Increased intracellular Cl concentration in pulmonary arterial myocytes is associated with chronic hypoxic pulmonary hypertension.

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]), 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 gene family-encoded Na-K-2Cl cotransporter 1 (NKCC1), K-Cl cotransporters (KCC) 1, 3, and 4, and gene family-encoded Na-independent and Na-dependent Cl/HCO exchangers. Exposure of rats to chronic hypoxia (10% O, 3 wk) caused CHPH and selectively increased the expression of Cl-accumulating NKCC1 and reduced the Cl-extruding KCC4. The intracellular Cl concentration ([Cl]) 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] 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.