Here we further examine the involvement of TRPC and SOCE in PH with a widely used rat model of monocrotaline (MCT)-induced PAH. Rats developed severe PAH, right ventricular hypertrophy, and significant increase in store-operated TRPC1 and TRPC4 mRNA and protein in endothelium-denuded pulmonary arteries (PAs) 3 wk after MCT injection. Contraction of PA and Ca 2ϩ influx in PASMC evoked by store depletion using cyclopiazonic acid (CPA) were enhanced dramatically, consistent with augmented SOCE in the MCT-treated group. The time course of increase in CPA-induced contraction corresponded to that of TRPC1 expression. Endothelin-1 (ET-1)-induced vasoconstriction was also potentiated in PAs of MCT-treated rats. The response was partially inhibited by SOCE blockers, including Gd 3ϩ , La 3ϩ , and SKF-96365, as well as the general TRPC inhibitor BTP-2, suggesting that TRPC-dependent SOCE was involved. Moreover, the ET-1-induced contraction and Ca 2ϩ response in the MCT group were more susceptible to the inhibition caused by the various SOCE blockers. Hence, our study shows that MCTinduced PAH is associated with increased TRPC expression and SOCE, which are involved in the enhanced vascular reactivity to ET-1, and support the hypothesis that TRPC-dependent SOCE is an important pathway for the development of PH.canonical transient receptor potential 1; store-operated calcium channels; monocrotaline; pulmonary hypertension; endothelin-1 PULMONARY HYPERTENSION (PH) is a pathophysiological condition associated with a board spectrum of diseases of different pathological features and etiological mechanisms (53). Among them, pulmonary arterial hypertension (PAH) is a severe progressive form characterized by vasoconstriction, plexiform formation, and vascular cell proliferation and remodeling, resulting in elevated pulmonary vascular resistance, right ventricular hypertrophy, and eventually right heart failure and death (16). There are different types of PAH, including idiopathic (IPAH) and heritable PAH (53). PH owing to lung diseases and hypoxia is another category of PH, which includes PH associated with chronic obstructive pulmonary disease, sleep disorders, and chronic exposure to high altitude. PH in this group is generally mild to moderate, but it worsens the prognosis of the diseases (9, 41). The etiologic mechanisms of the various forms of PH are different, but they all have the common features of abnormalities in pulmonary vascular function, vascular cell proliferation, and remodeling, suggesting that they may share some important downstream signaling mechanisms in the process of disease development.Intracellular Ca 2ϩ signaling plays pivotal roles in the regulation of numerous physiological and pathophysiological processes, including contraction, proliferation, hypertrophy, and migration, in pulmonary arterial smooth muscle cell (PASMC) (45). Previous studies indicate that there are major alterations in ion channel expression and Ca 2ϩ homeostasis, such as membrane depolarization, downregulation of voltage-gated K ϩ chan...

Rationale: Obesity leads to resistant hypertension and mechanisms are poorly understood, but high plasma levels of leptin have been implicated. Leptin increases blood pressure acting both centrally in the dorsomedial hypothalamus and peripherally. Sites of the peripheral hypertensive effect of leptin have not been identified. We previously reported that leptin enhanced activity of the carotid sinus nerve, which transmits chemosensory input from the carotid bodies (CBs) to the medullary centers, and this effect was abolished by nonselective blockers of Trp (transient receptor potential) channels. We searched our mouse CB transcriptome database and found that the Trpm7 (transient receptor potential melastatin 7) channel was the most abundant Trp channel. Objective: To examine if leptin induces hypertension acting on the CB Trpm7. Methods and Results: C57BL/6J (n=79), leptin receptor ( LepR b ) deficient db/db mice (n=22), and LepRb-EGFP (n=4) mice were used. CB Trpm7 and LepR b gene expression was determined and immunohistochemistry was performed; CB glomus cells were isolated and Trpm7-like current was recorded. Blood pressure was recorded continuously in (1) leptin-treated C57BL/6J mice with intact and denervated CB; (2) leptin-treated C57BL/6J mice, which also received a nonselective Trpm7 blocker FTY720 administered systemically or topically to the CB area; (3) leptin-treated C57BL/6J mice transfected with Trpm7 small hairpin RNA to the CB, and (4) Lepr b deficient obese db/db mice before and after Lepr b expression in CB. Leptin receptor and Trpm7 colocalized in the CB glomus cells. Leptin induced a nonselective cation current in these cells, which was inhibited by Trpm7 blockers. Leptin induced hypertension in C57BL/6J mice, which was abolished by CB denervation, Trpm 7 blockers, and Trpm7 small hairpin RNA applied to CBs. Lepr b overexpression in CB of Lepr b -deficient db/db mice demethylated the Trpm7 promoter, increased Trpm7 gene expression, and induced hypertension. Conclusions: We conclude that leptin induces hypertension acting on Trmp7 in CB, which opens horizons for new therapy.

Background: Pulmonary hypertension (PH) is characterized by profound vascular remodeling and alterations in Ca²⁺ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Multiple transient receptor potential melastatin-related (TRPM) subtypes have been identified in vascular tissue. However, the changes in the expression and function of TRPM channels in pulmonary hypertension have not been characterized in detail. Methods: We examined the expression of TRPM channels and characterized the functions of the altered TRPM channels in two widely used rat models of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH. Results: CH-exposed and MCT-treated rats developed severe PH and right ventricular hypertrophy, with a significant decrease in TRPM8 mRNA and protein expression in pulmonary arteries (PAs). The downregulation of TRPM8 was associated with significant reduction in menthol-induced cation-influx. Time-profiles showed that TRPM8 down-regulation occurred prior to the increase of right ventricular systolic pressure (RVSP) and right ventricular mass index (RVMI) in CH-exposed rats, but these changes were delayed in MCT-treated rats. The TRPM8 agonist menthol induced vasorelaxation in phenylephrine-precontracted PAs, and the vasorelaxing effects were significantly attenuated in PAs of both PH rat models, consistent with decreased TRPM8 expression. Conclusion: Downregulation of TRPM8 may contribute to the enhanced vasoreactivity in PH.

Background: To evaluate the antidepressant effects of auricular intradermal acupuncture (AIA) of areas innervated by both the auricular branch of the vagus nerve and the trigeminal nerve. Methods: Forty-nine patients with depression were randomly allocated into an AIA group ( n = 25) and a sham AIA group ( n = 24). Both groups received selective serotonin reuptake inhibitors (SSRIs) as conventional treatment. The AIA group received AIA stimulation, and the sham AIA group received sham AIA, which constituted being subjected to an attached needle that did not penetrate the skin. The needles were retained for 4 h each session, with five sessions a week for a total duration of 2 weeks. The outcomes were assessed by the 17-item Hamilton depression rating scale (HAMD-17), five factors (sleep disorder, retardation, cognitive dysfunction, anxiety/somatization, and weight) and self-rating depression scale (SDS) at weeks 0, 1, and 2. Results: Fifty-four patients were randomly assigned to the AIA ( n = 27) and sham AIA group ( n = 27), of whom 25 patients in the AIA and 24 patients in the sham AIA group were analyzed. AIA-treated patients displayed a significantly greater reduction from baseline in HAMD-17 scores ( p = 0.03) and SDS scores ( p = 0.02) at week 2 compared to patients receiving sham AIA. The AIA intervention also produced a higher rate of clinically significant responses in sleep disorders ( p = 0.07) compared to sham AIA. No adverse events occurred in either group. Conclusion: According to the findings of this preliminary study, AIA appears to have additional value compared to SSRIs alone in treating patients with depressive disorder.