Muscarinic modulation of nitrergic neurotransmission in guinea-pig gastric fundus.
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 micromol L(-1)) significantly increased the optical density of NADPH-d positive neurones, while blockade of nitric oxide synthase with N(omega)-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 micromol 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 M(3) receptor antagonist para-fluoro-hexahydro-sila-difenidol hydrochloride, but was significantly enhanced by M(1) 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 M(1) and M(3) subtype, (ii) prejunctional inhibition of NO-mediated relaxation via M(1) receptors. In addition, M(1) receptors may facilitate the non-nitrergic relaxation.
Kortezova
N I
NI
Institute of Physiology, Bulgarian Academy of Sciences, Sofia, Bulgaria. kort@iph.bio.bas.bg
Shikova
L I
LI
Milusheva
E A
EA
Itzev
D E
DE
Bagaev
V A
VA
Mizhorkova
Z N
ZN
D000818:Animals; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D007150:Immunohistochemistry; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009252:NADPH Dehydrogenase / Q000378:metabolism; D026602:Nitrergic Neurons / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013270:Stomach / Q000187:drug effects / Q000294:innervation*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009252:NADPH Dehydrogenase