Lim Dong-Yoon, Kim Yang-Soo, Miwa Soichi
Department of Pharmacology, College of Medicine, Chosun University, Gwangju 501-759, South Korea.
Auton Neurosci. 2004 Jan 30;110(1):27-35. doi: 10.1016/j.autneu.2003.10.001.
It has been shown that lobeline (alpha-lobeline) is a lipophilic, nonpyridine, naturally occurring alkaloid obtained from Indian tobacco, Lobelia inflata. The present study was attempted to investigate the effect of lobeline on secretion of catecholamines (CA) evoked by ACh, high K(+), 1.1-dimethyl-4-phenyl piperazinium iodide (DMPP) and (3-(m-chloro-phenyl-carbamoyl-oxy)-2-butynyl trimethyl ammonium chloride (McN-A-343) from the isolated perfused rat adrenal gland and to establish the mechanism of its action. l-Lobeline (30-300 microM) perfused into an adrenal vein for 60 min produced dose- and time-dependent inhibition in CA secretory responses evoked by ACh (5.32 x 10(-3) M), DMPP (10(-4) M for 2 min) and McN-A-343 (10(-4) M for 2 min). However, lower dose of lobeline did not affect CA secretion by high K(+) (5.6 x 10(-2) M), higher dose of it reduced greatly CA secretion of high K(+). l-Lobeline itself did also fail to affect basal catecholamine output. Furthermore, in adrenal glands loaded with lobeline (100 microM), CA secretory response evoked by methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate (Bay-K-8644), an activator of L-type Ca(2+) channels was markedly inhibited while CA secretion by cyclopiazonic acid, an inhibitor of cytoplasmic Ca(2+)-ATPase was not affected. However, nicotine (30 microM), given into the adrenal gland for 60 min, initially rather enhanced CA secretory responses evoked by ACh (5.32 x 10(-3) M) and high K(+) (5.6 x 10(-2) M) followed by great inhibition later, while responses evoked by DMPP (10(-4) M for 2 min) and McN-A-343 (10(-4) M for 2 min) were greatly inhibited. Taken together, these results suggest that lobeline inhibits greatly CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors. Lobeline at lower dose does not affect that by membrane depolarization, but at larger dose inhibits that. It is thought that this inhibitory effect of lobeline may be mediated by blocking the calcium influx into the rat adrenal medullary chromaffin cells without the inhibition of Ca(2+) release from the cytoplasmic calcium store, which is relevant to its nicotinic antagonistic activity. It also seems that there is a difference in the mode of action between nicotine and lobeline in rat adrenomedullary CA secretion.
业已表明，洛贝林（α-洛贝林）是一种亲脂性、非吡啶类天然生物碱，从印度烟草（北美山梗菜）中提取获得。本研究旨在探讨洛贝林对乙酰胆碱（ACh）、高钾（K⁺）、1,1-二甲基-4-苯基哌嗪碘化物（DMPP）和3-(间氯苯基氨基甲酰氧基)-2-丁炔基三甲基氯化铵（McN-A-343）诱发的离体灌注大鼠肾上腺儿茶酚胺（CA）分泌的影响，并确定其作用机制。将左旋洛贝林（30 - 300微摩尔）灌注到肾上腺静脉60分钟，可对ACh（5.32×10⁻³ M）、DMPP（10⁻⁴ M，作用2分钟）和McN-A-343（10⁻⁴ M，作用2分钟）诱发的CA分泌反应产生剂量和时间依赖性抑制。然而，较低剂量的洛贝林不影响高钾（5.6×10⁻² M）诱发的CA分泌，较高剂量则可显著降低高钾诱发的CA分泌。左旋洛贝林本身也未影响基础儿茶酚胺输出。此外，在加载了洛贝林（100微摩尔）的肾上腺中，L型钙通道激活剂甲基-1,4-二氢-2,6-二甲基-3-硝基-4-(2-三氟甲基苯基)-吡啶-5-羧酸酯（Bay-K-8644）诱发的CA分泌反应受到显著抑制，而细胞质钙ATP酶抑制剂环匹阿尼酸诱发的CA分泌则未受影响。然而，将尼古丁（30微摩尔）注入肾上腺60分钟，最初可增强ACh（5.32×10⁻³ M）和高钾（5.6×10⁻² M）诱发的CA分泌反应，随后则出现显著抑制，而DMPP（10⁻⁴ M，作用2分钟）和McN-A-343（10⁻⁴ M，作用2分钟）诱发的反应则受到显著抑制。综上所述，这些结果表明，洛贝林可显著抑制胆碱能（烟碱样和毒蕈碱样）受体刺激诱发的CA分泌。较低剂量的洛贝林不影响膜去极化诱发的CA分泌，但较高剂量则可抑制。据认为，洛贝林的这种抑制作用可能是通过阻断钙流入大鼠肾上腺髓质嗜铬细胞，而不抑制细胞质钙库中的钙释放来介导的，这与其烟碱样拮抗活性相关。在大鼠肾上腺髓质CA分泌中，尼古丁和洛贝林的作用方式似乎也存在差异。
