title: NO synthase inhibition attenuates EDHF-mediated relaxation induced by TRPV4 channel agonist GSK1016790A in the rat pulmonary artery: Role of TxA2.
abstract: BACKGROUND
  The aim of the present study was to observe the concomitant activation of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) pathways by TRPV4 channel agonist GSK1016790A in the rat pulmonary artery and explore the mechanism by which NO synthase inhibition attenuates EDHF-mediated relaxation in endothelium-intact rat pulmonary artery.
  
  
  METHODS
  Tension experiments were conducted on the pulmonary artery from male Wistar rats.
  
  
  RESULTS
  TRPV4 channel agonist GSK1016790A (GSK) caused concentration-dependent relaxation (Emax 86.9±4.6%; pD2 8.7±0.24) of the endothelium-intact rat pulmonary artery. Combined presence of apamin and TRAM-34 significantly attenuated the relaxation (Emax 61.1±6.0%) to GSK. l-NAME (100μM) significantly attenuated (8.2±2.9%) the relaxation response to GSK that was resistant to apamin plus TRAM-34. However, presence of ICI192605 or furegrelate alongwith l-NAME revealed the GSK-mediated EDHF-response (Emax of 28.5±5.2%; Emax 24.5±4.3%) in this vessel, respectively. Further, these two TxA2 modulators (ICI/furegrelate) alongwith l-NAME had no effect on SNP-induced endothelium-independent relaxation in comparison to l-NAME alone. This EDHF-mediated relaxation was sensitive to inhibition by K(+) channel blockers apamin and TRAM-34 or 60mMK(+) depolarizing solution. Further, combined presence of apamin and TRAM-34 in U46619 pre-contracted pulmonary arterial rings significantly reduced the maximal relaxation (Emax 71.6±6.9%) elicited by GSK, but had no effect on the pD2 (8.1±0.03) of the TRPV4 channel agonist in comparison to controls (Emax, 92.4±4.3% and pD2, 8.3±0.06).
  
  
  CONCLUSIONS
  The present study suggests that NO and EDHF are released concomitantly and NO synthase inhibition attenuates GSK-induced EDHF response through thromboxane pathway in the rat pulmonary artery.
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: M Pule
authors.initials: MP
authors.lastname: Addison
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India. Electronic address: tusingh80@gmail.com.
authors.forename: Thakur Uttam
authors.initials: TU
authors.lastname: Singh
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: Subhashree
authors.initials: S
authors.lastname: Parida
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: Soumen
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: Jaya Kiran
authors.initials: JK
authors.lastname: Kasa
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: Susanth V
authors.initials: SV
authors.lastname: Sukumaran
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: Sajad Ahmad
authors.initials: SA
authors.lastname: Darzi
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: Kannan
authors.initials: K
authors.lastname: Kandasamy
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: Vishakha
authors.initials: V
authors.lastname: Singh
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Mishra
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D001685:Biological Factors / Q000502:physiology*; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007930:Leucine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011188:Potassium / Q000494:pharmacology; D011651:Pulmonary Artery / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000819:agonists; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001572:Benzofurans; D001685:Biological Factors; D004146:Dioxanes; C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D011720:Pyrazoles; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides; C411671:TRAM 34; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; C067410:endothelium-dependent hyperpolarization factor; C057498:ICI 192605; D001030:Apamin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019001:Nitric Oxide Synthase; D007930:Leucine; C039936:furegrelate; D011188:Potassium; D019331:NG-Nitroarginine Methyl Ester
keywords: EDHF; Nitric oxide; Pulmonary artery; TRPV4 channels; Thromboxane