Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly.
Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly.
复制标题
对乙酰氨基酚（扑热息痛）代谢物通过直接和间接激活 Kv7 钾通道诱导血管舒张和低血压。
DOI：
10.1161/atvbaha.120.313997
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Jepps,ThomasA
中科院分区：
文献类型：
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作者：
vanderHorst,Jennifer;Manville,RianW;Hayes,Katie;Thomsen,MortenB;Abbott,GeoffreyW;Jepps,ThomasA
静脉注射对乙酰氨基酚/扑热息痛（APAP）是引起低血压的良好记录。由于接受静脉注射APAP的患者通常病情危重，任何严重的血流动力学变化，如与APAP相关的变化，都可能危及生命。APAP这种危险的医源性影响的机制是unknown.Approach and ResultsHere，我们表明，静脉注射APAP引起短暂的低血压大鼠，这是衰减的Kv 7通道阻滞剂，linopirdine。APAP代谢产物N-乙酰基-对苯醌亚胺引起离体大鼠肠系膜动脉血管舒张。这种血管舒张作用对利诺吡啶和降钙素基因相关肽拮抗剂BIBN 4096敏感。进一步的研究表明，N-乙酰基-对苯醌亚胺刺激降钙素基因相关肽从血管周围神经释放，导致cAMP依赖性激活Kv 7通道。我们还表明，N-乙酰基-对苯醌亚胺增强Kv7.4和Kv7.5通道在卵母细胞中过表达，这表明它可以激活Kv7.4和Kv7.5通道直接，引起vasodilatation.ConclusionsDirect和间接激活Kv 7通道的APAP代谢产物N-乙酰基-对苯醌亚胺降低动脉紧张度，这可能会导致血压下降。我们的研究结果为静脉内APAP依赖性短暂性低血压的临床现象提供了分子机制和潜在的预防干预。
ObjectiveIntravenous acetaminophen/paracetamol (APAP) is well documented to cause hypotension. Since the patients receiving intravenous APAP are usually critically ill, any severe hemodynamic changes, as with those associated with APAP, can be life-threatening. The mechanism underlying this dangerous iatrogenic effect of APAP was unknown.Approach and ResultsHere, we show that intravenous APAP caused transient hypotension in rats, which was attenuated by the Kv7 channel blocker, linopirdine. APAP metabolite N-acetyl-p-benzoquinone imine caused vasodilatation of rat mesenteric arteries ex vivo. This vasodilatation was sensitive to linopirdine and also the calcitonin gene-related peptide antagonist, BIBN 4096. Further investigation revealed N-acetyl-p-benzoquinone imine stimulates calcitonin gene-related peptide release from perivascular nerves, causing a cAMP-dependent activation of Kv7 channels. We also show that N-acetyl-p-benzoquinone imine enhances Kv7.4 and Kv7.5 channels overexpressed in oocytes, suggesting that it can activate Kv7.4 and Kv7.5 channels directly, to elicit vasodilatation.ConclusionsDirect and indirect activation of Kv7 channels by the APAP metabolite N-acetyl-p-benzoquinone imine decreases arterial tone, which can lead to a drop in blood pressure. Our findings provide a molecular mechanism and potential preventive intervention for the clinical phenomenon of intravenous APAP-dependent transient hypotension.