Mechanisms of U46619‐induced contraction of rat pulmonary arteries in the presence and absence of the endothelium
C McKenzie, A MacDonald… - British journal of …, 2009 - Wiley Online Library
C McKenzie, A MacDonald, AM Shaw
British journal of pharmacology, 2009•Wiley Online LibraryBackground 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 …
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 …
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
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