Effect of potassium channel blockade and α2‐adrenoceptor activation on the release of nitric oxide from non‐adrenergic non‐cholinergic nerves

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Abstract
1 Using a superfusion bioassay cascade, we studied the effect of K+ channel blockers and α2-adrenoceptor agents on the release of a transferable factor, previously characterized as nitric oxide (NO) or a nitric oxide-related substance (NO-R), in response to non-adrenergic non-cholinergic (NANC) nerve stimulation in the canine ileocolonic junction (ICJ). 2 The non-selective K+ channel blockers, 4-aminopyridine (4-AP, 50 μm) and tetraethylammonium (TEA, 1 mm) and the more selective blocker of Ca2+-activated K+ channels, charybdotoxin (Leiurus quinquestriatus venom (LQV), 0.4 μg ml−1), significantly enhanced the release of NO-R induced by low frequency stimulation (2–4 Hz). In the presence of 4-AP and TEA, the release of NO-R was nearly abolished by tetrodotoxin (2 μm), and by l-NG-nitroarginine (l-NOARG, 0.1 mm). Relaxations induced by direct injection of exogenous NO (5–50 pmol) or nitroglycerin (GTN, 10–30 pmol) onto the rabbit aortic detector ring were not affected. 3 The α2-adrenoceptor agonist, UK-14,304 (0.3 μm) inhibited the release of NO-R induced by low (2–4 Hz), but not that induced by high (16 Hz), frequency stimulation. This inhibitory effect was completely reversed by the α2-adrenoceptor antagonist, yohimbine (0.3 μm). Neither UK-14,304 nor yohimbine affected the relaxations induced by exogenous NO (5 pmol) or GTN (10 pmol) on the aortic detector ring. 4 On the other hand, in the presence of the K+ channel blockers 4-AP (50 μm) or charybdotoxin (LQV, 0.4 μg ml−1), UK-14,304 (0.3 μm) failed to inhibit the electrically-induced release of NO-R. 5 From these results, we conclude that the electrically-induced release of NO-R from NANC nerves of the canine ICJ is enhanced by K+ channel blockers but inhibited by α2-adrenoceptor activation. In addition, these results suggest that the prejunctional modulation of NO-R release by α2-adrenoceptors may involve neuronal K+ channels.