title: Vasodilator responses to acetylcholine are not mediated by the activation of soluble guanylate cyclase or TRPV4 channels in the rat.
abstract: The effects of 1H-[1,2,4]-oxadizaolo[4,3-]quinoxaline-1-one (ODQ), an inhibitor of the activation of soluble guanylate cyclase (sGC) on responses to NO donors acetylcholine (ACh) and bradykinin (BK) were investigated in the pulmonary and systemic vascular beds of the rat. In these studies the administration of ODQ in a dose of 5 mg/kg iv attenuated vasodilator responses to five different NO donors without inhibiting responses to ACh and BK in the systemic and pulmonary vascular beds of the rat. Vasodilator responses to ACh were not inhibited by l-NAME or the transient receptor vanilloid type 4 (TRPV4) antagonist GSK-2193874, which attenuated vasodilator responses to the TRPV4 agonist GSK-1016790A. ODQ did not inhibit vasodilator responses to agents reported to act in an NO-independent manner or to vasoconstrictor agents, and ODQ did not increase blood methemoglobin levels, suggesting that off target effects were minimal. These results show that ODQ in a dose that inhibited NO donor-mediated responses did not alter vasodilator responses to ACh in the pulmonary and systemic vascular beds and did not alter systemic vasodilator responses to BK. The present results indicate that decreases in pulmonary and systemic arterial pressures in response to ACh are not mediated by the activation of sGC or TRPV4 channels and that ODQ can be used to study the role of the activation of sGC in mediating vasodilator responses in the rat.
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana;
authors.forename: Edward A
authors.initials: EA
authors.lastname: Pankey
authors.affiliation: Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana;
authors.forename: Modar
authors.initials: M
authors.lastname: Kassan
authors.affiliation: Department of Physiology, Yonsei University College of Medicine, Seoul, Korea;
authors.forename: Soo-Kyoung
authors.initials: SK
authors.lastname: Choi
authors.affiliation: Department of Physiological Sciences, Eastern Virginia University Medical School, Norfolk, Virginia; and.
authors.forename: Khalid
authors.initials: K
authors.lastname: Matrougui
authors.affiliation: Department of Anesthesia, Ochsner Clinic Foundation, Jefferson, Louisiana.
authors.forename: Bobby D
authors.initials: BD
authors.lastname: Nossaman
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana;
authors.forename: Albert L
authors.initials: AL
authors.lastname: Hyman
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana; pkadowi@tulane.edu.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kadowitz
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D050916:TRPV Cation Channels / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; D014665:Vasodilator Agents; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D000109:Acetylcholine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester
keywords: pulmonary vascular bed; transient receptor vanilloid type; vasodilation