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

2020 ◽  
Vol 40 (5) ◽  
pp. 1207-1219 ◽  
Author(s):  
Jennifer van der Horst ◽  
Rian W. Manville ◽  
Katie Hayes ◽  
Morten B. Thomsen ◽  
Geoffrey W. Abbott ◽  
...  
Keyword(s):  
Preventive Intervention ◽  
Ex Vivo ◽  
Calcitonin Gene Related Peptide ◽  
Mesenteric Arteries ◽  
Benzoquinone Imine ◽  
Kv7 Channels ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Perivascular Nerves ◽  
Life Threatening

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.

Human calcitonin gene related peptide: a potent endogenous vasodilator in man

1986 ◽  
Vol 70 (4) ◽  
pp. 389-393 ◽  
Author(s):  
A. D. Struthers ◽  
M. J. Brown ◽  
D. W. R. Macdonald ◽  
J. L. Beacham ◽  
J. C. Stevenson ◽  
...  
Keyword(s):  
Diastolic Pressure ◽  
Normal Subjects ◽  
Calcitonin Gene Related Peptide ◽  
Plasma Calcium ◽  
Human Calcitonin ◽  
High Concentration ◽  
Plasma Adrenaline ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Perivascular Nerves

1. In addition to calcitonin and katacalcin, it is now known that the human calcitonin gene encodes a novel peptide called calcitonin gene related peptide (CGRP). In experimental animals, CGRP produces vasodilatation and complex changes in plasma calcium. 2. We have now assessed its biological activity in man by infusing human CGRP (hCGRP) into six normal volunteers. hCGRP (545 pmol/min) caused the diastolic pressure to fall from 64 ± 5 to 55 ± 7mmHg (P < 0.05), the heart rate to increase from 61 ± 7 to 87 ± 5 beats/min (P < 0.05) and the skin temperature to increase from 33.7 ± 0.9 to 34.9 ± 0.5°C. Plasma noradrenaline increased from 481 ± 126 to 835 ± 65 pg/ml (P < 0.05) and plasma adrenaline from 57 ± 17 to 82 ± 12 pg/ml (P < 0.05). There were no significant changes in the albumin-corrected plasma calcium. 3. hCGRP is thus a potent endogenous vasodilator in man and is in fact more potent than any other known vasodilator. Together with the observations that CGRP circulates in normal subjects at relatively high concentration (approximately 25 pmol/l) and that CGRP is present in perivascular nerves, this study suggests a possible role for CGRP in controlling peripheral vascular tone in man.

scholarly journals Endosomal proteolysis regulates calcitonin gene-related peptide responses in mesenteric arteries

2012 ◽  
Vol 167 (8) ◽  
pp. 1679-1690 ◽  
Author(s):  
AJ McNeish ◽  
BT Roux ◽  
S-B Aylett ◽  
AM Van Den Brink ◽  
GS Cottrell
Keyword(s):  
Calcitonin Gene Related Peptide ◽  
Mesenteric Arteries ◽  
Related Peptide ◽  
Calcitonin Gene

Effect of chronic sensory denervation on Ca2+-induced relaxation of isolated mesenteric resistance arteries

1998 ◽  
Vol 274 (5) ◽  
pp. H1655-H1661 ◽  
Author(s):  
Maria M. Mupanomunda ◽  
Yanlin Wang ◽  
Richard D. Bukoski
Keyword(s):  
Calcitonin Gene Related Peptide ◽  
Relaxation Response ◽  
Resistance Arteries ◽  
Related Peptide ◽  
Density Control ◽  
Calcitonin Gene ◽  
Perivascular Nerves ◽  
Sensory Denervation ◽  
Immunocytochemical Studies ◽  
Dose Dependent

