Muscarinic modulation of nitrergic neurotransmission in guinea‐pig gastric fundus

• Published in: Neurogastroenterology and motility 2004-04, Vol.16 (2), p.155-165
• Main Authors: Kortezova, N. I., Shikova, L. I., Milusheva, E. A., Itzev, D. E., Bagaev, V. A., Mizhorkova, Z. N.
• Format: Article
• Language: English
• Subjects: Animals; Electric Stimulation; Enzyme Inhibitors - pharmacology; Guinea Pigs; guinea‐pig gastric fundus; Immunohistochemistry; Male; Muscarinic Agonists - pharmacology; muscarinic subtype receptors; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle Relaxation - drug effects; Muscle Relaxation - physiology; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; NADPH Dehydrogenase - metabolism; Nitrergic Neurons - drug effects; Nitrergic Neurons - physiology; nitrergic neurotransmission; Nitric Oxide - metabolism; Nitric Oxide Synthase - drug effects; Nitric Oxide Synthase - metabolism; Organ Culture Techniques; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - physiology; Stomach - drug effects; Stomach - innervation; Synaptic Transmission - drug effects; Synaptic Transmission - physiology
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/j.1365-2982.2004.00514.x

Muscarinic receptor activation by (4‐Hydroxy‐2‐butynyl)‐1‐trimethylammonium‐m‐chlorocarbanilate chloride (McN‐A‐343) was investigated both on NADPH‐d staining and on electrically induced responses in guinea‐pig gastric fundus. McN‐A‐343 (10 μmol L−1) significantly increased the optical density of NADPH‐d positive neurones, while blockade of nitric oxide synthase with Nω‐nitro‐L‐arginine (L‐NA) decreased it, suggesting facilitation of nitric oxide (NO) production. Electrical field stimulation (EFS; 2 Hz, 0.2 ms, supramaximal current intensity, 10 s train duration) elicited on‐contraction followed by off‐relaxation in the circular muscle strips. McN‐A‐343 (10 μmol L−1) transformed the EFS‐evoked response from on‐contraction into on‐relaxation, which was neurogenic, tetrodotoxin‐sensitive and hexamethonium‐resistant. L‐NA partly reduced the EFS‐evoked relaxation, revealing two components: a nitrergic and a non‐nitrergic one. The effect of McN‐A‐343 on the amplitude of the EFS‐evoked relaxation was not changed by the M3 receptor antagonist para‐fluoro‐hexahydro‐sila‐difenidol hydrochloride, but was significantly enhanced by M1 receptor blockade with telenzepine. In the presence of telenzepine, the L‐NA‐dependent nitrergic component of the EFS‐induced relaxation predominates. We suggest that cholinergic receptor activation has a dual effect on nitrergic neurotransmission: (i) stimulation of NOS by muscarinic receptor(s) different from M1 and M3 subtype, (ii) prejunctional inhibition of NO‐mediated relaxation via M1 receptors. In addition, M1 receptors may facilitate the non‐nitrergic relaxation.