Roles of guanylate cyclase in responses to myogenic and neural nitric oxide in canine lower esophageal sphincter.
Whether cGMP and cytosolic guanylate cyclase (cGC) mediate responses of canine lower esophageal sphincter (LES) to nitric oxide (NO) released from nerves, produced in muscle, or added exogenously was evaluated in vitro. 1-H-(1,2,4)oxadiazole(4,3-alpha)quinoxalin-1-1 (ODQ), inhibitor of cGC, reduced relaxations to nerve stimulation and sodium nitroprusside but not to nitric-oxide synthase activity-dependent outward K(+)-currents in isolated muscle cells. ODQ also failed to increase tone after nerve blockade. Nonspecific K(+) channel blocker, TEA ion at 20 mM was previously shown to increase tone, occlude NO-mediated modulation of tone, and inhibit NO-dependent outward currents but not neural relaxation in LES cells. In this study, TEA abolished neural relaxation and nearly abolished relaxation to sodium nitroprusside when present with ODQ. We conclude that mechanisms coupling NO in canine LES to responses vary with the source of NO. ODQ-dependent mechanisms, presumably involving cGC, mediate actions of NO from nerves, but NO from muscle utilizes TEA-sensitive but not ODQ-dependent mechanisms to modulate tone and outward currents. Exogenous NO utilizes both TEA- and ODQ-dependent mechanisms.
Daniel
E E
EE
Department of Medicine, McMaster University, Hamilton, Ontario, Canada. edaniel@ualberta.ca
Bowes
T J
TJ
Jury
J
J
D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004943:Esophagogastric Junction / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D009412:Nerve Fibers / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D026902:Potassium Channel Blockers; D011810:Quinoxalines; D013757:Tetraethylammonium Compounds; D009569:Nitric Oxide; D006162:Guanylate Cyclase