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...

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Abnormal amplitude of low-frequency fluctuation has been implicated in heroin addiction. However, previous studies lacked consistency and didn’t consider the impact of confounding factors such as methadone and alcohol. Fifty-one heroin-dependent (HD) individuals and 40 healthy controls underwent resting-state functional magnetic resonance imaging. The ‘amplitude of low-frequency fluctuation’ (ALFF) value was calculated and support vector machine (SVM) classification analysis was applied to analyze the data. Compared with healthy controls, heroin addicts exhibited increased ALFF in the right angular gyrus (AG) and left superior occipital gyrus (SOG). A negative correlation was observed between increased ALFF in the right angular gyrus and left superior occipital gyrus and the duration of heroin use ( p 1 =0.004, r 1 =-0.426; p 2 =0.009, r 2 =-0.361). Moreover, the ALFF in the right AG and left SOG could discriminate the HD subjects from the controls with acceptable accuracy (Acc 1 =64.85%, p 1 =0.004; Acc 2 =63.80%, p 2 =0.005). HD patients showed abnormal ALFF in the brain areas involved in semantic memory and visual networks. The longer HD individuals abused heroin, the less the ALFF of associated brain regions increased. These observed patterns suggested that the accumulative effect of heroin’s neurotoxicity overpowered self-recovery of the brain and may be applied as a potential biomarker to identify HD individuals from the controls.

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