Gomisin A from Schisandra chinensis Induces Endothelium-Dependent and Direct Relaxation in Rat Thoracic Aorta

Abstract

Schisandra chinensis (SC), a member of the Magnoliaceae family, has been used to improve the vascular health for postmenopausal women in Korea. In order to provide some scientific rationales for such effectiveness, this study investigated the vascular effects of gomisin A (GA) from SC. In the endothelium (ED)-intact rings of rat thoracic aorta, GA (1 × 10^-6 to 3 × 10^-4 M) caused a concentration-dependent relaxation which was markedly attenuated not only by removal of ED but also by pretreatment with N ^G-nitro-L-arginine (10^-4 M) or 1H-[1] [2] [4]oxadiazolo[4,3-a]quinoxalin-1-one (3 × 10^-5 M). Direct measurement of nitrite, a metabolite of nitric oxide (NO), confirmed that NO production in isolated aorta was increased by GA. In the ED-denuded specimens, the relaxation by GA was not abolished but reduced significantly. The relaxation by GA in ED-denuded aortic rings were clearly inhibited by calyculin A (3 × 10^-8 M), an inhibitor of MLC phosphatase. Furthermore, the phenylephrine-enhanced phosphorylation ratio of MLC was significantly attenuated by GA. Based on these results, it is suggested that GA induced vascular relaxation by partially activating ED-dependent NO pathway, and partially dephosphorylation of MLC.

Schisandra chinensis - Magnoliaceae - gomisin A - vasodilation - nitric oxide

References

• 1 Sinclair S. Chinese herbs: a clinical review of Astragalus, Ligusticum, and Schizandrae .  Altern Med Rev. 1998;  3 338-44.
• 2 Nakajima K, Taquchi H, Ikeya Y, Endo T, Yosioka I. Constituents of Schizandra chinensis Baill. Xlll. Quantitative analysis of lignans in the fruits of Shcizandra chinensis Baill. By high performance liquid chromatography.  Yakuqaku Zasshi. 1983;  103 743-9.
• 3 He X -G, Lian L -Z, Lin L -Z. Analysis of lignan constituents from Schisandra chinensis by liquid chromatography-electrospray mass spectrometry.  J Chromatogr A. 1997;  757 81-7.
• 4 Chiu P Y, Mak D H, Poon M K, Ko K M. In vivo antioxidant action of a lignan-enriched extract of Schisandra fruit and an anthraquinone-containing extract of polygonum root in comparison with schisandrin B and emodin.  Planta Med. 2002;  68 951-6.
• 5 Wang C, Makela T, Hase T, Adlercreutz H, Kurzer M. Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes.  J Steroid Biochem Mol Biol. 1994;  50 205-12.
• 6 Yasukawa K, Ikeya Y, Mitsuhashi H, Iwasaki M, Aburada M, Nakagawa S. Gomisin A inhibits tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin.  Oncology. 1992;  49 68-71.
• 7 Fujihashi T, Hara H, Sakata T, Mori K, Hiquchi H, Tanaka A. et al . Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new non-nucleoside inhibitors of HIV type 1 reverse transcriptase.  Antimicrob Aqents Chemother. 1995;  39 2000-7.
• 8 Maeda S, Takeda S, Miyamoto Y, Aburada M, Harada M. Effects of gomisin A on liver functions in hepatotoxic chemicals-treated rats.  Jpn J Pharmacol. 1985;  38 347-53.
• 9 Yamada S, Murawaki Y, Kawasaki H. Preventive effect of gomisin A, a lignan component of Shizandra fruits, on acetaminophen-induced hepatotoxicity in rats.  Biochem Pharmacol. 1993;  46 1081-5.
• 10 Rhyu M R, Kim E Y, Yoon B K, Lee Y J, Chen S N. Aqueous extract of Schizandra chinensis fruit causes endothelium-dependent and -independent relaxation of isolated rat thoracic aorta.  Phytomedicine. 2006;  13 651-7.
• 11 Choi Y W, Takamatsu S, Khan S I, Srinivas P V, Ferreira D, Zhao J. et al . Schisandrene, a dibenzocyclooctadiene lignan from Schisandra chinensis: structure-antioxidant activity relationships of dibenzocyclooctadiene lignans.  J Nat Prod. 2006;  69 356-9.
• 12 Avula B, Choi Y W, Srinivas P V, Khan I A. Quantitative determination of lignan constituents from Schisandra chinensis by liquid chromatography.  Chromatographia. 2005;  61 515-8.
• 13 Ikeya Y, Taguchi H, Yosioka I, Kobayashi H. The constituents of Schisandra chinensis Baill. Isolation and structure determination of five new lignans, gomisin A, B, C, F and G and the absolute structure of schisandrin.  Chem Pharm Bull. 1979;  27 1383-94.
• 14 Raghavan S AV, Dikshit M. L-Citrulline mediated relaxation in the control and lipopolysaccharide-treated rat aortic rings.  Eur J Pharmacol. 2001;  431 61-9.
• 15 Rapoport R M, Murad F. Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP.  Circ Res. 1983;  52 352-7.
• 16 Haug L S, Jensen V, Hvalby O, Walaas S I, Ostvold A C. Phosphorylation of the inositol 1,4,5-triphosphate receptor by cyclic nucleotide-dependent kinases in vitro and in rat cerebellar slices in situ .  J Biol Chem. 1999;  274 7467-73.
• 17 Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G. et al . Regulation of intracellular calcium by a signaling complex of IRAG, IP3 receptor and cGMP kinase I_β .  Nature. 2000;  404 197-201.
• 18 Ammendola A, Geiselhoringer A, Hofmann F, Schlossmann J. Molecular determinants of the interaction between the inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate (IRAG) and cGMP kinase I_β .  J Biol Chem. 2001;  276 24 153-9.
• 19 Marin J, Rodriguez-Martinez M A. Role of nitric oxide in physiological and pathological conditions.  Pharmacol Ther. 1997;  75 111-34.
• 20 Fujita S, Roeriq D L, Bosnjak Z J, Stowe D F. Effects of vasodilators and perfusion pressure on coronary flow and simultaneous release of nitric oxide from guinea pig isolated hearts.  Cardiovasc Res. 1998;  38 655-67.
• 21 Kamm K E, Stull J T. The function of myosin and myosin light chain kinase phosphorylation in smooth muscle.  Annu Rev Pharmacol Toxicol. 1985;  25 593-620.
• 22 Bialojan C, Ruegg J C, DiSalvo J. A myosin phosphatase modulates contractility in skinned smooth muscle.  Pflugers Arch. 1987;  410 304-12.
• 23 Somlyo A P, Somlyo A V. Signal transduction and regulation in smooth muscle.  Nature. 1994;  372 231-6.

1 These authors contributed equally to this work