Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, PR China.
The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, 100029, PR China.
Biomed Pharmacother. 2019 Mar;111:188-197. doi: 10.1016/j.biopha.2018.12.061. Epub 2018 Dec 21.
Both Chuanxiong (Ligusticum chuanxiong Hort) and Tianma (Gastrodia elata Blume) have the effects of vasorelaxation and antihypertension. However, the effects of Tianshu Capsule (TSC, composed of Chuanxiong and Tianma in the mass ratio of 4:1) on antihypertensive activity have not been explored. This study aimed to investigate the eff ;ects of TSC on vascular tension and blood pressure in rats and to explore the underlying mechanisms.
The vasorelaxant effect of TSC was explored on thoracic aortic rings (both intact endothelium and denuded) preincubated with phenylephrine (Phe) or potassium chloride (KCL). The mechanism was investigated in the presence of antagonists or blockers on aorta isolated from normotensive rats. The in vivo antihypertensive effect was assessed using a tail-cuff method on spontaneously hypertensive rats (SHRs).
TSC (0.125-4 mg/mL) produced a concentration-dependent vasorelaxation on aortic rings preincubated with Phe (1 μM) or KCL (60 mM). Removal of aorta endothelium markedly attenuated the TSC activity. Pretreatment of aortic rings with β-adrenoceptor blocker propranolol (1 μM), muscarinic receptor antagonist atropine (1 μM), cyclooxygenase inhibitor indomethacin (IDO, 1 μM), adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 μM), K channel blockers 4-aminopyridine(4-AP, 1 mM) or barium chloride(BaCl, 1 mM) followed by addition of Phe (1 μM) prior to TSC did not influence the TSC-induced relaxation. In contrast, the vasorelaxant effects of TSC were markedly inhibited by the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 10 μM), guanylyl cyclase inhibitor 1H- [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 μM), K channel blockers, glibenclamide (100 μM) and clotrimazole (5 mM). Moreover, TSC (2 mg/mL, 4 mg/mL) inhibited CaCl-induced contractions and caused a concentration-dependent rightward shift of the response curves. Additionally, TSC (2 mg/mL, 4 mg/mL) depressed the constriction caused by Phe (1 μM) in the absence of extracellular Ca. Furthermore, TSC (2.15 g/kg) lowered the systolic blood pressure (SBP), with no alteration in heart rate (HR) in SHRs.
These findings demonstrated that TSC induced vasorelaxant effects via both endothelium-dependent and endothelium-independent pathways. The NO/sGC/cGMP pathway, ATP-sensitive K channels, Ca-activated K channels, inhibition of extracellular Ca influx and intracellular Ca2 release were probably involved in this relaxation. The vasorelaxant effects of TSC may make the greatest contribution to the reduction in high blood pressure.
川芎（Ligusticum chuanxiong Hort）和天麻（Gastrodia elata Blume）均具有血管舒张和降压作用。然而，天舒胶囊（TSC，由川芎和天麻以 4:1 的质量比组成）对降压活性的影响尚未得到探索。本研究旨在探讨 TSC 对血管张力和大鼠血压的影响，并探讨其潜在机制。
使用预先用苯肾上腺素（Phe）或氯化钾（KCL）孵育的胸主动脉环（均有完整内皮和无内皮）来研究 TSC 的血管舒张作用。在来自正常血压大鼠的主动脉上存在拮抗剂或阻滞剂的情况下，研究了机制。使用尾套法在自发性高血压大鼠（SHRs）上评估 TSC 的体内降压作用。
TSC（0.125-4mg/mL）对预先用 Phe（1μM）或 KCL（60mM）孵育的主动脉环产生浓度依赖性的血管舒张作用。去除主动脉内皮显著减弱了 TSC 活性。用β肾上腺素能受体阻滞剂普萘洛尔（1μM）、毒蕈碱受体拮抗剂阿托品（1μM）、环氧化酶抑制剂吲哚美辛（IDO，1μM）、腺苷酸环化酶抑制剂 9-（四氢-2-呋喃基）-9H-嘌呤-6-胺（SQ22536，100μM）、K 通道阻滞剂 4-氨基吡啶（4-AP，1mM）或氯化钡（BaCl，1mM）预处理主动脉环，然后加入 Phe（1μM），然后加入 TSC，不影响 TSC 诱导的松弛。相比之下，NO 合酶抑制剂 L-NG-硝基精氨酸甲酯（L-NAME，10μM）、鸟苷酸环化酶抑制剂 1H-[1,2,4]恶二唑-[4,3-a]喹喔啉-1-酮（ODQ，10μM）、K 通道阻滞剂格列本脲（100μM）和克霉唑（5mM）显著抑制了 TSC 的血管舒张作用。此外，TSC（2mg/mL，4mg/mL）抑制 CaCl2 诱导的收缩，并导致反应曲线的浓度依赖性右移。此外，TSC（2mg/mL，4mg/mL）在不存在细胞外 Ca 的情况下抑制了 Phe（1μM）引起的收缩。此外，TSC（2.15g/kg）降低了 SHRs 的收缩压（SBP），而心率（HR）没有变化。
这些发现表明，TSC 通过内皮依赖性和非内皮依赖性途径诱导血管舒张作用。NO/sGC/cGMP 途径、ATP 敏感性 K 通道、Ca 激活的 K 通道、抑制细胞外 Ca 内流和细胞内 Ca2 释放可能参与了这种松弛。TSC 的血管舒张作用可能对降低高血压有最大的贡献。
