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primary topic: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension

The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension
type: AcademicArticle
type: Article
abstract: Background and purpose Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) channels, of which the TASK-1 has been extensively investigated. Experimental Approach Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage- and current clamp methods. Intracellular [Ca2+] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model. Key Results TREK-1 was the most abundantly expressed K2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K+-current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML-335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK-1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML-335 hyperpolarised donor hPASMCs and normalised the Em of IPAH hPASMCs. A close link was found between TREK-1 activity and intracellular Ca2+-signalling using a channel activator, ML-335, and an inhibitor, spadin. In the rat, ML-335 relaxed isolated pre-constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung. Conclusions and Implications These data suggest that TREK-1is a key factor in Em setting and Ca2+ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK-1 may represent a new therapeutic target for PAH.
date: 2024
volume: 181
issue: 19
is part of: BRITISH JOURNAL OF PHARMACOLOGY
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
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subject: R1 Medicine (General) / orvostudomány általában

The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
type: Document
license: http://creativecommons.org/licenses/by/3.0/

The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
type: Document
has file: bph16426-toc-0001-m.jpg
has part: bph16426-toc-0001-m.jpg

BRITISH JOURNAL OF PHARMACOLOGY
type: Collection
issn: 00071188

Miklós Lengyel
type: Person
given name: Miklós
family name: Lengyel

Dusan Jeremic
type: Person
given name: Dusan
family name: Jeremic

Andrea Olschewski
type: Person
given name: Andrea
family name: Olschewski

János Almássy
type: Person
given name: János
family name: Almássy

Alice Dobolyi
type: Person
given name: Alice
family name: Dobolyi

Konrad Hoetzenecker
type: Person
given name: Konrad
family name: Hoetzenecker

Péter Enyedi
type: Person
given name: Péter
family name: Enyedi

Horst Olschewski
type: Person
given name: Horst
family name: Olschewski

Réka Csáki
type: Person
given name: Réka
family name: Csáki

Chandran Nagaraj
type: Person
given name: Chandran
family name: Nagaraj

Mohammad Ali Khozeimeh
type: Person
given name: Mohammad Ali
family name: Khozeimeh

Élettani Intézet SE / AOK / I ÉI [2000-]
type: Organization

The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Other)
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The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Other)
type: Document
is version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
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The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Other)
type: Document
is version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
is volatile version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
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The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Other)
type: Document
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The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Other)
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is version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
is volatile version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
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The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Other)
type: Document
is version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
is volatile version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
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The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Other)
type: Document
is version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
is volatile version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
ispreview thumbnail version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
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The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Other)
type: Document
is version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
is volatile version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
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The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Other)
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is volatile version of: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension (Text)
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primary topic: The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension

R1 Medicine (General) / orvostudomány általában
type: Concept