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

Abstract

*These authors contributed equally to this work. BACKGROUND AND PURPOSESustained 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 APPROACHIsometric 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 Ca 2+ concentration levels in PA smooth muscle cells (PASMCs). Patch-clamp experiments were performed to assess the activity of voltagedependent Ca 2+ channels (VDCCs) in PASMC. Rats exposed to hypoxia (10% O 2 ) for 3 weeks were used as the model of HPH or Sugen5416/hypoxia (SuHx) for in vivo experiments. KEY RESULTSChloroquine 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 Ca 2+ entry and ATP-induced Ca 2+ entry. Furthermore, chloroquine also inhibited whole-cell Ba 2+ currents through VDCC in PASMC. In vivo experiments demonstrated that chloroquine treatment ameliorated the HPH and SuHx models. CONCLUSIONS AND IMPLICATIONSChloroquine is a potent pulmonary vasodilator that may directly or indirectly block VDCC, store-operated Ca 2+ channels and receptor-operated Ca 2+ 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. BJP British Journal of PharmacologyBritish Journal of Pharmacology (2017)

Complex interplay between autophagy and oxidative stress in the development of pulmonary disease

“…In concordance with these findings, several autophagy inhibitors have been tested in animal models and were able to attenuate PAH development. Lysosomal inhibitors, chloroquine and hydroxychloroquine, which inhibit autophagy by preventing autophagosome maturation, were reported to diminish proliferation of SMC and reduce PAH pathogenesis in monocrotaline-treated rats [ 320 ] and hypoxia-exposed mice [ 324 ]. Zhang and colleagues reported hypoxia-induced proliferation of PASMC can be reversed by another inhibitor of autophagy, 3-MA [ 323 ].…”

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

“…Since autophagy is necessary in cell homeostasis, cardiac QT elongation [140,141] and anaemia [142] are common CQ/HCQ side effects related to autophagy inhibition and need to be used with care. Additionally, CQ induces autophagy-independent effects, like Golgi disorganization [143] and pulmonary vasodilation [144], contributing to its controversial clinical activity. To avoid these effects and to obtain a limitation of autophagy in order to reduce cytokine activation, IL-6R mAb has been found effective in different settings [145,146].…”

Chloroquine differentially modulates coronary vasodilation in control and diabetic mice

“…Sai et al () demonstrated that chloroquine induces vasodilation in rat aorta at high concentration (>100 μmol·L −1 ) via inhibiting voltage‐dependent L‐type Ca 2+ channel (VDCC). We have also found that pretreatment with chloroquine (200 μmol·L −1 ) attenuates vascular contraction in mouse pulmonary artery through inhibition of VDCC in smooth muscle cells (SMCs; Wu et al, ). Pestana et al () show that chloroquine relaxes vessels in a dose‐dependent manner by increasing NO production in rat aorta.…”

“…The vascular response to the same agonist is not always the same among different organs and branches of vessels. Although there are several studies investigating the effect of chloroquine on vascular response (Manson et al, ; Pestana et al, ; Sai et al, ; Wu et al, ), there is no report so far that examines the effect of chloroquine on vasodilation in CAs isolated from healthy and diabetic mice. Muscarinic agonist (e.g.…”

“…Recently, there is increasing evidence that chloroquine also regulates the function of vascular cells (Manson et al, 2014;Pestana, Oishi, Salistre-Araujo, & Rodrigues, 2015;Sai et al, 2014;Wu et al, 2017) and cardiac myocytes (Sanchez-Chapula, Salinas-Stefanon, Torres-Jacome, Benavides-Haro, & Navarro-Polanco, 2001;Tona, Ng, Akera, & Brody, 1990). Sai et al (2014) demonstrated that chloroquine induces vasodilation in rat aorta at high concentration (>100 μmol·L −1 ) via inhibiting voltage-dependent L-type Ca 2+ channel (VDCC).…”