title: Involvement of guanylyl cyclase, protein kinase A and Na+ K+ ATPase in relaxations of bovine isolated bronchioles induced by GEA 3175, an NO donor.
abstract: The present study was designed to investigate the role of the sodium potassium adenosine triphosphatase (the Na(+)K(+) ATPase) in relaxation of bovine isolated bronchioles by a new NO donor, GEA 3175 (3-(3-chloro-2-methylphenyl)-5-[[(4-methylphenyl)sulphonyl]amino]-)hydroxide)). Bronchioles were mounted in a wire myograph for isometric tension recordings and contracted with 5-hydroxytryptamine (5-HT) or a K(+) rich solution. Concentration-dependent relaxations evoked by GEA 3175 were inhibited by ouabain or K(+) free solution. The guanylyl cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 3 microM) and ouabain (10 nM) reduced GEA 3175-evoked relaxations to the same extent without any additive effect. Iberiotoxin (10 nM), an inhibitor of large conductance Ca(2+)-activated K(+) channels inhibited GEA 3175-evoked relaxations to the same extent as ouabain. Combining ouabain and iberiotoxin completely abolished GEA 3175 relaxation. An inhibitor of protein kinase G (PKG), Rp-beta-phenyl-1,N(2)-etheno-8-bromo-guanosine-3'-5'-cyclic monophosphorothioate (Rp-8-Br-PET-cGMPs), slightly reduced GEA 3175-induced relaxations. An inhibitor of cyclic AMP-dependent kinase (PKA), Rp-adenosine-3'-5'-cyclic phosphorothioate (Rp-cAMPs), inhibited the GEA 3175-induced relaxations to the same extent as ouabain. Inhibition of both PKG and PKA abolished GEA 3175 relaxation. The study provides evidence that the NO donor GEA 3175 causes guanylyl cyclase-dependent relaxations, taking place through cyclic GMP and cyclic AMP-dependent protein kinases followed by opening of large conductance Ca(2+)-activated K(+) channels and activation of smooth muscle Na(+)K(+) ATPase.
authors: Department of Pharmacology, The Bartholin Building, University of Aarhus, Denmark.
authors: B
authors: B
authors: Elmedal Laursen
authors: M J
authors: MJ
authors: Mulvany
authors: U
authors: U
authors: Simonsen
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D002417:Cattle; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D026422:S-Nitrosoglutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C104224:8-bromo-beta-phenylethenoguanosine 3',5'-cyclic monophosphate; C093084:GEA 3175; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D010455:Peptides; D011810:Quinoxalines; D013873:Thionucleotides; D014230:Triazoles; D005576:Colforsin; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D012701:Serotonin; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D026422:S-Nitrosoglutathione; D010042:Ouabain; C002385:linsidomine; C064719:iberiotoxin; D008981:Molsidomine; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP; D011188:Potassium; D002118:Calcium