OBJECTIVE Intravenous 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 Results: Here, 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. CONCLUSIONS Direct 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.

中文翻译：

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对乙酰氨基酚（对乙酰氨基酚）代谢物通过直接和间接激活Kv7钾通道而引起血管舒张和低血压。

目的静脉注射对乙酰氨基酚/扑热息痛（APAP）已被证明可引起低血压。由于接受静脉内APAP的患者通常病情较重，因此任何严重的血液动力学变化（如与APAP相关的血液动力学变化）都可能危及生命。APAP的这种危险医源性作用的潜在机制尚不清楚。方法和结果：在这里，我们显示静脉内APAP引起大鼠暂时性低血压，并被Kv7通道阻滞剂利诺吡丁减弱。APAP代谢物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丁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-苯醌亚胺可刺激降钙素基因相关肽从血管周围神经释放，导致依赖于cAMP的Kv7通道激活。我们还显示，N-乙酰基-对-苯醌亚胺增强了在卵母细胞中过表达的Kv7.4和Kv7.5通道，表明它可以直接激活Kv7.4和Kv7.5通道，引起血管舒张。结论APAP代谢物N-乙酰基-对-苯醌亚胺直接和间接激活Kv7通道会降低动脉张力，从而导致血压下降。我们的发现为静脉依赖APAP的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措施。结论APAP代谢物N-乙酰基-对-苯醌亚胺直接和间接激活Kv7通道会降低动脉张力，从而导致血压下降。我们的发现为静脉依赖APAP的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措施。结论APAP代谢物N-乙酰基-对-苯醌亚胺直接和间接激活Kv7通道会降低动脉张力，从而导致血压下降。我们的发现为静脉依赖APAP的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措施。