Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

Abstract

altitude diseases that are associated with significant morbidity and mortality, such as high-altitude pulmonary edema and heart diseases [3] . Echinacoside (ECH) (Figure 1) is a phenylethanoid glycoside found in a variety of Chinese herbs such as the Tibetan herb Lagotis brevituba Maxim and Cistanche tubulosa [4,5] . Lagotis brevituba Maxim is a species of Lagotis spp belonging to the Scrophulariaceae and grows widely at an altitude over 3000 meter in the Qinghai-Tibet Plateau. ECH has various desirable pharmacological characteristics, such as antioxidative, anti-inflammatory, neuroprotective, hepatoprotective, and nitric oxide (NO) radical-scavenging properties [6] . It can also elicit endothelium-dependent relaxation in rat thoracic aortic rings and cure cardiovascular diseases [7] . HowEchinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BK Ca channels and reducing intracellular Ca 2+ levels Aim: Sustained pulmonary vasoconstriction as experienced at high altitude can lead to pulmonary hypertension (PH). The main purpose of this study is to investigate the vasorelaxant effect of echinacoside (ECH), a phenylethanoid glycoside from the Tibetan herb Lagotis brevituba Maxim and Cistanche tubulosa, on the pulmonary artery and its potential mechanism. Methods: Pulmonary arterial rings obtained from male Wistar rats were suspended in organ chambers filled with Krebs-Henseleit solution, and isometric tension was measured using a force transducer. Intracellular Ca 2+ levels were measured in cultured rat pulmonary arterial smooth muscle cells (PASMCs) using Fluo 4-AM. Results: ECH (30-300 μmol/L) relaxed rat pulmonary arteries precontracted by noradrenaline (NE) in a concentration-dependent manner, and this effect could be observed in both intact endothelium and endothelium-denuded rings, but with a significantly lower maximum response and a higher EC 50 in endothelium-denuded rings. This effect was significantly blocked by L-NAME, TEA, and BaCl 2 . However, IMT, 4-AP, and Gli did not inhibit ECH-induced relaxation. Under extracellular Ca 2+ -free conditions, the maximum contraction was reduced to 24.54%±2.97% and 10.60%±2.07% in rings treated with 100 and 300 μmol/L of ECH, respectively. Under extracellular calcium influx conditions, the maximum contraction was reduced to 112.42%±7.30%, 100.29%±8.66%, and 74.74%±4.95% in rings treated with 30, 100, and 300 μmol/L of ECH, respectively. After cells were loaded with Fluo 4-AM, the mean fluorescence intensity was lower in cells treated with ECH (100 μmol/L) than with NE. Conclusion: ECH suppresses NE-induced contraction of rat pulmonary artery via reducing intracellular Ca 2+ levels, and induces its relaxation through the NO-cGMP pathway and opening of K + channels (BK Ca and K IR ).

Echinacoside‑induced nitric oxide production in endothelial�cells: Roles of androgen receptor and the PI3K‑Akt pathway

“…EcH is a natural compound isolated from Herba Cistanche, with various pharmacological properties. It was previously demonstrated that EcH exerted an endothelium-dependent vascular relaxation effect by opening NO-cGMP-PKG-BK ca channels in blood vessel smooth muscle cells (7,8). The current findings provide evidence that ECH exerted AR-dependent activation of eNOS to induce NO production with the involvement of the PI3K/Akt signaling pathway in vascular endothelial cells.…”

“…It was previously demonstrated that EcH at 350-400 µM directly acts on vascular smooth muscle and inhibits hypoxia-induced proliferation in rat pulmonary artery smooth muscle cells (6), whereas 30-300 µM EcH caused acute vasorelaxation in endothelium-intact rings in a concentration-dependent manner, and enhanced cGMP production in the corpus cavernosum smooth muscle of aortic rings contracted by phenylephrine (7). By opening the NO-cGMP-PKG-BK ca channels in smooth muscle cells, 100 or 300 µM EcH suppressed noradrenaline-induced contraction in the pulmonary arteries of rats, particularly in endothelium-denuded rings (8). Endothelial cells are key regulators of cardiovascular function and, in several cases, it has been found that the endothelial-dependent relaxation was due to a transferrable substance, such as NO, released from the endothelium (9).…”

Tsantan Sumtang Alleviates Chronic Hypoxia-Induced Pulmonary Hypertension by Inhibiting Proliferation of Pulmonary Vascular Cells

“…Based on the above results, the PGI2-cAMP pathway, NO-cGMP pathway, and the opening of K + channels (inward rectifier K + channels, large conductance Ca 2+ -activated K + channels, and voltage-dependent K + channels) seemed to be the main factors in Tsantan Sumtang-induced concentration-dependent pulmonary artery vasorelaxation. For monomer vascular dilators, acetylcholine shows weaker maximum vasorelaxation influence via the NO-cGMP pathway, but echinacoside is a very similar dilator at its highest concentration through the opening of NO-cGMP-PKG-BK Ca channels [37, 38]. According to these reports, both Tsantan Sumtang and monomers exhibited concentration-dependent vasorelaxation effects and reached their maximum rates at one specific dose, while as a compound medicine, the role of Tsantan Sumtang in vasorelaxation occurs through a combination of more pathways than that of monomers; however, further research is still needed [37, 38].…”

Protective role of phenylethanoid glycosides, Torenoside�B and Savatiside A, in Alzheimer's disease

“…However, PhG compounds serve an essential role in the maintenance of calcium homeostasis. For instance, echinacoside induces pulmonary artery vasorelaxation in mice by increasing the number of open NO-cGMP-PKG-BKCa channels and decreasing intracellular Ca 2+ levels (42). In addition, acteoside inhibits the invasive and migrating capabilities of phorbol-12-myristate-13-acetate-induced human fibrosarcoma cells by regulating the Ca 2+ -dependent calmodulin-dependent protein kinase/extracellular regulated kinase and Jun amino-terminal kinase/NF-κB pathways (43).…”