We recently reported that Ca2+-induced relaxation could be linked to a Ca2+ receptor (CaR) present in perivascular nerves. The present study assessed the effect of chronic sensory denervation on Ca2+-induced relaxation. Mesenteric resistance arteries were isolated from rats treated as neonates with capsaicin (50 mg/kg), vehicle, or saline. The effect of cumulative addition of Ca2+ was assessed in vessels precontracted with 5 μM norepinephrine. Immunocytochemical studies showed that capsaicin treatment significantly reduced the density of nerves staining positively for calcitonin gene-related peptide (CGRP) and for the CaR (CGRP density: control, 51.1 ± 3.9 μm2/mm2; capsaicin treated, 31.4 ± 2.8 μm2/mm2, P = 0.01; control CaR density, 46 ± 4 μm2/mm2, n = 7; capsaicin-treated CaR density, 24 ± 4 μm2/mm2, n = 8, P = 0.002). Dose-dependent relaxation to Ca2+ (1–5 mM) was significantly depressed in vessels from capsaicin-treated rats (overall P < 0.001, n = 6 or 7), whereas the relaxation response to acetylcholine remained intact. These data support the hypothesis that Ca2+-induced relaxation is mediated by activation of the CaR associated with capsaicin-sensitive perivascular neurons.

NPY modulates neurotransmission of CGRP-containing vasodilator nerves in rat mesenteric arteries

1991 ◽  
Vol 261 (3) ◽  
pp. H683-H690 ◽  
Author(s):  
H. Kawasaki ◽  
C. Nuki ◽  
A. Saito ◽  
K. Takasaki
Keyword(s):  
Neuropeptide Y ◽  
Cold Storage ◽  
Nerve Stimulation ◽  
Calcitonin Gene Related Peptide ◽  
Mesenteric Arteries ◽  
Related Peptide ◽  
Vasodilator Response ◽  
Calcitonin Gene ◽  
Vascular Beds ◽  
Distinct Distribution

The effect of neuropeptide Y (NPY) in neurotransmission of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves was investigated in rats. In perfused mesenteric vascular beds with active tone, perivascular nerve stimulation (PNS; 1-8 Hz) caused a frequency-dependent vasodilator response, which was abolished by 300 nM tetrodotoxin (TTX), 500 nM capsaicin, 1 microM human CGRP-(8-37), or cold storage denervation (4 degrees C for 72 h). NPY (5, 10, and 50 nM) concentration dependently inhibited the vasodilator response to PNS, whereas NPY had little effect on vasodilation induced by exogenous CGRP (10 and 100 pmol) or 1 nmol acetylcholine (ACh). NPY (10 nM) inhibited the neurogenic release of CGRP-like immunoreactivity induced by PNS (4 and 8 Hz), which was abolished by 300 nM TTX and the removal of Ca2+ from the medium. Combined perfusion with 5 nM NPY and 10 nM norepinephrine additively inhibited the vasodilator response to PNS but not to exogenous CGRP and ACh. Immunohistochemistry showed the distinct distribution of CGRP- and NPY-like immunoreactivity-containing fibers in rat mesenteric arteries. These results suggest that NPY modulates presynaptically the release of CGRP from CGRP-containing vasodilator nerves in rat mesenteric arteries.

scholarly journals Release of calcitonin gene-related peptide (CGRP) from perivascular nerves in the rat mesenteric artery

1989 ◽  
Vol 49 ◽  
pp. 244
Author(s):  
Akira Fujimori ◽  
Akira Saito ◽  
Sadao Kimura ◽  
Yasuo Uchiyama ◽  
Hiromu Kawasaki ◽  
...  
Keyword(s):  
Mesenteric Artery ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Rat Mesenteric Artery ◽  
Perivascular Nerves

The origin of circulating calcitonin gene-related peptide in the rat

1986 ◽  
Vol 110 (1) ◽  
pp. 185-190 ◽  
Author(s):  
M. Zaidi ◽  
P. J. R. Bevis ◽  
G. Abeyasekera ◽  
S. I. Girgis ◽  
S. J. Wimalawansa ◽  
...  
Keyword(s):  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Potent Vasodilator ◽  
Perivascular Nerves ◽  
Old Rats ◽  
Different Sources

ABSTRACT It is known that in addition to the calcitonin precursor the calcitonin gene also encodes a novel peptide, calcitonin gene-related peptide (CGRP). This potent vasodilator has been found in the circulation of man. This present study demonstrates that CGRP is also found in the circulation of the rat and that plasma CGRP comes from two different sources: the thyroid, a major source in old rats, and the perivascular nerves probably at all ages. J. Endocr. (1986) 110, 185–190

scholarly journals Contribution of Kv7.4/Kv7.5 Heteromers to Intrinsic and Calcitonin Gene-Related Peptide–Induced Cerebral Reactivity

