Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly

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Standard

Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly. / Van Der Horst, Jennifer; Manville, Rian W.; Hayes, Katie; Thomsen, Morten B.; Abbott, Geoffrey W.; Jepps, Thomas A.

I: Arteriosclerosis, Thrombosis, and Vascular Biology, Bind 40, Nr. 5, 2020, s. 1207-1219.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Van Der Horst, J, Manville, RW, Hayes, K, Thomsen, MB, Abbott, GW & Jepps, TA 2020, 'Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly', Arteriosclerosis, Thrombosis, and Vascular Biology, bind 40, nr. 5, s. 1207-1219. https://doi.org/10.1161/ATVBAHA.120.313997

APA

Van Der Horst, J., Manville, R. W., Hayes, K., Thomsen, M. B., Abbott, G. W., & Jepps, T. A. (2020). Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly. Arteriosclerosis, Thrombosis, and Vascular Biology, 40(5), 1207-1219. https://doi.org/10.1161/ATVBAHA.120.313997

Vancouver

Van Der Horst J, Manville RW, Hayes K, Thomsen MB, Abbott GW, Jepps TA. Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40(5):1207-1219. https://doi.org/10.1161/ATVBAHA.120.313997

Author

Van Der Horst, Jennifer ; Manville, Rian W. ; Hayes, Katie ; Thomsen, Morten B. ; Abbott, Geoffrey W. ; Jepps, Thomas A. / Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly. I: Arteriosclerosis, Thrombosis, and Vascular Biology. 2020 ; Bind 40, Nr. 5. s. 1207-1219.

Bibtex

@article{7472d4284dad49d184485247a11b8d55,
title = "Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly",
abstract = "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.",
keywords = "acetaminophen, hypotension, linopirdine, potassium channels, vasodilation",
author = "{Van Der Horst}, Jennifer and Manville, {Rian W.} and Katie Hayes and Thomsen, {Morten B.} and Abbott, {Geoffrey W.} and Jepps, {Thomas A.}",
year = "2020",
doi = "10.1161/ATVBAHA.120.313997",
language = "English",
volume = "40",
pages = "1207--1219",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams & Wilkins",
number = "5",

}

RIS

TY - JOUR

T1 - Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly

AU - Van Der Horst, Jennifer

AU - Manville, Rian W.

AU - Hayes, Katie

AU - Thomsen, Morten B.

AU - Abbott, Geoffrey W.

AU - Jepps, Thomas A.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - acetaminophen

KW - hypotension

KW - linopirdine

KW - potassium channels

KW - vasodilation

U2 - 10.1161/ATVBAHA.120.313997

DO - 10.1161/ATVBAHA.120.313997

M3 - Journal article

C2 - 32188278

AN - SCOPUS:85083892736

VL - 40

SP - 1207

EP - 1219

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 5

ER -

ID: 244691552