Calcitonin gene-related peptide (human α-CGRP) counteracts vasoconstriction in human subarachnoid haemorrhage

doi:10.1016/0304-3940(94)90240-2

Neuroscience Letters

Volume 170, Issue 1, 28 March 1994, Pages 67-70

https://doi.org/10.1016/0304-3940(94)90240-2 Get rights and content

Abstract

Calcitonin gene-related peptide (CGRP) is a neuropeptide co-stored with tachykinins (substance P, neurokinin A) in cerebrovascular sensory fibers in the trigeminal ganglion. Preceding studies on subarachnoid hemorrhage (SAH) revealed that an enhanced release of CGRP resulted in the selective loss of perivascular CGRP. Therefore, the present study was designed to evaluate the effects of intravenous administration of human α-CGRP on cerebral vasoconstriction in the postoperative course after SAH in 5 patients (8 infusions). Cerebral vasoconstriction was evaluated with transcranial Doppler sonography. The increase in the relationship between middle cerebral artery (MCA) velocity and internal carotid artery (ICA) velocity (the hemodynamic index) was used as an indicator of vasoconstriction and compared to the contralateral side. A significant reduction was found in the hemodynamic index during the CGRP infusion (4.3 ± 0.5, P < 0.05) as to compared to before infusion (6.2 ± 0.5). There was no measurable change in the hemodynamic index on the contralateral side. No significant change was observed in pulsatility index, blood pressure or consciousness during the peptide infusion. A significant increase in heart rate was observed during the infusion as compared to before and after infusion (90 ± 4 vs. 76 ± 5). Cardiac ultrasound data indicated a mean cardiac output increase of 1.9 liter/min, and a mean decrease in total peripheral resistance of 538 dynes s/cm⁵. The results obtained show that infusion of human α-CGRP may induce normalisation of cerebrovascular tone in SAH.

References (17)

L. Edvinsson et al.
Reduced levels of calcitonin gene-related peptide-like immunoreactivity in human brain vessels after subarachnoid hemorrhage
Neurosci. Lett.
(1991)
F.G. Johnston et al.
The effect of calcitonin gene-related peptide on post-operative neurological deficits following subarachnoid haemorrhage
Lancet
(1990)
G. Teasdale et al.
Assessment of coma and impaired consciousness
A practical scale
Lancet
(1974)
R. Aaslid et al.
Evaluation of cerebrovascular spasm with transcranial Doppler ultrasound
J. Neurosurg.
(1984)
R. Aaslid et al.
Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries
J. Neurosurg.
(1982)
L. Edvinsson et al.
Perivascular peptides relax cerebral arteries concomitant with stimulation of cyclic adenosine monophosphate accumulation or release of an endothelium-derived relaxing factor in the cat
Neurosci. Lett.
(1985)
L. Edvinsson et al.
Perivascular neuropeptides (NPY, VIP, CGRP and SP) in human brain vessels after subarachnoid haemorrhage
Acta Neurol. Scand.
(1994)
C. Gennari et al.
Cardiovascular action of calcitonin gene-related peptide in humans
Calcif. Tissue Int.
(1985)

There are more references available in the full text version of this article.

Cited by (51)

