title: Mechanisms of U46619-induced contraction of rat pulmonary arteries in the presence and absence of the endothelium.
abstract: OBJECTIVE
  Thromboxane A(2) and endothelial dysfunction are implicated in the development of pulmonary hypertension. The receptor-transduction pathway for U46619 (9,11-dideoxy-9 alpha, 11 alpha-methanoepoxy prostaglandin F(2 alpha))-induced contraction was examined in endothelium-intact (E+) and denuded (E-) rat pulmonary artery rings.
  
  
  METHODS
  Artery rings were mounted on a wire myograph under a tension of 7-7.5 mN at 37 degrees C and gassed with 95% O(2)/5% CO(2). Isometric recording was made by using Powerlab data collection and Chart 5 software.
  
  
  RESULTS
  Both E+ and E- contractile responses were sensitive to Rho-kinase inhibition and the chloride channel blocker NPPB [5-nitro-2-(3-phenylpropylamino)benzoic acid]. The E+ response was sensitive to the store-operated calcium channel blockers SKF-96365 {1-[B-[3-(4-methoxyphenyl)propoxy]-4-methoxy-phenethyl]-1H-imidazole hydrochloride} and 2-APB (2-amino ethoxy diphenylborate) (75-100 micromol x L(-1)). The E- response was sensitive to 2-APB (10-30 micromol x L(-1)), a putative IP(3) receptor antagonist, and the calcium and chloride channel blockers nifedipine, DIDS (4,4'-diisothiocyanostilbene-2,2'-disulphonic acid) and niflumic acid but was insensitive to SKF-96365. Inhibiting K(V) with 4-AP in E+ rings exposed a contraction sensitive to nifedipine, DIDS and niflumic acid, whereas inhibiting BK(Ca) exposed a contraction sensitive to mibefradil, DIDS and niflumic acid. This indicates that removal of the endothelium allows the TP receptor to inhibit K(V), which may involve coupling to phospholipase C, because inhibition of phospholipase C with U73122 (1-[6-[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-y]amino]hexyl]- 1H-pyrrole-2,5-dione) switched the E- pathway to the E+ pathway.
  
  
  CONCLUSIONS
  The results from this study indicate that distinct transduction pathways can be employed by the TP receptor to produce contraction and that the endothelium is able to influence the coupling of the TP receptor.
authors.affiliation: Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK.
authors.forename: C
authors.initials: C
authors.lastname: McKenzie
authors.forename: A
authors.initials: A
authors.lastname: MacDonald
authors.forename: A M
authors.initials: AM
authors.lastname: Shaw
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology*; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000819:agonists / Q000037:antagonists & inhibitors; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018118:Chloride Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D026902:Potassium Channel Blockers; D011448:Prostaglandin Antagonists; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D054460:rho-Associated Kinases; D010738:Type C Phospholipases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases