Department of Pharmacology, University of Minnesota, Minneapolis, United States of America.
Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, United States of America.
PLoS Negl Trop Dis. 2018 Apr 18;12(4):e0006420. doi: 10.1371/journal.pntd.0006420. eCollection 2018 Apr.
The anthelmintic praziquantel (±PZQ) serves as a highly effective antischistosomal therapy. ±PZQ causes a rapid paralysis of adult schistosome worms and deleterious effects on the worm tegument. In addition to these activities against the parasite, ±PZQ also modulates host vascular tone in blood vessels where the adult worms reside. In resting mesenteric arteries ±PZQ causes a constriction of basal tone, an effect mediated by (R)-PZQ activation of endogenous serotoninergic G protein coupled receptors (GPCRs). Here, we demonstrate a novel vasodilatory action of ±PZQ in mesenteric vessels that are precontracted by high potassium-evoked depolarization, an effect previously reported to be associated with agonists of the transient receptor potential melastatin 8 channel (TRPM8). Pharmacological profiling a panel of 17 human TRPs demonstrated ±PZQ activity against a subset of human TRP channels. Several host TRP channels (hTRPA1, hTRPC3, hTRPC7) were activated by both (R)-PZQ and (S)-PZQ over a micromolar range whereas hTRPM8 showed stereoselective activation by (S)-PZQ. The relaxant effect of ±PZQ in mesenteric arteries was caused by (S)-PZQ, and mimicked by TRPM8 agonists. However, persistence of both (S)-PZQ and TRPM8 agonist evoked vessel relaxation in TRPM8 knockout tissue suggested that canonical TRPM8 does not mediate this (S)-PZQ effect. We conclude that (S)-PZQ is vasoactive over the micromolar range in mesenteric arteries although the molecular mediators of this effect remain to be identified. These data expand our knowledge of the polypharmacology and host vascular efficacy of this clinically important anthelmintic.
驱虫药吡喹酮（±PZQ）是一种非常有效的抗血吸虫药物。±PZQ 可迅速使成体血吸虫麻痹，并对虫体表皮产生有害影响。除了对寄生虫的这些作用外，±PZQ 还可调节成虫寄生的血管中宿主血管的张力。在静息肠系膜动脉中，±PZQ 引起基础张力的收缩，这种作用是由（R）-PZQ 激活内源性 5-羟色胺能 G 蛋白偶联受体（GPCR）介导的。在这里，我们证明了 ±PZQ 在肠系膜血管中的一种新的血管扩张作用，该作用可使由高钾引起的去极化引起的预收缩血管舒张，这种作用先前被报道与瞬时受体电位 melastatin 8 通道（TRPM8）激动剂有关。对一组 17 个人类 TRP 的药理学分析表明，±PZQ 对人类 TRP 通道的一部分具有活性。几种宿主 TRP 通道（hTRPA1、hTRPC3、hTRPC7）在微摩尔范围内被（R）-PZQ 和（S）-PZQ 激活，而 hTRPM8 对（S）-PZQ 表现出立体选择性激活。±PZQ 在肠系膜动脉中的舒张作用是由（S）-PZQ 引起的，并且被 TRPM8 激动剂模拟。然而，在 TRPM8 敲除组织中，（S）-PZQ 和 TRPM8 激动剂持续引起血管舒张表明，经典的 TRPM8 不介导这种（S）-PZQ 作用。我们得出的结论是，（S）-PZQ 在肠系膜动脉中的微摩尔范围内具有血管活性，尽管这种作用的分子介质仍有待确定。这些数据扩展了我们对这种临床上重要的驱虫药的多药理学和宿主血管功效的认识。
