Evidence that NO acts as a redundant NANC inhibitory neurotransmitter in the guinea-pig isolated taenia coli

Abstract

1. The relative contribution of the putative transmitters, nitric oxide (NO) and an apamin-sensitive factor, possibly ATP, to inhibitory responses evoked by electrical field stimulation (EFS; 0.2–5 Hz, 0.2 ms duration, supra-maximal voltage for 10 s) of non-adrenergic, non-cholinergic (NANC) nerves was investigated in the guinea-pig isolated taenia coli contracted with histamine (1 μM).

2. Peak relaxations to EFS (0.2–5 Hz) were tetrodotoxin (1 μM)-sensitive, maximal at 0.2 Hz and completely resistant to the nitric oxide synthase inhibitor, N^G-nitro-L-arginine (L-NOARG; 100 μM) in either the presence or absence of atropine (1 μM). Furthermore, the specific inhibitor of soluble guanylyl cyclase, 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ; 10 μM), the cytochrome P₄₅₀ inhibitor and free radical generator, 7-ethoxyresorufin (7-ER; 10 μM) and the NO scavenger, oxyhaemoglobin (HbO; 30 μM) had no effect on EFS-induced relaxations alone and in combination with L-NOARG (100 μM).

3. Maximum relaxation to the NO donor, sodium nitroprusside (SNP; 1 μM) was significantly reduced by HbO (30 μM), abolished by 7-ER (10 μM) and ODQ (10 μM) but was unaffected by apamin (0.1 μM), an inhibitor of small conductance Ca²⁺-activated K⁺ channels.

4. The relaxation to EFS at 0.2 Hz was resistant to apamin but those to 0.5 and 5 Hz were significantly reduced. EFS (0.2–5 Hz)-evoked relaxations that persisted in the presence of apamin were further significantly inhibited by L-NOARG (100 μM) or ODQ (10 μM), but not by HbO (30 μM) or 7-ER (10 μM).

5. ATP (1–30 μM) produced concentration-dependent relaxations that were abolished by apamin (0.1 μM), unaffected by ODQ (10 μM) but only significantly reduced by L-NOARG (100 μM) at the lowest concentration of ATP (1 μM) used.

6. Nifedipine (0.3 μM), abolished contractions to 67 mM KCl, histamine (10 μM), endothelin-1 (0.03 μM), 5-hydroxytryptamine (5-HT; 10 μM) and the thromboxane-mimetic, 9-11-dideoxy-9α, 11α-methano-epoxy-prostaglandin F_2α (U46619; 0.1 μM).

7. The findings of the present study suggest that NO is released during NANC nerve stimulation, but plays no role in NANC relaxations in the guinea-pig taenia coli unless the effects of another apamin-sensitive, nerve-derived hyperpolarizing factor (NDHF) are blocked. Thus, we propose that in this tissue, NO acts as a ‘backup' or redundant NANC nerve inhibitory transmitter and like NDHF mediates relaxation via hyperpolarization.

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