Nitrergic relaxation of the mouse gastric fundus is mediated by cyclic GMP-dependent and ryanodine-sensitive mechanisms

1 Ryanodine-sensitive, Ca2+ release ('Ca2+ sparks') from the sarcoplasmic r eticulum (SR) can activate plasmalemmal Ca2+-activated K+ channels (K-Ca) t o cause membrane hyperpolarization and smooth muscle relaxation. Since cycl ic guanosine monophosphate (cyclic GMP) can modulate Ca2+ spark activity, t he aim of the present study was to determine if Ca2+ spark-like events are involved in NO-dependent, NANC relaxations to electrical field stimulation (EFS) of mouse, longitudinal smooth muscle of the gastric fundus in isolate d strips contracted to similar to 40% of their maximum contraction. 2 NANC relaxations to EFS were almost abolished by both the NO synthase inh ibitor, N-G-nitro-L-arginine (L-NOARG; 100 mu M) and the guanylate cyclase inhibitor, 1-H-oxodiazol-[1,2,4]-[4,3-alpha] quinoxaline-1-one (ODQ; 10 mu M). Also, ODQ abolished relaxations to the NO donor, sodium nitroprusside ( SNP; 1 nM-30 mu M). NANC relaxations and SNP-evoked relaxations were both p artly ryanodine (10 mu M)- and nifedipine (0.3 mu M)-sensitive, but in each case, the inhibitory effects of ryanodine and nifedipine were additive. 3 Apamin (1 mu M), charybdotoxin (0.1 mu M), iberiotoxin (0.1 mu M), tetrae thylammonium (TEA; 1 mM), glibenclamide (10 mu M) and 4-aminopyridine (1 mM ) had no effect on either NANC- or SNP-evoked relaxations, the latter of wh ich were also unaffected by high extracellular K+ (68 mM). 4 Caffeine (0.1-1 mM) caused concentration-dependent relaxations of gastric fundus which were inhibited by ryanodine but unaffected by L-NOARG. 5 Relaxation to ATP (30 mu M) was abolished by nifedipine, partly inhibited by apamin and ryanodine, but was unaffected by L-NOARG. 6 In conclusion, the results of the present study show that nitrergic relax ations in the mouse longitudinal gastric fundus occur via a cyclic GMP-acti vated ryanodine-sensitive mechanism, which does not appear to involve activ ation of K+ channels.