Mechanisms of the vasorelaxant effect of 1, 5-dihydroxy-2, 3-dimethoxy-xanthone, an active metabolite of 1-hydroxy-2, 3, 5-trimethoxy-xanthone isolated from a Tibetan herb, Halenia elliptica, on rat coronary artery.
Mechanisms of the vasorelaxant effect of 1, 5-dihydroxy-2, 3-dimethoxy-xanthone, an active metabolite of 1-hydroxy-2, 3, 5-trimethoxy-xanthone isolated from a Tibetan herb, Halenia elliptica, on rat coronary artery.
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DOI：
10.1016/j.lfs.2007.10.014
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发表时间：
2008-01
期刊：
影响因子：
6.1
通讯作者：
Yan Wang;Jiangong Shi;Mu-zou Wang;C. Che;J. Yeung
中科院分区：
文献类型：
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作者：
Yan Wang;Jiangong Shi;Mu-zou Wang;C. Che;J. Yeung
1，5-二羟基-2，3-二甲氧基-口山酮（HM-5）是一种天然存在于藏药椭圆叶花锚（Halenia elliptica）中的口山酮。最近研究表明，HM-5是H.具有强有力的血管舒张作用的椭圆形。本研究探讨HM-5的血管舒张作用及其机制。HM-5（0.35-21.9 μM）对1 μM 5-羟色胺（5-HT）预收缩的大鼠冠状动脉环产生浓度依赖性舒张作用，EC_（50）为4.40±1.08 μM。与HM-1不同，HM-5的作用是内皮非依赖性的，因此去除内皮不会影响其血管舒张效力。一氧化氮合酶（NOS）抑制剂Nω-硝基-l-精氨酸甲酯（l-NAME，100 μM）、可溶性鸟苷酸环化酶抑制剂1H-[1，2，4]恶二唑并[4，3-α]喹喔啉-1-酮（ODQ，10 μM）不影响HM-5的血管舒张作用，因此证实不涉及内皮相关机制。在内皮剥脱的冠状动脉环中，HM-5的血管舒张作用被钾通道阻滞剂TEA（10 mM）和4-氨基吡啶（4-AP，一种Kv阻滞剂; 1 mM）抑制，但不被其他K+通道阻滞剂如伊比利亚毒素（100 nM）、氯化钡（100 μM）和格列本脲（10 μM）抑制。用无钙缓冲液（完整内皮或去内皮）预孵育的动脉环，在加入CaCl 2诱导收缩前，用1 μM 5-HT或60 mM KCl预处理，研究Ca 2+通道的参与。在5-HT预处理的制剂中，HM-5（34.7 μM）显著抑制CaCl 2诱导的血管收缩（在完整内皮动脉环中抑制率为89.9%;在内皮剥脱环中抑制率为83.3%）。在KCl预处理的制备物中，HM-5（34.7 μM）在内皮剥脱环中产生34%的抑制作用。相同浓度的HM-5抑制10 μM佛波醇12，13-二乙酸酯（PDA）引起的无钙收缩反应（抑制率为62.3%）。综上所述，本研究表明HM-5的血管舒张作用的机制与其母体药物HM-1明显不同。HM-5的血管舒张作用是通过开放钾通道（4-AP）和部分抑制L-型电压操纵性Ca ~（2+）通道和细胞内Ca ~（2+）库的Ca ~（2+）内流而改变细胞内Ca ~（2+）来介导的。
1, 5-Dihydroxy-2, 3-dimethoxy-xanthone (HM-5) is one of the naturally-occurring xanthones of a Tibetan medicinal herb Halenia elliptica. Recently, it has been shown that HM-5 is one of the phase I metabolites of 1-hydroxy-2, 3, 5-trimethoxy-xanthone (HM-1), the major active component of H. elliptica with potent vasorelaxant actions. This study investigated the vasorelaxant effect of HM-5 and its mechanism(s). HM-5 (0.35–21.9 μM) produced a concentration-dependent relaxation in rat coronary artery rings pre-contracted with 1 μM 5-hydroxytryptamine (5-HT), with an EC50of 4.40±1.08 μM. Unlike HM-1, the effect of HM-5 was endothelial-independent such that removal of the endothelium did not affect its vasodilator potency. Nitric oxide synthase (NOS) inhibitor Nω-nitro-l-arginine methyl ester (l-NAME, 100 μM), the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-α] quinoxalin-1-one (ODQ, 10 μM) did not affect the vasodilatory effects of HM-5, thus confirming the non-involvement of endothelium related mechanisms. In endothelium-denuded coronary artery rings, the vasorelaxant effect of HM-5 was inhibited by a potassium channel blocker, TEA (10 mM), and 4-aminopyridine (4-AP, a Kvblocker; 1 mM) but not by other K+channel blockers such as iberiotoxin (100 nM), barium chloride (100 μM) and glibenclamide (10 μM). The involvement of Ca2+channel was studied in artery rings pre-incubated with Ca2+-free buffer (intact endothelium or endothelium-denuded) and primed with 1 μM 5-HT or 60 mM KCl prior to the addition of CaCl2to elicit contraction. In the 5-HT-primed preparations, HM-5 (34.7 μM) significantly inhibited the CaCl2-induced vasoconstriction (89.9% inhibition in intact endothelium artery rings; 83.3% inhibition in endothelium-denuded rings). In the KCl-primed preparations, HM-5 (34.7 μM) produced a 34% inhibition in endothelium-denuded rings. The same concentration of HM-5 inhibited (by 62.3%) the contractile response to 10 μM phorbol 12, 13-diacetate (PDA), a protein kinase C activator, in Ca2+-free solutions. Taken together, this study showed that the mechanisms of the vasorelaxant effects of HM-5 were distinctly different from those of its parent drug HM-1. The vasorelaxant effect of HM-5 was mediated through opening of potassium channel (4-AP) and altering intracellular calcium by partial inhibition of Ca2+influx through L-type voltage-operated Ca2+channels and intracellular Ca2+stores.