Inhibition of non-adrenergic non-cholinergic relaxations by nitric oxide donors

Abstract

The effects of pretreatment with the nitric oxide (NO)-releasing substances 3-morpholino-sydnoninime (SIN-1) and nitroglycerin were investigated on relaxations induced by non-adrenergic non-cholinergic (NANC) nerve stimulation, authentic NO and vasoactive intestinal polypeptide (VIP) in the rat gastric fundus. Short periods of electrical stimulation (0.5–16 Hz, 1 ms, pulse trains of 10 s) induced frequency-dependent transient relaxations, previously shown to be mainly mediated by NO. Both SIN-1 (10–100 μM) and nitroglycerin (0.5 mM) pretreatment significantly reduced these electrically induced responses to a similar extent as the inhibitor of the NO biosynthesis l-nitroarginine (30–300 μM). Prolonged periods of electrical stimulation (16 Hz, 1 ms, pulse trains of 180 s) induced a sustained relaxation, previously shown to be mediated by NO and VIP. l-Nitroarginine (30–300 μM) or pretreatment with SIN-1 (100 μM) or nitroglycerin (0.5 mM) did not affect the amplitude of this relaxation but slowed down its onset. Authentic NO (0.01–10 μM) and VIP (0.01–10 nM) induced respectively transient and sustained concentration-dependent relaxations. SIN-1 or nitroglycerin pretreatment had no effect on the concentration-response curves to NO and VIP. These results indicate that prolonged exposure to NO donors inhibits electrically induced nerve-mediated NANC relaxations without affecting the postjunctional response to NO and VIP. As similar results are obtained with NO biosynthesis inhibitors, our results illustrate a prejunctional inhibitory effect of NO on the NANC nerves of the rat gastric fundus and suggest the presence of an autoregulatory mechanism for the nitrergic innervation.