Ent-7α-hydroxytrachyloban-18-oic acid, a trachylobane diterpene from
Xylopia langsdorfiana, has previously been shown to relax the guinea-pig trachea in a concentration-dependent manner. In this study we aimed to elucidate the mechanisms underlying this action and so contribute to the discovery of natural products with therapeutic potential. A possible interaction between diterpene and the Ca
2+-calmodulin complex was eliminated as chlorpromazine (10
-6 M), a calmodulin inhibitor, did not significantly alter the diterpene-induced relaxation (pD
2 = 4.38 ± 0.07 and 4.25 ± 0.07; mean ± S.E.M.,
n=5). Trachylobane-318 showed a higher relaxant potency when the trachea was contracted by 18 mM KCl than it did with 60 mM KCl (pD
2 = 4.90 ± 0.25 and 3.88 ± 0.01,
n=5), suggesting the possible activation of K
+ channels. This was confirmed, as in the presence of 10 mM TEA
+ (a non-selective K
+ channel blocker), diterpene relaxation potency was significantly reduced (pD
2 = 4.38 ± 0.07 to 4.01 ± 0.06,
n=5). Furthermore, K
+ channel subtypes K
ATP, K
V, SK
Ca and BK
Ca seem to be modulated positively by trachylobane-318 (pD
2 = 3.91 ± 0.003, 4.00 ± 0.06, 3.45 ± 0.14 and 3.80 ± 0.05,
n=5) but not the K
ir subtype channel (pD
2 = 4.15 ± 0.10,
n=5). Cyclic nucleotides were not involved as the relaxation due to aminophylline (pD
2 = 4.27 ± 0.09,
n=5) was not altered in the presence of 3 × 10
-5 M trachylobane-318 (pD
2 = 4.46 ± 0.08,
n=5). Thus, at a functional level, trachylobane-318 seems to relax the guinea-pig trachea by positive modulation of K
+ channels, particularly the K
ATP, K
V, SK
Ca and BK
Ca subtypes.
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