2014 ◽  
Vol 34 (4) ◽  
pp. 887-893 ◽  
Author(s):  
Preet S. Chadha ◽  
Thomas A. Jepps ◽  
Georgina Carr ◽  
Jennifer B. Stott ◽  
Hei-Lei Zhu ◽  
...  
Keyword(s):  
Cerebral Arteries ◽  
Calcitonin Gene Related Peptide ◽  
Isometric Tension ◽  
Proximity Ligation Assay ◽  
Kv7 Channels ◽  
Proximity Ligation ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Systemic Arteries ◽  
First Time

Objective— Middle cerebral artery (MCA) diameter is regulated by inherent myogenic activity and the effect of potent vasodilators such as calcitonin gene-related peptide (CGRP). Previous studies showed that MCAs express KCNQ1, 4, and 5 potassium channel genes, and the expression products (Kv7 channels) participate in the myogenic control of MCA diameter. The present study investigated the contribution of Kv7.4 and Kv7.5 isoforms to myogenic and CGRP regulation of MCA diameter and determined whether they were affected in hypertensive animals. Approach and Results— Isometric tension recordings performed on MCA from normotensive rats produced CGRP vasodilations that were inhibited by the pan-Kv7 channel blocker linopirdine ( P <0.01) and after transfection of arteries with siRNA against KCNQ4 ( P <0.01) but not KCNQ5. However, isobaric myography revealed that myogenic constriction in response to increases in intravascular pressure (20–80 mm Hg) was affected by both KCNQ4 and KCNQ5 siRNA. Proximity ligation assay signals were equally abundant for Kv7.4/Kv7.4 or Kv7.4/Kv7.5 antibody combinations but minimal for Kv7.5/Kv7.5 antibodies or Kv7.4/7.1 combinations. In contrast to systemic arteries, Kv7 function and Kv7.4 abundance in MCA were not altered in hypertensive rats. Conclusions— This study reveals, for the first time to our knowledge, that in cerebral arteries, Kv7.4 and Kv7.5 proteins exist predominantly as a functional heterotetramer, which regulates intrinsic myogenicity and vasodilation attributed to CGRP. Surprisingly, unlike systemic arteries, Kv7 activity in MCAs is not affected by the development of hypertension, and CGRP-mediated vasodilation is well maintained. As such, cerebrovascular Kv7 channels could be amenable for therapeutic targeting in conditions such as cerebral vasospasm.

scholarly journals Up-regulation of calcitonin gene-related peptide receptors underlying elevation of skin temperature in ovariectomized rats

2002 ◽  
Vol 175 (1) ◽  
pp. 177-183 ◽  
Author(s):  
M Noguchi ◽  
Y Ikarashi ◽  
M Yuzurihara ◽  
K Mizoguchi ◽  
K Kurauchi ◽  
...  
Keyword(s):  
Skin Temperature ◽  
Calcitonin Gene Related Peptide ◽  
Mesenteric Arteries ◽  
Hormone Deficiency ◽  
Ovariectomized Rats ◽  
Dependent Manner ◽  
Ovarian Hormone ◽  
Related Peptide ◽  
Ovx Rats ◽  
Calcitonin Gene

We investigated the mechanism for the augmentation of the calcitonin gene-related peptide (CGRP)-induced elevation of skin temperature in ovariectomized (OVX) rats. I.v. injection of alphaCGRP (10 micro g/kg) elevated skin temperature of the hind paws. The elevation was significantly greater in OVX rats than in sham-operated rats and was inhibited by pretreatment with human CGRP(8-37) (100-1000 micro g/kg i.v.), a CGRP receptor antagonist, in a dose-dependent manner. In addition, ovariectomy not only potentiated vasorelaxation due to alphaCGRP but increased the number of CGRP receptors in mesenteric arteries. Further, the plasma concentration of endogenous CGRP was significantly lower in OVX rats. These results suggest that the low concentration of plasma CGRP due to ovarian hormone deficiency may induce the increase in the number of CGRP receptors due to up-regulation. Therefore, the increased number of CGRP receptors may be responsible for potentiation of exogenous alphaCGRP-induced elevation of skin temperature in OVX rats. The mechanism underlying the hot flashes observed in menopausal women may also involve, in part, the up-regulation of CGRP receptors following ovarian hormone deficiency.

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