EFFECT OF POTASSIUM CHANNEL BLOCKADE AND ALPHA(2)-ADRENOCEPTOR ACTIVATION ON THE RELEASE OF NITRIC-OXIDE FROM NONADRENERGIC NONCHOLINERGIC NERVES

1 Using a superfusion bioassay cascade, we studied the effect of K+ ch annel blockers and alpha(2)-adrenoceptor agents on the release of a tr ansferable factor, previously characterized as nitric oxide (NO) or a nitric oxide-related substance (NO-R), in response to non-adrenergic n on-cholinergic (NANC) nerve stimulation in the canine ileocolonic junc tion (ICJ). 2 The non-selective K+ channel blockers, 4-aminopyridine ( 4-AP, 50 mu M) and tetraethylammonium (TEA, 1 mM) and the more selecti ve blocker of Ca2+-activated K+ channels, charybdotoxin (Leiurus guinq uestriatus venom (LQV), 0.4 mu g ml(-1)), significantly enhanced the r elease of NO-R induced by low frequency stimulation (2-4 Hz). In the p resence of 4-AP and TEA, the release of NO-R was nearly abolished by t etrodotoxin (2 mu M), and by L-N-G-nitroarginine (L-NOARG, 0.1 mM). Re laxations induced by direct injection of exogenous NO (5-50 pmol) or n itroglycerin (GTN, 10-30 pmol) onto the rabbit aortic detector ring we re not affected. 3 The alpha(2)-adrenoceptor agonist, UK-14,304 (0.3 m u M) inhibited the release of NO-R induced by low (2-4 Hz), but not th at induced by high (16 Hz), frequency stimulation. This inhibitory eff ect was completely reversed by the alpha(2)-adrenoceptor antagonist, y ohimbine (0.3 mu M). Neither UK-14,304 nor yohimbine affected the rela xations induced by exogenous NO (5 pmol) or GTN (10 pmol) on the aorti c detector ring. 4 On the other hand, in the presence of the K+ channe l blockers 4-AP (50 mu M) or charybdotoxin (LQV, 0.4 mu g ml(-1)), UK- 14,304 (0.3 mu M) failed to inhibit the electrically-induced release o f NO-R. 5 From these results, we conclude that the electrically-induce d release of NO-R from NANC nerves of the canine ICJ is enhanced by K channel blockers but inhibited by alpha(2)-adrenoceptor activation. I n addition, these results suggest that the prejunctional modulation of NO-R release by alpha(2)-adrenoceptors may involve neuronal K+ channe ls.