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

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.

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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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Stimulation of acetylcholine release in myenteric plexus by calcitonin gene-related peptide

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1990.259.6.g934 ◽

1990 ◽

Vol 259 (6) ◽

pp. G934-G939 ◽

Cited By ~ 1

Author(s):

M. W. Mulholland ◽

S. Jaffer

Keyword(s):

Myenteric Plexus ◽

Acetylcholine Release ◽

Calcitonin Gene Related Peptide ◽

Ach Release ◽

Related Peptide ◽

Calcitonin Gene ◽

Dose Dependent Increase ◽

Dose Dependent ◽

Dependent Mechanism ◽

Stimulation Of

The effects of calcitonin gene-related peptide (CGRP) on acetylcholine (ACh) release from myenteric plexus neurons in primary culture were investigated. CGRP (10(-12) to 10(-6) M) produced a dose-dependent increase in [3H]ACh release. The ACh release caused by CGRP was significantly inhibited (74 +/- 24%) by preincubation with dideoxyadenosine but was increased more than threefold by preincubation with theophylline. Incubation of myenteric plexus neurons with CGRP (10(-8) M) in the presence of diltiazem (10(-5) M) or in a calcium-free medium markedly reduced [3H]ACh release. CGRP potentiated [3H]ACh release stimulated by potassium or substance P but not by cholecystokinin octapeptide or forskolin. The results demonstrate that CGRP cause release of ACh from guinea pig myenteric plexus neurons and suggest that the peptide acts through an adenosine 3',5'-cyclic monophosphate-dependent mechanism that involves neuronal calcium channels.

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Mechanisms Leading to Increased Vasodilator Responses to Calcitonin-Gene-Related Peptide in Mesenteric Resistance Arteries of Early Pregnant Rats

Journal of Vascular Research ◽

10.1159/000119754 ◽

2008 ◽

Vol 45 (4) ◽

pp. 350-356 ◽

Cited By ~ 8

Author(s):

H.W.F. van Eijndhoven ◽

G.M.J. Janssen ◽

R. Aardenburg ◽

M.E.A. Spaanderman ◽

L.L.H. Peeters ◽

...

Keyword(s):

Calcitonin Gene Related Peptide ◽

Resistance Arteries ◽

Pregnant Rats ◽

Related Peptide ◽

Calcitonin Gene

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

Clinical Science ◽

10.1042/cs0700389 ◽

1986 ◽

Vol 70 (4) ◽

pp. 389-393 ◽

Cited By ~ 160

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.

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