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

Kang Wu, Qian Zhang, Xiongting Wu, Wenju Lu, Haiyang Tang, Zhihao Liang, Yali Gu, Shanshan Song, Ramon J. Ayon, Ziyi Wang, Kimberly M. McDermott, Angela Balistrieri, Christina Wang, Stephen Matthew Black, Joe G.N. Garcia, Ayako Makino, Jason X.J. Yuan, Jian Wang

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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.

Original languageEnglish (US)
Pages (from-to)4155-4172
Number of pages18
JournalBritish Journal of Pharmacology
Volume174
Issue number22
DOIs
StatePublished - Nov 2017

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ASJC Scopus subject areas

  • Pharmacology

Cite this

Wu, K., Zhang, Q., Wu, X., Lu, W., Tang, H., Liang, Z., Gu, Y., Song, S., Ayon, R. J., Wang, Z., McDermott, K. M., Balistrieri, A., Wang, C., Black, S. M., Garcia, J. G. N., Makino, A., Yuan, J. X. J., & Wang, J. (2017). Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia-induced pulmonary hypertension. British Journal of Pharmacology, 174(22), 4155-4172. https://doi.org/10.1111/bph.13990