Effect of Cholecystokinin-8 (CCK-8) on Blood Pressure and Blood Content of Calcitonin-Gene-Related Peptide (CGRP) in Rats with Hypertension Caused by Fructose or Inhibition of Nitric Oxide Synthesis

Calcitonin gene-related peptide (CGRP), one of the most potent endogenous vasodilators known, has been implicated in vascular adaptations and placental functions during pregnancy. The present study was designed to examine the existence of CGRP-A receptor components, the calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 1 (RAMP1), in the human placenta and the vasoactivity of CGRP in the fetoplacental circulation. Immunofluorescent staining of the human placenta in term labor using polyclonal anti-CRLR and RAMP1 antibodies revealed that labeling specifically concentrated in the vascular endothelium and the underlying smooth muscle cells in the umbilical artery/vein, chorionic artery/vein, and stem villous vessels as well as in the trophoblast layer of the placental villi. In vitro isometric force measurement showed that CGRP dose dependently relaxes the umbilical artery/vein, chorionic artery/vein, and stem villous vessels. Furthermore, CGRP-induced relaxation of placental vessels are inhibited by a CGRP receptor antagonist (CGRP8–37), ATP-sensitive potassium (KATP) channel blocker (glybenclamide), and cAMP-dependent protein kinase A inhibitor (Rp-cAMPS) and partially inhibited by a nitric oxide inhibitor ( Nω-nitro-l-arginine methyl ester). We propose that CGRP may play a role in the control of human fetoplacental vascular tone, and the vascular dilations in response to CGRP may involve activation of KATP channels, cAMP, and a nitric oxide pathway.

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Mechanisms of calcitonin gene-related peptide-induced increases of pulmonary blood flow in fetal sheep

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.4.h1654 ◽

2000 ◽

Vol 279 (4) ◽

pp. H1654-H1660 ◽

Cited By ~ 6

Author(s):

Yasushi Takahashi ◽

Maartje De Vroomen ◽

Christine Roman ◽

Michael A. Heymann

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Pulmonary Blood Flow ◽

Pulmonary Arteries ◽

Calcitonin Gene Related Peptide ◽

Fetal Sheep ◽

Nitric Oxide Synthase Inhibitor ◽

Flow Transducer ◽

Related Peptide ◽

Calcitonin Gene

Fetal pulmonary blood flow is regulated by various vasoactive substances. One, calcitonin gene-related peptide (CGRP), increases pulmonary blood flow. We examined four key physiological mechanisms underlying this response using the blocker drugs CGRP receptor blocker (CGRP8–37), nitric oxide synthase inhibitor [ N ω-nitro-l-arginine (l-NNA)], adenosine triphosphate-dependent potassium (KATP) channel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin) in 17 near-term fetal sheep. Catheters were placed in the left (LPA) and main pulmonary arteries, and an ultrasonic flow transducer was placed around the LPA to measure flow continuously. CGRP was injected directly into the LPA (mean 1.02 μg/kg) before and after blockade, and responses to CGRP were statistically compared. Before blockade, CGRP increased LPA blood flow from 23 ± 25 to 145 ± 77 ml/min (means ± SD), and these increases were significantly attenuated by CGRP8–37( n = 6; 91% inhibition), l-NNA ( n = 6; 86% inhibition), and glibenclamide ( n = 6; 69% inhibition). No significant changes were found with indomethacin ( n = 6; 4% inhibition). Thus, in the fetal pulmonary circulation, CGRP increases pulmonary blood flow not only through its specific receptor but also, in part, through nitric oxide release and KATP channel activation.

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Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation elicited by cortical spreading depression

Brain Research ◽

10.1016/0006-8993(94)91234-3 ◽

1994 ◽

Vol 637 (1-2) ◽

pp. 204-210 ◽

Cited By ~ 106

Author(s):

M. Wahl ◽

L. Schilling ◽

A.A. Parsons ◽

A. Kaumann

Keyword(s):

Nitric Oxide ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Pial Artery ◽

Calcitonin Gene

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Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation

Cephalalgia ◽

10.1177/0333102413502735 ◽

2013 ◽

Vol 34 (2) ◽

pp. 136-147 ◽

Cited By ~ 48

Author(s):

Roshni Ramachandran ◽

Deepak Kumar Bhatt ◽

Kenneth Beri Ploug ◽

Anders Hay-Schmidt ◽

Inger Jansen-Olesen ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Femoral Vein ◽

Calcitonin Gene Related Peptide ◽

Human Model ◽

Neuronal Activation ◽

Related Peptide ◽

Calcitonin Gene ◽

Pre Treatment ◽

Oxide Synthase

Background and aim Infusion of glyceryltrinitrate (GTN), a nitric oxide (NO) donor, in awake, freely moving rats closely mimics a universally accepted human model of migraine and responds to sumatriptan treatment. Here we analyse the effect of nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP) systems on the GTN-induced neuronal activation in this model. Materials and methods The femoral vein was catheterised in rats and GTN was infused (4 µg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP and Western blot for measuring nNOS protein expression. The effect of olcegepant, L-nitro-arginine methyl ester (L-NAME) and neurokinin (NK)-1 receptor antagonist L-733060 were analysed on Fos activation. Results GTN-treated rats showed a significant increase of nNOS and CGRP in dura mater and CGRP in the trigeminal nucleus caudalis (TNC). Upregulation of Fos was observed in TNC four hours after the infusion. This activation was inhibited by pre-treatment with olcegepant. Pre-treatment with L-NAME and L-733060 also significantly inhibited GTN induced Fos expression. Conclusion The present study indicates that blockers of CGRP, NOS and NK-1 receptors all inhibit GTN induced Fos activation. These findings also predict that pre-treatment with olcegepant may be a better option than post-treatment to study its inhibitory effect in GTN migraine models.

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