title: Nitrergic relaxation of the mouse gastric fundus is mediated by cyclic GMP-dependent and ryanodine-sensitive mechanisms.
abstract: 1. Ryanodine-sensitive, Ca(2+) release ('Ca(2+) sparks') from the sarcoplasmic reticulum (SR) can activate plasmalemmal Ca(2+)-activated K(+) channels (K(Ca)) to cause membrane hyperpolarization and smooth muscle relaxation. Since cyclic guanosine monophosphate (cyclic GMP) can modulate Ca(2+) spark activity, the aim of the present study was to determine if Ca(2+) 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 isolated strips contracted to approximately 40% of their maximum contraction. 2. NANC relaxations to EFS were almost abolished by both the NO synthase inhibitor, N(G)-nitro-L-arginine (L-NOARG; 100 microM) and the guanylate cyclase inhibitor, 1-H-oxodiazol-[1,2,4]-[4,3-alpha] quinoxaline-1-one (ODQ; 10 microM). Also, ODQ abolished relaxations to the NO donor, sodium nitroprusside (SNP; 1 nM - 30 microM). NANC relaxations and SNP-evoked relaxations were both partly ryanodine (10 microM)- and nifedipine (0.3 microM)-sensitive, but in each case, the inhibitory effects of ryanodine and nifedipine were additive. 3. Apamin (1 microM), charybdotoxin (0.1 microM), iberiotoxin (0.1 microM), tetraethylammonium (TEA; 1 mM), glibenclamide (10 microM) and 4-aminopyridine (1 mM) had no effect on either NANC- or SNP-evoked relaxations, the latter of which 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 microM) 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 relaxations in the mouse longitudinal gastric fundus occur via a cyclic GMP-activated ryanodine-sensitive mechanism, which does not appear to involve activation of K(+) channels.
authors.affiliation: Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Selemidis
authors.forename: T M
authors.initials: TM
authors.lastname: Cocks
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005748:Gastric Fundus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D012433:Ryanodine; D009599:Nitroprusside; D019335:Nitroarginine; D009569:Nitric Oxide; D002110:Caffeine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D009543:Nifedipine