Schindler Charles W, Thorndike Eric B, Blough Bruce E, Tella Srihari R, Goldberg Steven R, Baumann Michael H
Preclinical Pharmacology, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.
Br J Pharmacol. 2014 Jan;171(1):83-91. doi: 10.1111/bph.12423.
The cardiovascular effects produced by 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats.
Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP, heart rate (HR) and locomotor activity in conscious male rats.
MDMA (1-20 mg·kg(-1)) produced dose-related increases in BP, HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N-demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA. The metabolite 3,4-dihydroxymethamphetamine (HHMA; 1-10 mg·kg(-1)) increased HR more potently and to a greater extent than MDMA, whereas 3,4-dihydroxyamphetamine (HHA) increased HR, but to a lesser extent than HHMA. Neither dihydroxy metabolite altered motor activity. The metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA) and 4-hydroxy-3-methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the β-adrenoceptor antagonist propranolol.
Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo. As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study.
3,4-亚甲基二氧甲基苯丙胺（MDMA；“摇头丸”）产生的心血管效应导致其具有急性毒性，但其代谢产物在这些心血管效应中的潜在作用尚不清楚。在此，我们研究了MDMA代谢产物对大鼠心血管功能的影响。
采用放射遥测技术评估皮下注射外消旋MDMA及其I相代谢产物对清醒雄性大鼠血压、心率（HR）和运动活性的影响。
MDMA（1 - 20 mg·kg⁻¹）可使血压、心率和活性呈剂量依赖性增加。对心率的峰值效应出现在比血压或活性峰值效应更低的剂量下。N-去甲基代谢产物3,4-亚甲基二氧苯丙胺（MDA）产生的效应与MDMA相似。代谢产物3,4-二羟基甲基苯丙胺（HHMA；1 - 10 mg·kg⁻¹）比MDMA更有效且程度更大地增加心率，而3,4-二羟基苯丙胺（HHA）增加心率，但程度小于HHMA。两种二羟基代谢产物均未改变运动活性。代谢产物4-羟基-3-甲氧基甲基苯丙胺（HMMA）和4-羟基-3-甲氧基苯丙胺（HMA）对所测任何参数均无影响。MDMA和HHMA产生的心动过速被β-肾上腺素能受体拮抗剂普萘洛尔阻断。
我们的结果表明，HHMA可能在体内对MDMA的心血管效应有显著贡献。因此，确定HHMA及MDMA其他羟基代谢产物的分子作用机制值得进一步研究。
