Open AccessIncreased intracellular Cl− concentration in pulmonary arterial myocytes is associated with chronic hypoxic pulmonary hypertension
Author(s) -
Hui Sun,
Omkar Paudel,
James S.K. Sham
Publication year - 2021
Publication title -
american journal of physiology. cell physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.432
H-Index - 181
eISSN - 1522-1563
pISSN - 0363-6143
DOI - 10.1152/ajpcell.00172.2021
Subject(s) - intracellular , cotransporter , homeostasis , intracellular ph , pulmonary hypertension , chemistry , contraction (grammar) , hypoxia (environmental) , hypoxic pulmonary vasoconstriction , myocyte , medicine , endocrinology , biophysics , biology , biochemistry , sodium , oxygen , organic chemistry
Chloride channels play an important role in regulating smooth muscle contraction and proliferation, and contribute to the enhanced constriction of pulmonary arteries (PAs) in pulmonary hypertension (PH). The intracellular Cl - concentration ([Cl - ] i ), tightly regulated by various Cl - transporters, determines the driving force for Cl - conductance, thereby the functional outcome of Cl - channel activation. This study characterizes for the first time the expression profile of Cl - transporters/exchangers in PA smooth muscle and provides the first evidence that the intracellular Cl - homeostasis is altered in PA smooth muscle cells (PASMCs) associated with chronic hypoxic PH (CHPH). Quantitative RT-PCR revealed that the endothelium-denuded intralobar PA of rats expressed Slc12a gene family-encoded Na-K-2Cl cotransporter 1 (NKCC1), K-Cl cotransporters (KCC) 1, 3, and 4, and Slc4a gene family-encoded Na + -independent and Na + -dependent Cl - /HCO 3 - exchangers. Exposure of rats to chronic hypoxia (10% O 2 , 3 wk) caused CHPH and selectively increased the expression of Cl - -accumulating NKCC1 and reduced the Cl - -extruding KCC4. The intracellular Cl - concentration ([Cl - ] i ) averaged at 45 mM and 47 mM in normoxic PASMCs as determined by fluorescent indicator MEQ and by gramicidin-perforated patch-clamp technique, respectively. The ([Cl - ] i was increased by ∼10 mM in PASMCs of rats with CHPH. Future studies are warranted to further establish the hypothesis that the altered intracellular Cl - homeostasis contributes to the pathogenesis of CHPH.