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

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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Basal tail skin temperature elevation and augmented response to calcitonin gene-related peptide in ovariectomized rats

Journal of Endocrinology ◽

10.1677/joe.0.1460431 ◽

1995 ◽

Vol 146 (3) ◽

pp. 431-437 ◽

Cited By ~ 17

Author(s):

T Kobayashi ◽

O Ushijima ◽

J-T Chen ◽

M Shiraki ◽

T Ohta ◽

...

Keyword(s):

Skin Temperature ◽

Temperature Response ◽

Calcitonin Gene Related Peptide ◽

Female Rats ◽

Ovariectomized Rats ◽

Dependent Manner ◽

Related Peptide ◽

Ovx Rats ◽

Calcitonin Gene ◽

Drastic Increase

Abstract Hyper-release of calcitonin gene-related peptide (CGRP) plays a direct and pivotal role in the induction of menopausal hot flushes (HFs), in which a drastic increase in skin temperature occurs. However, it is not possible to investigate whether CGRP induces skin temperature increase and whether skin temperature response to CGRP changes and contributes to the occurrence of HFs in postmenopausal women who are in oestrogen deficiency. By using rats' tail skin temperature (TST), a good marker to evaluate skin temperature regulation, we examined the effects of CGRP and calcitonin (3, 10 and 30 μg/kg, i.v.) on TST in female rats and further investigated the TST change induced by CGRP (10 μg/kg, i.v.) in ovariectomized (OVX) rats compared with that in sham-operated (Sham) rats. We found that CGRP, but not calcitonin, induced a TST increase in a dose-dependent manner and that the TST change induced by CGRP (0·6 ±0·2 °C for OVX rats vs 0·3 ±0·1 °C for Sham rats, P<0·05) and also the basal TST (26·0 ± 0·2 °C for OVX rats vs 25·5 ±0·1 °C for Sham rats) were significantly greater in OVX rats (P<0·05). Furthermore, treatment with oestradiol (30 μg/kg, s.c.) for 8 days partially inhibited the augmented TST response to CGRP in OVX rats and almost completely inhibited (P<0·05) the basal TST elevation, with the concomitant recovery of the serum oestradiol level to that in Sham rats. These results suggest that the augmented skin temperature response to CGRP and the elevation of basal skin temperature that are found in OVX rats, animals which are oestradiol deficient, may also occur in menopausal women and contribute to their HFs. Journal of Endocrinology (1995) 146, 431–437

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Effects of the Japanese herbal medicine Keishi-bukuryo-gan and 17beta-estradiol on calcitonin gene-related peptide-induced elevation of skin temperature in ovariectomized rats

Journal of Endocrinology ◽

10.1677/joe.0.1760359 ◽

2003 ◽

Vol 176 (3) ◽

pp. 359-366 ◽

Cited By ~ 25

Author(s):

M Noguchi ◽

Y Ikarashi ◽

M Yuzurihara ◽

Y Kase ◽

JT Chen ◽

...

Keyword(s):

Herbal Medicine ◽

Skin Temperature ◽

Hormone Replacement ◽

Calcitonin Gene Related Peptide ◽

Ovariectomized Rats ◽

Dependent Manner ◽

Related Peptide ◽

Ovx Rats ◽

Calcitonin Gene ◽

Japanese Herbal Medicine

The effects of a Japanese herbal medicine, Keishi-bukuryo-gan, and 17beta-estradiol on calcitonin gene-related peptide (CGRP)-induced elevation of skin temperature were investigated in ovariectomized (OVX) rats. Ovariectomy not only potentiated CGRP-induced elevation of skin temperature and arterial vasorelaxation but also induced a lower concentration of endogenous CGRP in plasma and up-regulation of arterial CGRP receptors, suggesting that lowered CGRP in plasma due to ovarian hormone deficiency increases the number of CGRP receptors and consequently amplifies the stimulatory effects of CGRP to elevate skin temperature. Oral Keishi-bukuryo-gan (100-1000 mg/kg, once a day for 7 days) restored a series of CGRP-related responses observed in OVX rats by normalizing plasma CGRP levels in a dose-dependent manner as effectively as s.c. injection. 17Beta-estradiol (0.010 mg/kg, once a day for 7 days). However, Keishi-bukuryo-gan did not affect the lower concentration of plasma estradiol and the decreased uterine weight due to ovariectomy, although the hormone replacement of 17beta-estradiol restored them. These results suggest that Keishi-bukuryo-gan, which does not confer estrogen activity on plasma, may be useful for the treatment of hot flashes in patients for whom estrogen replacement therapy is contraindicated, as well as menopausal women.