Calcitonin gene-related peptide and neurologic injury: An emerging target for headache management
2022, Clinical Neurology and Neurosurgery
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide known to be involved in the trigeminovascular system and to function as a potent vasodilator. Although it has emerged as a viable target for headache management with targeted treatments developed for migraine, a highly disabling neurovascular disorder, less is known about CGRP’s role in other neurologic conditions such as traumatic brain injury and subarachnoid hemorrhage. The literature has shown that during these injury cascades, CGRP receptors are modulated in varying ways. Therefore, CGRP or its receptors might be viable targets to manage secondary injuries following acute brain injury. In this review, we highlight the pathophysiology of the CGRP pathway and its relation to migraine pathogenesis. Using these same principles, we assess the existing preclinical data for CGRP and its role in acute brain injury. The findings are promising, and set the basis for further work, with specific focus on the therapeutic benefit of CGRP modulation following neurologic injury.
Fremanezumab inhibits vasodilatory effects of CGRP and capsaicin in rat cerebral artery - Potential role in conditions of severe vasoconstriction
2019, European Journal of Pharmacology
Citation Excerpt :
The physiology of CGRP is a double-edged sword. On one side CGRP plays a detrimental pathophysiological role in migraine via the trigeminovascular system and on the other side endogenous perivascular CGRP protects organs during states of severe vasoconstriction, e. g. subarachnoid hemorrhage (SAH) (Juul et al., 1990; Juul et al., 1994) or acute myocardial infarct (AMI) (Mair et al., 1990; Huang et al., 2008). Consequently, the CGRP-antagonistic antibodies might challenge endogenous neurovasular protection during local protection from severe vasoconstriction.
CGRP plays a major role in the pathophysiology of migraine. Concomitant, CGRP plays a role in endogenous neurovascular protection from severe vasoconstriction associated with e.g. cerebral or cardiac ischemia.
The CGRP antagonistic antibodies Fremanezumab (TEVA Pharmaceuticals) and Erenumab (Novartis/Amgen) have successfully been developed for the prevention of frequent migraine attacks. Whereas these antibodies might challenge endogenous neurovasular protection during severe cerebral or coronary vasoconstriction, potential future therapeutic CGRP agonists might induce migraine-like headaches in migraineurs.
In the current study segments of cerebral artery have been used to obtain mechanistic insight of the CGRP-neutralizing anti-body Fremanezumab in neurovascular regulation in vitro. The basilar artery was selected due to its relevance in subarachnoid hemorrhage (SAH).
Erenumab is known to block the human CGRP receptor and Fremanezumab to neutralize both human and rat CGRP. Results confirmed that Erenumab does not block the rat CGRP receptor and that Fremanezumab inhibits the vasodilatory effect induced by both human CGRP, rat CGRP and the metabolically stable CGRP analog, SAX in rat basilar artery.
Fremanezumab also inhibits the vasodilatory effect of capsaicin in constricted segments of basilar artery. Capsaicin is used as a pharmacological tool to induce secretion of endogenous perivascular CGRP and our studies confirm that the antibody reach the perivascular sensory synaptic cleft and blocks the vasodilatory response of released CGRP in the present in vitro model.
Thus, CGRP neutralization might have the mechanistic potential to block vasoprotective responses to severe vasoconstriction provided they reach the site of action and Fremanezumab is an important tool for future investigations of the impact of CGRP physiology.
Vascular pathology of large cerebral arteries in experimental subarachnoid hemorrhage: Vasoconstriction, functional CGRP depletion and maintained CGRP sensitivity
2019, European Journal of Pharmacology
Citation Excerpt :
CGRP is a powerful endothelium-independent vasodilator located in sensory nerves innervating the cerebral circulation (Eftekhari and Edvinsson, 2010). The role of CGRP in SAH-induced vasoconstriction is not fully characterized, yet CGRP is released from perivascular sensory nerves potentially as a reflex response to prolonged SAH-induced vasoconstriction (Juul et al., 1994). However, eventually the perivascular CGRP stores might be functionally depleted and the vasodilatory counterbalance to SAH-induced vasospasm inefficient.
Subarachnoid hemorrhage (SAH) is associated with increased cerebral artery sensitivity to vasoconstrictors and release of the perivascular sensory vasodilator CGRP.
In the current study the constrictive phenotype and the vasodilatory effects of exogenous and endogenous perivascular CGRP were characterized in detail applying myograph technology to cerebral artery segments isolated from experimental SAH and sham-operated rats.
Following experimental SAH, cerebral arteries exhibited increased vasoconstriction to endothelin-1, 5-hydroxytryptamine and U46419. In addition, depolarization-induced vasoconstriction (60 mM potassium) was significantly increased, supporting a general SAH-associated vasoconstrictive phenotype.
