Published in:
British Journal of Pharmacology (2024)
Language:
English
DOI:
10.1111/bph.16426
ISSN:
0007-1188;
1476-5381
Origination:
Footnote:
Description:
AbstractBackground and purposePulmonary 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 ApproachIon 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 ResultsTREK‐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 ImplicationsThese 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.