Activation of iberiotoxin-sensitive, Ca²⁺-activated K⁺ channels of porcine isolated left anterior descending coronary artery by diosgenin

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• 作者：Au ; Alice Lai Shan ; Kwok ; Ching Chi ; Lee ; Allen Ting Chun ; Kwan ; Yiu Wa ; Lee ; Macey Mei Sze ; et. al.
• 关键词：Diosgenin ; Porcine coronary artery ; Oestrogen receptor ; Iberiotoxin-sensitive ; Ca²⁺-activated K⁺ (BK_Ca) channel
• 刊名：European Journal of Pharmacology
• 出版年：2004
• 出版时间：October 11, 2004
• 年：2004
• 卷：502
• 期：1-2
• 页码：123-133
• 全文大小：477 K

文摘

The objective of this study was to determine the vasodilating effect of 3??-hydroxy-5-spirostene (diosgenin), a phytoestrogen found in wild yams, using porcine resistance left anterior descending coronary artery. In 5-hydroxytryptamine (3 ??M) pre-contracted preparation, diosgenin caused a concentration-dependent (0.01 to 1 ??M), endothelium-independent relaxation, with a maximum relaxation of ???72 % at 1 ??M. No apparent effect was observed with 17??-oestradiol and progesterone with concentrations ???0.3 ??M, and a relaxation of ???15 % and ???23 % caused by 17??-oestradiol (1 ??M) and progesterone (1 ??M), respectively. Diosgenin-elicited relaxation was not altered by 7??,17??-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI 182,780), mifepristone, (+)-bicuculline, cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12330A), glibenclamide and scavengers of reactive oxygen species. The iberiotoxin-sensitive, Ca²⁺-activated K⁺ (BK_Ca) current of single vascular myocytes recorded, using patch-clamp techniques, was markedly enhanced by diosgenin, 17??-oestradiol and progesterone. Application of (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3???,2???,1???-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT 5823, 300 nM) eradicated the enhancement of BK_Ca amplitude. Diosgenin, 17??-oestradiol and progesterone did not affect whereas phloretin, biochanin A and zearalanone (1 ??M each) significantly suppressed [Ca²⁺]_o-induced contraction. In oestrogen competition essay using human breast cancer cell (MCF-7 cells), diosgenin (0.001 nM to 10 ??M) did not interact with oestrogen receptor-??, and no displacement of [³H]17??-oestradiol was observed. In oestrogen receptor ??- and ??-fluorescence polarization competitor assay, diosgenin (100 ??M) demonstrated a greater competition with the ??-isoform of oestrogen receptor. These results suggest that diosgenin caused an acute, endothelium-independent coronary artery relaxation via protein kinase G signalling cascade and an activation of BK_Ca channel of arterial smooth muscle cells. The oestrogen receptor (?? and ??-isoforms) and progesterone receptor are probably not involved.