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

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Abstract
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). 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, NG‐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). 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. 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). 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. 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 F2α (U46619; 0.1 μM). 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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