Influence of a selective guanylate cyclase inhibitor, and of the contraction level, on nitrergic relaxations in the gastric fundus

Abstract

1. The influence of the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) on non-adrenergic non-cholinergic (NANC) relaxations and the possible role of a nerve-derived hyperpolarizing factor in NANC relaxation were investigated in the rat gastric fundus. 2. ODQ (10-6 and 10-5 M) concentration-dependently inhibited the short-lasting relaxations by NO (2 x 10-6 M-10-4 M) administered as a bolus without influencing the relaxation by 3 x 10-8 M isoprenaline. The relaxation by an infusion of NO was reduced to the same extent by 10-6 and 10-5 M ODQ. 3. The electrically induced short-lasting and sustained relaxations (40 V, 1 ms, 0.5-16 Hz, 10 s trains at 2 min interval or cumulative increase in the frequency every 2 min) in NANC conditions were inhibited to a similar extent by 10-6 and 10-5 M ODQ, and by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 3 x 10-4 M. 4. ODQ (10-6 M) and L-NAME (3 x 10-4 M), administered after 5, 10 or 20 min of long-term stimulation, reversed the relaxation to a similar extent (approximately 50% at 2 Hz and 20% at 8 Hz). 5. When the tissues were contracted to 40% of maximum by adapting the concentration of prostaglandin F(2α), (PGF(2α)), the inhibitory effect of 3 x 10-4 M L-NAME on relaxations induced by train and cumulative stimulation was the same as when tissues were contracted with 3 x 10-7 M PGF(2α). 6. The findings of this study illustrate that the relaxation by exogenous and endogenous NO in the rat gastric fundus is due to activation of soluble guanylate cyclase. During long-term electrical stimulation, the partial contribution of NO to NANC relaxation is maintained but it is small at higher frequencies of stimulation. Evidence for the contribution of a nerve-derived hyperpolarizing factor to NANC relaxation was not obtained.