Inhibition of periarterial nerve stimulation-induced vasodilation of the mesenteric arterial bed by CGRP (8–37) and CGRP receptor desensitization

doi:10.1016/0006-291X(90)92390-L

Biochemical and Biophysical Research Communications

Volume 168, Issue 2, 30 April 1990, Pages 786-791

https://doi.org/10.1016/0006-291X(90)92390-L Get rights and content

Abstract

We provide the first functional evidence that calcitonin gene-related peptide (8–37) induces a direct vasoconstriction and reversibly antagonizes vasodilation of the mesenteric arterial bed induced by calcitonin gene-related peptide (CGRP) suggesting that CGRP (8–37) is a competitive antagonist of vascular CGRP receptors. Vasodilation induced by periarterial nerve stimulation was inhibited both by CGRP (8–37) and by desensitization of CGRP receptors. These results further support the evidence that the periarterial nerve stimulation-induced nonadrenergic noncholinergic vasodilation of the mesenteric vasculature is mediated by endogenous CGRP and its receptors.

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What is known is that periarterial nerve stimulation leads to vasodilation resistant to propranolol and atropine in the isolated mesenteric vascular bed (Kawasaki et al., 1988). Concurrent CGRP release during the vasodilation response (Fujimori et al., 1989), and the ability to block vasodilatation with CGRP antiserum (Han et al., 1990) demonstrates that this nonadrenergic, noncholinergic vasodilation is regulated by endogenous CGRP (Han et al., 1990). Thus, CGRP-containing nerves tonically mediate vascular tone in mesenteric resistance vessels.
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The dynamic regulation of blood flow is essential for meeting the high metabolic demands of the brain and maintaining brain function. Cerebral blood flow is regulated primarily by 1) the intrinsic mechanisms that determine vascular contractility and 2) signals from neurons and astrocytes that alter vascular contractility. Stimuli from neurons and astrocytes can also initiate a signaling cascade in the brain capillary endothelium to increase regional blood flow. Recent studies provide evidence that TRP channels in endothelial cells, smooth muscle cells, neurons, astrocytes, and perivascular nerves control cerebrovascular contractility and cerebral blood flow. TRP channels exert their functional effects either through cell membrane depolarization or by serving as a Ca²⁺ influx pathway. Endothelial cells and astrocytes also maintain the integrity of the blood-brain barrier. Both endothelial cells and astrocytes express TRP channels, and an increase in endothelial TRP channel activity has been linked with a disrupted endothelial barrier function. Therefore, TRP channels can play a potentially important role in regulating blood-brain barrier integrity. Here, we review the regulation of cerebrovascular contractility by TRP channels under healthy and disease conditions and their potential roles in maintaining blood-brain barrier function.
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Citation Excerpt :
In addition, periarterial nerve stimulation of the perfused mesenteric vascular bed causes the tetrodotoxin-sensitive release of CGRP associated with vasodilation (Kawasaki et al., 1988). Moreover, the results obtained with periarterial nerve stimulation-induced nonadrenergic noncholinergic vasodilation with CGRP (8-37) (CGRP-receptor antagonist) (Nuki et al., 1994) confirmed that the vasodilation is mediated by endogenous CGRP released from CGRPergic vasodilator nerves (Han et al., 1990). The present study demonstrated that, in rat mesenteric arteries without an endothelium and with active tone, α-methylhistamine attenuated periarterial nerve stimulation-induced vasodilation in a concentration-dependent manner.
The rat mesenteric artery has been shown to be innervated by adrenergic vasoconstrictor nerves and calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves. The present study was designed to investigate the involvement of histamine H₃ receptors in the neurotransmission of perivascular adrenergic and CGRPergic nerves. The mesenteric vascular beds without an endothelium isolated from male Wistar rats were perfused with Krebs solution and perfusion pressure was measured. In preparations with resting tension, the selective H₃ receptor agonist (R)-α-methylhistamine (α-methylhistamine; 10–100 nM) significantly reduced periarterial nerve stimulation (2–8 Hz)-induced vasoconstriction and noradrenaline release in the perfusate without an effect on the vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0 nmol). In preparations with active tone produced by methoxamine (2 μM) and in the presence of guanethidine (5 μM), the periarterial nerve stimulation (1, 2 Hz)-induced vasodilator response was inhibited by α-methylhistamine (0.1–1 μM) perfusion without affecting vasodilation induced by exogenously injected CGRP (5 pmol). Clobenpropit (histamine H₃ receptor antagonist, 1 μM) canceled the α-methylhistamine-induced decrease in the periarterial nerve stimulation-induced vasoconstriction and noradrenaline release and periarterial nerve stimulation-induced vasodilation. These results suggest that the stimulation of H₃ receptors located in rat perivascular nerves inhibits presynaptically the neurotransmission of not only adrenergic nerves, but also CGRP nerves, by decreasing neurotransmitters.
Activation of 5-HT<inf>1B</inf> receptors inhibits the vasodepressor sensory CGRPergic outflow in pithed rats
2010, European Journal of Pharmacology
The importance of calcitonin gene-related peptide (CGRP) in the regulation of vascular tone has been widely documented. Indeed, stimulation of the perivascular sensory outflow in pithed rats results in vasodepressor responses, which are mediated by CGRP release. These vasodepressor responses are inhibited by clonidine via prejunctional α_2A/2C-adrenoceptors, but no study has yet reported the role of prejunctional 5-hydroxytryptamine (5-HT) receptors in this experimental model. Since activation of prejunctional 5-HT₁ receptors results in inhibition of neurotransmitter release, this study sets out to investigate as an initial approach the role of 5-HT_1B receptors in the inhibition of the vasodepressor sensory outflow in pithed rats. Male Wistar pithed rats were pretreated with hexamethonium (2 mg/kg.min) followed by i.v. continuous infusions of methoxamine (20 µg/kg.min), and then by saline (0.02 ml/min) or CP-93,129 (a rodent 5-HT_1B receptor agonist; 0.1, 1 and 10 µg/kg.min). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T₉-T₁₂) resulted in frequency-dependent decreases in diastolic blood pressure. The infusions of CP-93,129, as compared to those of saline, inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i.v. bolus injections of exogenous α-CGRP (0.1, 0.18, 0.31, 0.56 and 1 μg/kg). This inhibition by CP-93,129 was abolished by the antagonists GR127935 (5-HT_1B/1D) or SB224289 (5-HT_1B), but not by BRL15572 (5-HT_1D). The above results suggest that CP-93,129-induced inhibition of the vasodepressor (perivascular) sensory outflow in pithed rats is mainly mediated by activation of prejunctional 5-HT_1B receptors.

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: This study was supported by USPHS Grants HL 26319 and HL 35202.

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Inhibition of periarterial nerve stimulation-induced vasodilation of the mesenteric arterial bed by CGRP (8–37) and CGRP receptor desensitization

Abstract

Biochem. Biophys. Res. Commun.

Nature