Background: Pulmonary hypertension (PH) is characterized by sustained vasoconstriction, enhanced vasoreactivity and vascular remodeling, which leads to right heart failure and death. Despite several treatments are available, many forms of PH are still incurable. Ginsenoside Rb1, a principle active ingredient of Panax ginseng, exhibits multiple pharmacological effects on cardiovascular system, and suppresses monocrotaline (MCT)-induced right heart hypertrophy. However, its effect on the pulmonary vascular functions related to PH is unknown. Methods: We examined the vasorelaxing effects of ginsenoside Rb1 on endothelin-1 (ET-1) induced contraction of pulmonary arteries (PAs) and store-operated Ca²⁺ entry (SOCE) in pulmonary arterial smooth muscle cells (PASMCs) from chronic hypoxia (CH) and MCT-induced PH. Results: Ginsenoside Rb1 elicited concentration-dependent relaxation of ET-1-induced PA contraction. The vasorelaxing effect was unaffected by nifedipine, but abolished by the SOCE blocker Gd³⁺. Ginsenoside Rb1 suppressed cyclopiazonic acid (CPA)-induced PA contraction, and CPA-activated cation entry and Ca²⁺ transient in PASMCs. ET-1 and CPA-induced contraction, and CPA-activated cation entry and Ca²⁺ transients were enhanced in PA and PASMCs of CH and MCT-treated rats; the enhanced responses were abolished by ginsenoside Rb1. Conclusion: Ginsenoside Rb1 attenuates ET-1-induced contractile response via inhibition of SOCE, and it can effectively antagonize the enhanced pulmonary vasoreactivity in PH.

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Pulmonary hypertension (PH) is characterized by profound vascular remodeling and alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Members of multiple transient receptor potential subfamilies (TRPC, TRPV, and TRPM) have been identified in pulmonary vascular tissue. Our previous studies showed that the expression and functions of the store‐operated TRPC1, receptor‐operated TRPC6, and the mechanosensitive TRPV4 channels are augmented in PASMCs during PH, and their upregulation contribute to PH development. In contrast, TRPM8 is down‐regulated in PASMCs of rats PH models, and activation of TRPM8 with agonists causes relaxation of pulmonary arteries (PAs)(Liu et al., Cell Physiol Biochem 2013, 31:892–904). However, the mechanism of TRPM8‐induced PA relaxation has not been determined. In this study, we examined the possible interactions of TRPM8 activation and store‐operated Ca2+ entry (SOCE) in PAs and PASMCs of normoxic and chronic hypoxic pulmonary hypertensive (CHPH) rats. We found that TRPM8 expression was down‐regulated in PAs and the TRPM8‐mediated cation entry was reduced significantly in the PASMCs of rats after 3 weeks of hypoxia (10% O2) exposure. Activation of TRPM8 with icilin (0.1–100 μM) caused concentration‐dependent relaxation of cyclopiazonic acid (CPA) and ET‐1 pre‐contracted endothelium‐denuded PAs in the presence of nifedipine. The vasorelaxant effect of icilin was abolished in the presence of the SOCE antagonist Gd3+ at submicromolar concentration. Icilin suppressed the CPA‐induced cation entry in PASMCs determined by the Mn2+ quenching technique and by Ca2+ transient measurement. The inhibitory effect of icilin on SOCE‐induced PA relaxation and Ca2+ entry were abolished by the TRPM8 antagonist AMTB, indicating that the effect was mediated specifically by TRPM8 channels. Moreover, TRPM8‐mediated inhibitory effects on CPA‐induced contraction in PAs and SOCE in PASMCs were significantly augmented in CHPH rats, probably related to the enhanced SOCE caused by PH. These results demonstrate for the first time that TRPM8 activation can cause relaxation of PA through inhibition of SOCE. Since SOCE plays many important roles in pulmonary vascular functions and is crucial for the vascular remodeling and the enhanced vasoconstriction in PH, the downregulation of TRPM8 expression and activity in PASMCs during PH may minimized the TRPM8‐dependent inhibition of SOCE, and allow unimpeded SOCE activity for PH development. Support or Funding Information Supported by grants NSFC31571179, NSFC31371165, NSF of Fujian Province 2015J01313, and Fujian Province Hundred Experts Award. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.