INFLUENCE OF A SELECTIVE GUANYLATE-CYCLASE INHIBITOR, AND OF THE CONTRACTION LEVEL, ON NITRERGIC RELAXATIONS IN THE GASTRIC FUNDUS

1 The influence of the soluble guanylate cyclase inhibitor 1H-[1,2,4]o xadiazolo[4,3,-a]quinoxalin-1-one (ODQ) on non-adrenergic non-choliner gic (NANC) relaxations and the possible role of a nerve-derived hyperp olarizing factor in NANC relaxation were investigated in the rat gastr ic fundus. 2 ODQ (10(-6) and 10(-5) M) concentration-dependently inhib ited the short-lasting relaxations by NO (2x10(-6) M-10(-4) M) adminis tered as a bolus without influencing the relaxation by 3x10(-8) M isop renaline. 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-last ing and sustained relaxations (40 V, 1 ms, 0.5-16 Hz, 10 a 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, rever sed 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-2 alpha (PGF(2 alpha)), 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 co ntracted with 3x10(-7) M PGF(2 alpha). 6 The findings of this study il lustrate that the relaxation by exogenous and endogenous NO in the rat gastric fundus is due to activation of soluble guanylate cyclase. Dur ing long-term electrical stimulation, the partial contribution of NO t o NANC relaxation is maintained but it is small at higher frequencies of stimulation. Evidence for the contribution of a nerve-derived hyper polarizing factor to NANC relaxation was not obtained.