Dataset Information

Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia-induced pulmonary hypertension.

ABSTRACT:

Background and purpose

Sustained pulmonary vasoconstriction and excessive pulmonary vascular remodelling are two major causes of elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension. The purpose of this study was to investigate whether chloroquine induced relaxation in the pulmonary artery (PA) and attenuates hypoxia-induced pulmonary hypertension (HPH).

Experimental approach

Isometric tension was measured in rat PA rings pre-constricted with phenylephrine or high K⁺ solution. PA pressure was measured in mouse isolated, perfused and ventilated lungs. Fura-2 fluorescence microscopy was used to measure cytosolic free Ca²⁺ concentration levels in PA smooth muscle cells (PASMCs). Patch-clamp experiments were performed to assess the activity of voltage-dependent Ca²⁺ channels (VDCCs) in PASMC. Rats exposed to hypoxia (10% O₂ ) for 3 weeks were used as the model of HPH or Sugen5416/hypoxia (SuHx) for in vivo experiments.

Key results

Chloroquine attenuated agonist-induced and high K⁺ -induced contraction in isolated rat PA. Pretreatment with l-NAME or indomethacin and functional removal of endothelium failed to inhibit chloroquine-induced PA relaxation. In PASMC, extracellular application of chloroquine attenuated store-operated Ca²⁺ entry and ATP-induced Ca²⁺ entry. Furthermore, chloroquine also inhibited whole-cell Ba²⁺ currents through VDCC in PASMC. In vivo experiments demonstrated that chloroquine treatment ameliorated the HPH and SuHx models.

Conclusions and implications

Chloroquine is a potent pulmonary vasodilator that may directly or indirectly block VDCC, store-operated Ca²⁺ channels and receptor-operated Ca²⁺ channels in PASMC. The therapeutic potential of chloroquine in pulmonary hypertension is probably due to the combination of its vasodilator, anti-proliferative and anti-autophagic effects.

SUBMITTER: Wu K

PROVIDER: S-EPMC5659991 | biostudies-literature |

REPOSITORIES: biostudies-literature

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