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Effects of the vasoactive neuropeptides calcitonin gene-related peptide, substance P and vasoactive intestinal polypeptide on skin temperature in ovariectomized rats

Neuropeptides ◽

10.1016/s0143-4179(02)00090-2 ◽

2002 ◽

Vol 36 (5) ◽

pp. 327-332 ◽

Cited By ~ 7

Author(s):

M Noguchi ◽

M Yuzurihara ◽

Y Ikarashi

Keyword(s):

Substance P ◽

Skin Temperature ◽

Vasoactive Intestinal Polypeptide ◽

Calcitonin Gene Related Peptide ◽

Ovariectomized Rats ◽

Related Peptide ◽

Calcitonin Gene ◽

Intestinal Polypeptide

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.313997 ◽

2020 ◽

Vol 40 (5) ◽

pp. 1207-1219 ◽

Cited By ~ 2

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.

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Effects of calcitonin gene-related peptide on vascular resistance in rats: role of sex steroids

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.276.6.h2063 ◽

1999 ◽

Vol 276 (6) ◽

pp. H2063-H2068 ◽

Cited By ~ 1

Author(s):

Michelle Grewal ◽

Janis Cuevas ◽

Gautam Chaudhuri ◽

Lauren Nathan

Keyword(s):

Sex Steroids ◽

Perfusion Pressure ◽

Pressor Response ◽

Calcitonin Gene Related Peptide ◽

Ovariectomized Rats ◽

Synthesis Inhibitor ◽

Pregnant Rats ◽

Related Peptide ◽

Calcitonin Gene

It has been demonstrated in reflex-intact animals that the sensitivity to calcitonin gene-related peptide (CGRP) is increased during pregnancy and that this action is mediated by sex steroids but not by nitric oxide (NO). We assessed the effects of CGRP in the following groups of anesthetized ganglion-blocked rats: 1) pregnant, 2) ovariectomized, and 3) ovariectomized and treated with estradiol and progesterone. Changes in mean arterial pressure (MAP) were assessed after the administration of varying doses of CGRP. Decreases in MAP after CGRP administration were significantly greater in pregnant rats and ovariectomized rats administered sex steroids than in ovariectomized controls. The CGRP antagonist CGRP8–37 produced a pressor response of similar magnitude in both pregnant and ovariectomized rats. We also assessed the effects of CGRP and the modulating role of NO in the isolated uterine vascular bed preparation. CGRP reduced perfusion pressure to a greater degree in ovariectomized animals treated with sex steroids than in ovariectomized animals. This response was attenuated by pretreatment with an NO synthesis inhibitor. CGRP8–37 produced a similar increase in perfusion pressure in both groups. We conclude that 1) the increased vascular sensitivity observed during pregnancy or after treatment with sex steroids is in part mediated by NO, and 2) CGRP8–37 has a vasoconstrictor action of its own.

