TY  - JOUR
ID  - REAL225005
UR  - https://doi.org/10.1111/bph.16426
IS  - 19
A1  - Csáki, Réka
A1  - Nagaraj, Chandran
A1  - Almássy, János
A1  - Khozeimeh, Mohammad Ali
A1  - Jeremic, Dusan
A1  - Olschewski, Horst
A1  - Dobolyi, Alice
A1  - Hoetzenecker, Konrad
A1  - Olschewski, Andrea
A1  - Enyedi, Péter
A1  - Lengyel, Miklós
N2  - 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.
VL  - 181
TI  - The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension
AV  - public
EP  - 3593
N1  - Funding Agency and Grant Number: Nemzeti Kutatsi Fejlesztsi s Innovcis Hivatal
            Funding text: The skilful technical assistance provided by Elisabeth Blanz is much appreciated.
Y1  - 2024///
JF  - BRITISH JOURNAL OF PHARMACOLOGY
KW  - Spadin; TREK-1; pulmonary arterial hypertension (PAH); ML-335; pulmonary arterial smooth muscle cells (PASMC);
SN  - 0007-1188
SP  - 3576
ER  -