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 McDermott, Angela Balistrieri, Christina Wang, Stephen M. Black, Joe GN Garcia, Ayako Makino, Jason Yuan, Jian Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 1 2017

Fingerprint

Chloroquine
Vasodilator Agents
Pulmonary Hypertension
Pulmonary Artery
Lung
Smooth Muscle Myocytes
Hypoxia
Fura-2
Phenylephrine
Vasoconstriction
Fluorescence Microscopy
Indomethacin
Vascular Resistance
Endothelium
Adenosine Triphosphate
Pressure
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia-induced pulmonary hypertension. / Wu, Kang; Zhang, Qian; Wu, Xiongting; Lu, Wenju; Tang, Haiyang; Liang, Zhihao; Gu, Yali; Song, Shanshan; Ayon, Ramon J.; Wang, Ziyi; McDermott, Kimberly; Balistrieri, Angela; Wang, Christina; Black, Stephen M.; Garcia, Joe GN; Makino, Ayako; Yuan, Jason; Wang, Jian.

In: British Journal of Pharmacology, Vol. 174, No. 22, 01.11.2017, p. 4155-4172.

Research output: Contribution to journalArticle

Wu, K, Zhang, Q, Wu, X, Lu, W, Tang, H, Liang, Z, Gu, Y, Song, S, Ayon, RJ, Wang, Z, McDermott, K, Balistrieri, A, Wang, C, Black, SM, Garcia, JGN, Makino, A, Yuan, J & Wang, J 2017, 'Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia-induced pulmonary hypertension', British Journal of Pharmacology, vol. 174, no. 22, pp. 4155-4172. https://doi.org/10.1111/bph.13990
Wu, Kang ; Zhang, Qian ; Wu, Xiongting ; Lu, Wenju ; Tang, Haiyang ; Liang, Zhihao ; Gu, Yali ; Song, Shanshan ; Ayon, Ramon J. ; Wang, Ziyi ; McDermott, Kimberly ; Balistrieri, Angela ; Wang, Christina ; Black, Stephen M. ; Garcia, Joe GN ; Makino, Ayako ; Yuan, Jason ; Wang, Jian. / Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia-induced pulmonary hypertension. In: British Journal of Pharmacology. 2017 ; Vol. 174, No. 22. pp. 4155-4172.
@article{bab11e21808b4e72998c307fc31e3609,
title = "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.",
author = "Kang Wu and Qian Zhang and Xiongting Wu and Wenju Lu and Haiyang Tang and Zhihao Liang and Yali Gu and Shanshan Song and Ayon, {Ramon J.} and Ziyi Wang and Kimberly McDermott and Angela Balistrieri and Christina Wang and Black, {Stephen M.} and Garcia, {Joe GN} and Ayako Makino and Jason Yuan and Jian Wang",
year = "2017",
month = "11",
day = "1",
doi = "10.1111/bph.13990",
language = "English (US)",
volume = "174",
pages = "4155--4172",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "22",

}

TY - JOUR

T1 - Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia-induced pulmonary hypertension

AU - Wu, Kang

AU - Zhang, Qian

AU - Wu, Xiongting

AU - Lu, Wenju

AU - Tang, Haiyang

AU - Liang, Zhihao

AU - Gu, Yali

AU - Song, Shanshan

AU - Ayon, Ramon J.

AU - Wang, Ziyi

AU - McDermott, Kimberly

AU - Balistrieri, Angela

AU - Wang, Christina

AU - Black, Stephen M.

AU - Garcia, Joe GN

AU - Makino, Ayako

AU - Yuan, Jason

AU - Wang, Jian

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85032301630&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032301630&partnerID=8YFLogxK

U2 - 10.1111/bph.13990

DO - 10.1111/bph.13990

M3 - Article

C2 - 28849593

AN - SCOPUS:85032301630

VL - 174

SP - 4155

EP - 4172

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 22

ER -