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Renal microvascular actions of calcitonin gene-related peptide

AJP Renal Physiology ◽

10.1152/ajprenal.1998.274.6.f1078 ◽

1998 ◽

Vol 274 (6) ◽

pp. F1078-F1085 ◽

Cited By ~ 12

Author(s):

Martina Reslerova ◽

Rodger Loutzenhiser

Keyword(s):

Angiotensin Ii ◽

Rat Kidney ◽

Elevated Pressure ◽

Calcitonin Gene Related Peptide ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Renal Vasoconstriction ◽

Related Peptide ◽

Calcitonin Gene

Calcitonin gene-related peptide (CGRP) is a potent vasodilator that is suggested to act via ATP-sensitive K channels (KATP). In the present study, we examined the actions of CGRP on pressure- and angiotensin II-induced vasoconstriction, using the in vitro perfused hydronephrotic rat kidney. Elevated pressure (from 80 to 180 mmHg) and 0.1 nM angiotensin II elicited similar decreases in afferent diameter in this model. CGRP inhibited myogenic reactivity in a concentration-dependent manner, completely preventing pressure-induced constriction at 10 nM (95 ± 10% inhibition). These effects were partially attenuated by 10 μM glibenclamide (62 ± 16% inhibition, P = 0.025), indicating both KATP-dependent and -independent actions of CGRP. In contrast, 10 nM CGRP inhibited angiotensin II-induced vasoconstriction by only 54 ± 11%, and this action was not affected by glibenclamide (41 ± 11%, P = 0.31). CGRP also inhibited the efferent arteriolar response to angiotensin II in the absence and presence of glibenclamide. Pinacidil (1.0 μM), a KATP opener also preferentially inhibited pressure- vs. angiotensin II-induced vasoconstriction (97 ± 5 and 59 ± 13% inhibition, respectively; P = 0.034). We conclude that the renal vasodilatory mechanisms of CGRP are pleiotropic and involve both KATP-dependent and -independent pathways. The effectiveness of CGRP in opposing renal vasoconstriction and the role of KATP in this action appear to depend on the nature the underlying vasoconstriction. We suggest that this phenomenon reflects an inhibition of KATP activation by angiotensin II.

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A new era for migraine: Pharmacokinetic and pharmacodynamic insights into monoclonal antibodies with a focus on galcanezumab, an anti-CGRP antibody

Cephalalgia ◽

10.1177/0333102419840780 ◽

2019 ◽

Vol 39 (10) ◽

pp. 1284-1297 ◽

Cited By ~ 18

Author(s):

William Kielbasa ◽

Danielle L Helton

Keyword(s):

Oral Absorption ◽

Free Ligand ◽

Subcutaneous Administration ◽

Calcitonin Gene Related Peptide ◽

Convective Transport ◽

Systemic Absorption ◽

Therapeutic Effects ◽

Dependent Manner ◽

Related Peptide ◽

Calcitonin Gene

Purpose To review pharmacokinetic and pharmacodynamic characteristics of antibodies that bind to soluble ligands within the framework of calcitonin gene-related peptide antibodies. Overview Calcitonin gene-related peptide has been implicated in the pathophysiology of migraine. Galcanezumab is an antibody that binds to the ligand calcitonin gene-related peptide. Other antibodies that target calcitonin gene-related peptide include eptinezumab and fremanezumab. To understand how antibodies can affect the extent and duration of free ligand concentrations, it is important to consider the dose and pharmacokinetics of an antibody, and the kinetics of the ligand and antibody–ligand complex. Insights regarding the pharmacokinetic/pharmacodynamic properties of galcanezumab as a probe antibody drug and calcitonin gene-related peptide as its binding ligand regarding its clinical outcomes are provided. Discussion Antibodies are administered parenterally because oral absorption is limited by gastrointestinal degradation and inefficient diffusion through the epithelium. The systemic absorption of antibodies following intramuscular or subcutaneous administration most likely occurs via convective transport through lymphatic vessels into blood. The majority of antibody elimination occurs via intracellular catabolism into peptides and amino acids following endocytosis. Binding of ligand to an antibody reduces the free ligand that is available to interact with the receptor and efficacy is driven by the magnitude and duration of the reduction in free ligand concentration. A galcanezumab pharmacokinetic/pharmacodynamic model shows that galcanezumab decreases free calcitonin gene-related peptide concentrations in a dose- and time-dependent manner and continues to suppress free calcitonin gene-related peptide with repeated dosing. The model provides evidence for a mechanistic linkage to galcanezumab therapeutic effects for the preventive treatment of migraine.

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