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

Br J Pharmacol. 2017 Nov;174(22):4155-4172. doi: 10.1111/bph.13990. Epub 2017 Oct 2.

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.

MeSH terms

  • Animals
  • Calcium Channels / physiology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chloroquine / pharmacology
  • Chloroquine / therapeutic use*
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / physiopathology
  • Hypoxia / complications
  • Hypoxia / physiopathology*
  • Male
  • Mice, Inbred C57BL
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / physiology
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / physiology
  • Rats, Sprague-Dawley
  • Vasodilator Agents / pharmacology
  • Vasodilator Agents / therapeutic use*

Substances

  • Calcium Channels
  • Vasodilator Agents
  • Chloroquine