Using exogenous CGRP, we demonstrated that sensitivity of the arteries to CGRP-induced vasodilation was unchanged after SAH. However, vasodilation in response to capsaicin (100 nM), a sensory nerve activator used to release perivascular CGRP, was significantly reduced by SAH (P = 0.0079). Because CGRP-mediated dilation is an important counterbalance to increased arterial contractility, a reduction in CGRP release after SAH would exacerbate the vasospasms that occur after SAH.
A similar finding was obtained with artery culture (24 h), an in vitro model of SAH-induced vascular dysfunction. The arterial segments maintained sensitivity to exogenous CGRP but showed reduced capsaicin-induced vasodilation.
To test whether a metabolically stable CGRP analogue could be used to supplement the loss of perivascular CGRP release in SAH, SAX was systemically administered in our in vivo SAH model. SAX treatment, however, induced CGRP-desensitization and did not prevent the development of vasoconstriction in cerebral arteries after SAH.
CGRP/CGRP Receptor Antibodies: Potential Adverse Effects Due to Blockade of Neovascularization?
2019, Trends in Pharmacological Sciences
Migraine is a severe neurological disorder in which calcitonin gene-related peptide (CGRP) is a key molecule in pathophysiology. Neuronal system-derived CGRP enhances neovascularization in several important pathological conditions and sends a cue to the vascular system. In 2018, the FDA approved erenumab and fremanezumab, antibodies against CGRP receptor and CGRP, as the first new class of drugs for migraine. Treatment of migraine with these antibodies requires great care because neovascularization-related adverse effects may be induced in some patients. Here, we focus on enhancement of neovascularization by CGRP and discuss possible adverse effects resulting from blocking neovascularization. We also suggest that CGRP antibodies may also be used as novel antitumor agents by suppressing tumor-associated angiogenesis.
Wiping Out CGRP: Potential Cardiovascular Risks
2016, Trends in Pharmacological Sciences
Migraine is a common episodic neurovascular brain disorder associated with increased risk of cardio- and cerebrovascular ischemia. Migraine headache is likely caused by activation of the trigeminovascular system and release of calcitonin gene-related peptide (CGRP). Monoclonal antibodies against CGRP or its receptor are currently being evaluated for the prevention of migraine attacks. Preliminary efficacy data are promising. However, because CGRP may act as a vasodilatory safeguard during cerebral and cardiac ischemia, CGRP blockade could transform transient mild ischemic events into full-blown infarcts. Here, we review the cerebro- and cardiovascular risks that might be associated with CGRP blockade and which clinical and preclinical studies should be conducted to better assess the potential safety issues of this new promising class of drug.
Biomarkers of vasospasm development and outcome in aneurysmal subarachnoid hemorrhage
2014, Journal of the Neurological Sciences
Aneurysmal subarachnoid hemorrhage (SAH) is a neurologic emergency caused by a brain aneurysm burst, resulting in a bleeding into the subarachnoid space. Its incidence is estimated between 4 and 28/10,000 inhabitants and it is the main cause of sudden death from stroke. The prognosis of patients with SAH is directly related to neurological status on admission, to the magnitude of the initial bleeding, as well as to the development of cerebral vasospasm (CVS). Numerous researchers have studied the role of different biomarkers in CVS development. These biomarkers form part of the metabolic cascade that is triggered as a result of the SAH. Hence, among these metabolites we found biomarkers of oxidative stress, inflammation biomarkers, indicators of brain damage, and markers of vascular pathology. However, to the author knowledge, none of these biomarkers has been demonstrated as a useful tool for predicting neither CVS development nor outcome after SAH. In order to reach success on future researches, firstly it should be stated which pathophysiological process is mainly responsible for CVS development. Once this process has been determined, the temporal course of this pathophysiologic cascade should be characterized, and then, perform further studies on biomarkers already analyzed, as well as on new biomarkers not yet studied in the SAH pathology, focusing attention on the temporal course of the diverse metabolites and the sampling time for its quantification.

View all citing articles on Scopus

View full text

Calcitonin gene-related peptide (human α-CGRP) counteracts vasoconstriction in human subarachnoid haemorrhage

Abstract

Neurosci. Lett.

Lancet

Lancet

Evaluation of cerebrovascular spasm with transcranial Doppler ultrasound

J. Neurosurg.

Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries

J. Neurosurg.

Perivascular peptides relax cerebral arteries concomitant with stimulation of cyclic adenosine monophosphate accumulation or release of an endothelium-derived relaxing factor in the cat

Neurosci. Lett.

Perivascular neuropeptides (NPY, VIP, CGRP and SP) in human brain vessels after subarachnoid haemorrhage

Acta Neurol. Scand.

Cardiovascular action of calcitonin gene-related peptide in humans

Calcif. Tissue Int.