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

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.261.3.h683 ◽

1991 ◽

Vol 261 (3) ◽

pp. H683-H690 ◽

Cited By ~ 14

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.

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

Journal of Endocrinology ◽

10.1677/joe.0.1750177 ◽

2002 ◽

Vol 175 (1) ◽

pp. 177-183 ◽

Cited By ~ 12

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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