Vainio P J, Törnquist K, Tuominen R K
Department of Pharmacology and Toxicology, University of Helsinki, Helsinki, FIN-00014, Finland.
Toxicol Appl Pharmacol. 2000 Mar 1;163(2):183-7. doi: 10.1006/taap.1999.8863.
Cotinine is the major metabolite of nicotine. It has some biological activity, but its pathophysiological effects are largely unclear. We studied whether cotinine initiates calcium transients or affects those induced by nicotine. In bovine adrenal chromaffin cells labeled with the fluorescent calcium indicator Fura 2, cotinine (0. 32-3.2 mM) concentration-dependently increased the intracellular Ca(2+) concentration (Ca(2+)). The effect was abolished by omitting extracellular Ca(2+) during the stimulations. Also nicotinic receptor channel blockers hexamethonium (10 microM-1 mM) and chlorisondamine (100 microM), as well as a competitive nicotinic receptor antagonist dihydro-beta-erythroidine (10-100 microM), inhibited the response. Cotinine (0.32-3.2 mM) preincubation for 2 min inhibited both the nicotine-induced and the cotinine-induced increases in Ca(2+). Also nicotine (3.2-10 microM) inhibited the cotinine-induced increase in Ca(2+). Tetrodotoxin (1 microM) and thapsigargin (1 microM) pretreatments did not affect the responses to cotinine, while 300 nM nimodipine partially inhibited the cotinine-induced increase in Ca(2+). The results indicate that cotinine has nicotine-like effects on chromaffin cells. It may also desensitize the nicotinic cholinergic receptors, possibly by acting as a low-affinity agonist at these receptors.
可替宁是尼古丁的主要代谢产物。它具有一定的生物活性，但其病理生理效应在很大程度上尚不清楚。我们研究了可替宁是否会引发钙瞬变或影响由尼古丁诱导的钙瞬变。在用荧光钙指示剂Fura 2标记的牛肾上腺嗜铬细胞中，可替宁（0.32 - 3.2 mM）浓度依赖性地增加细胞内Ca(2+)浓度（[Ca(2+)]i）。在刺激过程中省略细胞外Ca(2+)可消除该效应。烟碱受体通道阻滞剂六甲铵（10 microM - 1 mM）和氯异吲哚铵（100 microM）以及竞争性烟碱受体拮抗剂二氢 - β - 刺桐碱（10 - 100 microM）也抑制该反应。可替宁（0.32 - 3.2 mM）预孵育2分钟可抑制尼古丁诱导的和可替宁诱导的[Ca(2+)]i增加。同样，尼古丁（3.2 - 10 microM）也抑制可替宁诱导的[Ca(2+)]i增加。河豚毒素（1 microM）和毒胡萝卜素（1 microM）预处理不影响对可替宁的反应，而300 nM尼莫地平部分抑制可替宁诱导的[Ca(2+)]i增加。结果表明，可替宁对嗜铬细胞具有类似尼古丁的作用。它还可能使烟碱胆碱能受体脱敏，可能是通过作为这些受体的低亲和力激动剂起作用。
