*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)
Background and Purpose: Tetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH).Experimental Approach: Three well-defined models of PH -chronic hypoxia (10% O 2 )-induced PH (HPH), monocrotaline-induced PH (MCT-PH) and Sugen 5416/hypoxia-induced PH (SuHx-PH) -were used in Sprague-Dawley rats, and assessed by echocardiography, along with haemodynamic and histological techniques. Primary cultures of rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to study intracellular calcium levels. Western blots and RT-qPCR assays were also used.In the clinical cohort, patients with PAH or CTEPH were recruited. The effects of TMP were evaluated in all systems.Key Results: TMP (100 mgÁkg −1 Áday −1 ) prevented rats from developing experimental PH and ameliorated three models of established PH: HPH, MCT-PH and SuHx-PH.The therapeutic effects of TMP were accompanied by inhibition of intracellular calcium homeostasis in PASMCs. In a small cohort of patients with PAH or CTEPH, oral Abbreviations: 2D, 2-dimensional; 6MWD, 6-min walking distance; Ccr, creatinine clearance; CTEPH, chronic thromboembolic pulmonary hypertension; EIP, End-inspiratory plateau pressure; FAC, Fractional area change; H&E, haematoxylin and eosin; HPH, hypoxia-induced pulmonary hypertension; HRR1, heart rate recovery at 1 min of rest; IPAH, idiopathic pulmonary arterial hypertension; KRBS, Krebs Ringer bicarbonate solution; LV, left ventricle; LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; MCT, monocrotaline; mPAP, mean pulmonary arterial pressure; PA, pulmonary artery; PAD, pulmonary arterial diameter; PAH, pulmonary arterial hypertension; PAP, pulmonary arterial pressure; PASMC, pulmonary arterial smooth muscle cells; PAT, pulmonary arterial acceleration time; PET, pulmonary arterial ejection time; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RAD, right atrium diameter; RHC, right heart catheterization; ROCC, receptor-operated Ca 2+ channels; ROCE, receptor-operated Ca 2+ entry; RV, right ventricle; RVEDD, Right ventricular end diastolic diameter; RVEDWT, right ventricular end-diastolic free-wall thickness; RVSP, right ventricular systolic pressure; S, septum; SOCC, store-operated Ca 2+ channels; SOCE, store-operated Ca 2+ entry; SuHx-PH, Sugen/hypoxia-induced pulmonary hypertension; TAPSE, tricuspid annular plane systolic excursion; TMP, tetramethylpyrazine; VDCC, voltage-dependent Ca 2+ channels. administration of TMP (100 mg, t.i.d. for 16 weeks) increased the 6-min walk distance and improved the 1-min heart rate recovery.Conclusion and Implications: Our results s...
Although it is well established that motor vehicle exhaust (MVE) has a close association with the occurrence and exacerbation of chronic obstructive pulmonary disease (COPD), very little is known about the combined effects of MVE and intermittent or chronic subclinical inflammation on COPD pathogenesis. Therefore, given the crucial role of inflammation in the development of COPD, we wanted to establish an animal model of COPD using both MVE exposure and airway inflammation, which could mimic the clinical pathological changes observed in COPD patients and greatly benefit the study of the molecular mechanisms of COPD. In the present study, we report that mice undergoing chronic exposure to MVE and intratracheal instillation of lipopolysaccharide (LPS) successfully established COPD, as characterized by persistent air flow limitation, airway inflammation, inflammatory cytokine production, emphysema and small airway remodelling. Moreover, the mice showed significant changes in ventricular and vascular pathology, including an increase in right ventricular pressure, right ventricular hypertrophy and remodelling of pulmonary arterial walls. We have thus established a new mouse COPD model by combining chronic MVE exposure with early intratracheal instillation of LPS, which will allow us to study the relationship between air pollution and the development of COPD and to investigate the underlying molecular mechanisms.
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