the contraction induced by a lower concentration (0.1 microM) of carbachol were not changed by the treatment with phorbol ester. Pretreatment with phorbol ester attenuated the inhibitory effect of carbachol on the high K(+)-induced contraction. These results suggest that the inhibitory effects of carbachol is composed of two phases: protein kinase C-independent transient inhibition and protein kinase C-dependent sustained inhibition.
Department of Veterinary Phamacology, Graduate School of Agriculture and Life Science, University of Tokyo, Japan.
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Mitsui-Saito
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Karaki
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D002432:Cecum / Q000187:drug effects / Q000502:physiology; D018678:Cholinergic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011188:Potassium / Q000037:antagonists & inhibitors / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology*
D018678:Cholinergic Agents; D018721:Muscarinic Agonists; D002217:Carbachol; D011493:Protein Kinase C; D000109:Acetylcholine; D011188:Potassium