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Arterioscler Thromb Vasc Biol
2020 May 01;405:1207-1219. doi: 10.1161/ATVBAHA.120.313997.
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Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly.
van der Horst J
,
Manville RW
,
Hayes K
,
Thomsen MB
,
Abbott GW
,
Jepps TA
.
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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.
Abbott,
Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity.
2016,
Pubmed
Andersson,
TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ(9)-tetrahydrocannabiorcol.
2011,
Pubmed
Athersuch,
Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective.
2018,
Pubmed
Barrese,
KCNQ-Encoded Potassium Channels as Therapeutic Targets.
2018,
Pubmed
Bol,
Influence of methanandamide and CGRP on potassium currents in smooth muscle cells of small mesenteric arteries.
2012,
Pubmed
Boyle,
Paracetamol induced skin blood flow and blood pressure changes in febrile intensive care patients: An observational study.
2010,
Pubmed
Brueggemann,
Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels.
2014,
Pubmed
Cantais,
Acetaminophen-Induced Changes in Systemic Blood Pressure in Critically Ill Patients: Results of a Multicenter Cohort Study.
2016,
Pubmed
Chadha,
Reduced KCNQ4-encoded voltage-dependent potassium channel activity underlies impaired β-adrenoceptor-mediated relaxation of renal arteries in hypertension.
2012,
Pubmed
Chadha,
Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity.
2014,
Pubmed
Chalmers,
Effects of indomethacin, sulindac, naproxen, aspirin, and paracetamol in treated hypertensive patients.
1984,
Pubmed
Chiam,
The haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: a double-blind, randomized, triple crossover trial.
2016,
Pubmed
Curhan,
Frequency of analgesic use and risk of hypertension in younger women.
2002,
Pubmed
Eberhardt,
Reactive metabolites of acetaminophen activate and sensitize the capsaicin receptor TRPV1.
2017,
Pubmed
Fleming,
Cytochrome p450 and vascular homeostasis.
2001,
Pubmed
Gamper,
Oxidative modification of M-type K(+) channels as a mechanism of cytoprotective neuronal silencing.
2006,
Pubmed
Graham,
The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings.
2013,
Pubmed
Hinz,
Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man.
2008,
Pubmed
Jepps,
Vasorelaxant effects of novel Kv 7.4 channel enhancers ML213 and NS15370.
2014,
Pubmed
Jepps,
Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone.
2015,
Pubmed
Kawasaki,
Paracrine control of mesenteric perivascular axo-axonal interaction.
2011,
Pubmed
Kawasaki,
Calcitonin gene-related peptide acts as a novel vasodilator neurotransmitter in mesenteric resistance vessels of the rat.
1988,
Pubmed
Khanamiri,
Contribution of Kv7 channels to basal coronary flow and active response to ischemia.
2013,
Pubmed
Krajčová,
Mechanism of paracetamol-induced hypotension in critically ill patients: a prospective observational cross-over study.
2013,
Pubmed
Lei,
Characterization of the CGRP receptor and mechanisms of action in rat mesenteric small arteries.
1994,
Pubmed
Mackenzie,
Effects of acetaminophen administration to patients in intensive care.
2000,
Pubmed
Mackie,
Vascular KCNQ potassium channels as novel targets for the control of mesenteric artery constriction by vasopressin, based on studies in single cells, pressurized arteries, and in vivo measurements of mesenteric vascular resistance.
2008,
Pubmed
Mani,
Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents.
2016,
Pubmed
Manville,
KCNQ5 activation is a unifying molecular mechanism shared by genetically and culturally diverse botanical hypotensive folk medicines.
2019,
Pubmed
Maxwell,
Intravenous Acetaminophen-Induced Hypotension: A Review of the Current Literature.
2019,
Pubmed
McCrae,
Long-term adverse effects of paracetamol - a review.
2018,
Pubmed
McGill,
Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis.
2013,
Pubmed
Mulvany,
Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats.
1977,
Pubmed
Nelson,
Arterial dilations in response to calcitonin gene-related peptide involve activation of K+ channels.
1990,
Pubmed
Ng,
Expression and function of the K+ channel KCNQ genes in human arteries.
2011,
Pubmed
Ramachandran,
Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives.
2018,
Pubmed
Ray,
The paracetamol metabolite N-acetylp-benzoquinone imine reduces excitability in first- and second-order neurons of the pain pathway through actions on KV7 channels.
2019,
Pubmed
Rockwood,
A randomized, controlled trial of linopirdine in the treatment of Alzheimer's disease.
1997,
Pubmed
Stott,
Kv7 Channel Activation Underpins EPAC-Dependent Relaxations of Rat Arteries.
2016,
Pubmed
Stott,
Complex role of Kv7 channels in cGMP and cAMP-mediated relaxations.
2015,
Pubmed
Stueber,
Activation of the capsaicin-receptor TRPV1 by the acetaminophen metabolite N-arachidonoylaminophenol results in cytotoxicity.
2018,
Pubmed
Suemaru,
Anticonvulsant effects of acetaminophen in mice: Comparison with the effects of nonsteroidal anti-inflammatory drugs.
2018,
Pubmed
Wang,
Impaired vasodilation in response to perivascular nerve stimulation in mesenteric arteries of TRPV1-null mutant mice.
2006,
Pubmed
Yaman,
Paracetamol infusion-related severe hypotension and cardiac arrest in a child.
2016,
Pubmed
Yeung,
Molecular expression and pharmacological identification of a role for K(v)7 channels in murine vascular reactivity.
2007,
Pubmed
de Maat,
Paracetamol for intravenous use in medium--and intensive care patients: pharmacokinetics and tolerance.
2010,
Pubmed