Mechanisms of U46619‐induced contraction of rat pulmonary arteries in the presence and absence of the endothelium

Background and purpose:  Thromboxane A2 and endothelial dysfunction are implicated in the development of pulmonary hypertension. The receptor‐transduction pathway for U46619 (9,11‐dideoxy‐9α, 11α‐methanoepoxy prostaglandin F2α)‐induced contraction was examined in endothelium‐intact (E+) and denuded...

Full description

Saved in:
Bibliographic Details
Published in:British journal of pharmacology 2009-06, Vol.157 (4), p.581-596
Main Authors: McKenzie, C, MacDonald, A, Shaw, AM
Format: Article
Language:English
Subjects:
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology
Animals
Calcium Channel Blockers - pharmacology
Calcium Channels - drug effects
chloride channels
Chloride Channels - antagonists & inhibitors
Drug Interactions
endothelium
Endothelium, Vascular - pathology
Endothelium, Vascular - physiology
In Vitro Techniques
Inositol 1,4,5-Trisphosphate Receptors - antagonists & inhibitors
Male
Nitric Oxide - antagonists & inhibitors
Potassium Channel Blockers - pharmacology
potassium channels
Prostaglandin Antagonists - pharmacology
Pulmonary Artery - drug effects
Pulmonary Artery - pathology
Pulmonary Artery - physiology
rat pulmonary arteries
Rats
Rats, Wistar
Receptors, Thromboxane - agonists
Receptors, Thromboxane - antagonists & inhibitors
rho-Associated Kinases - antagonists & inhibitors
Rho‐kinase
Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors
store‐operated calcium channels
Themed Section: Research Papers
thromboxane A2
Thromboxane A2 - agonists
Thromboxane A2 - antagonists & inhibitors
Type C Phospholipases - antagonists & inhibitors
U46619
Vasoconstriction - drug effects
Vasoconstrictor Agents - pharmacology
voltage‐operated calcium channels
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Background and purpose:  Thromboxane A2 and endothelial dysfunction are implicated in the development of pulmonary hypertension. The receptor‐transduction pathway for U46619 (9,11‐dideoxy‐9α, 11α‐methanoepoxy prostaglandin F2α)‐induced contraction was examined in endothelium‐intact (E+) and denuded (E−) rat pulmonary artery rings. Experimental approach:  Artery rings were mounted on a wire myograph under a tension of 7–7.5 mN at 37°C and gassed with 95% O2/5% CO2. Isometric recording was made by using Powerlab data collection and Chart 5 software. Key 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 µmol·L−1). The E− response was sensitive to 2‐APB (10–30 µmol·L−1), a putative IP3 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 KV with 4‐AP in E+ rings exposed a contraction sensitive to nifedipine, DIDS and niflumic acid, whereas inhibiting BKCa exposed a contraction sensitive to mibefradil, DIDS and niflumic acid. This indicates that removal of the endothelium allows the TP receptor to inhibit KV, which may involve coupling to phospholipase C, because inhibition of phospholipase C with U73122 (1‐[6‐[[(17β)‐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 and implications:  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. British Journal of Pharmacology (2009) 157, 581–596; doi:10.1111/j.1476‐5381.2008.00084.x; published online 22 April 2009 This article is part of a themed section on Endothelium in Pharmacology. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
ISSN:0007-1188
1476-5381
DOI:10.1111/j.1476-5381.2008.00084.x