Nerve stimulation-induced nitric oxide release as a consequence of muscarinic M1 receptor activation.
The aim of the present study was to investigate whether nerve stimulation-induced nitric oxide (NO) release in the guinea-pig colon is affected by acetylcholine and to identify the muscarinic receptor subtype involved. Nerve-smooth muscle preparations were suspended in a superfusion chamber and NO/NO2- overflow in the superfusate was detected by chemiluminescence analysis. Transmural nerve stimulation evoked a significant increase in NO/NO2- release, which was inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME) and abolished by tetrodotoxin. Exogenous acetylcholine concentration-dependently increased NO/NO2- release and atropine reduced nerve stimulation-evoked NO/NO2- release. The muscarinic M1 receptor selective antagonist telenzepine (10(-8) M) was as effective as atropine (10(-6) M) in inhibiting NO/NO2- release. The muscarinic M3 receptor antagonists 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and para-fluoro-hexahydrosila-difenidol (p-F-HHSiD) markedly inhibited cholinergic contractions at 3 x 10(-8) M and 3 x 10(-7) M respectively, but did not affect NO/NO2- release. In conclusion, nerve-induced NO/NO2- release in the guinea-pig colon is to a substantial part due to muscarinic M1 receptor activation. Thus acetylcholine, a major contractile neurotransmitter in the gut, can release NO which could act as a negative feedback mechanism on intestinal smooth muscle or neuronal activity.
Iversen
H H
HH
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Wiklund
N P
NP
Olgart
C
C
Gustafsson
L E
LE
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000294:innervation*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000109:Acetylcholine