Olcegepant blocks neurogenic and non‐neurogenic CGRPergic vasodepressor responses and facilitates noradrenergic vasopressor responses in pithed rats

Avilés-Rosas, Victor H.; Rivera‐Mancilla, Eduardo; Marichal‐Cancino, Bruno A.; Manrique-Maldonado, Guadalupe; Altamirano-Espinoza, Alain H.; MaassenVanDenBrink, Antoinette; Villalón, Carlos M.

doi:10.1111/bph.13799

Cited by 21 publications

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References 39 publications

(95 reference statements)

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“…Control groups received the same volume of identical vehicle via the same route. The selected olcegepant doses were within the previously reported dose range (1μg/kg–30mg/kg) in experimental models in rodents 29,30,32–37 . In rats, 1mg/kg olcegepant, which we used herein, has yielded a peak plasma concentration of 0.8μM compared with peak plasma concentrations of approximately 0.15μM after a 10mg dose in clinical studies 34,38–41 .…”

Section: Methodsmentioning

confidence: 87%

“…Finally, we sought to examine the relative potencies of olcegepant and rimegepant in isolated mouse and human blood vessels to confirm the dose ranges we selected based on previous work (Fig 8). 32–37,42,43 To this end, we tested these drugs. In mouse aorta, the 1μM, 3μM, and 10μM concentrations of olcegepant all significantly shifted the concentration–response curve to rat α‐CGRP (control pEC 50 = 8.02 ± 0.08, 1μM pEC 50 = 6.55 ± 0.16, 3μM pEC 50 = 6.35 ± 0.11, 10μM pEC 50 = 5.41 ± 0.18, p < 0.001, mean ± SEM, 1‐way ANOVA for repeated measures).…”

Section: Resultsmentioning

confidence: 99%

“…Guided by previously published studies, 29–31 we obtained the drugs from commercial vendors (Tocris Bioscience, MedChemExpress), rather than the pharmaceutical companies that developed the clinical preparations, and relied upon the product data sheets and purity reports provided by these vendors, all of which are publicly available. Although we have picked the dose ranges from the existing literature, 29–38,42–45 as a caveat we have not measured the plasma or brain drug levels to inform us about the relevance of the dose–route combination used in our study to clinical dose–route combinations. However, as both antagonists we tested showed much higher potency in human compared with mouse vessels, lower plasma levels may be sufficient to observe the same effect on stroke outcomes in humans.…”

Section: Discussionmentioning

confidence: 99%

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Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Mulder

Vries

et al. 2020

Annals of Neurology

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Objective: Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRPmediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia. Methods: Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro. Results: Olcegepant (1mg/kg, single dose) increased infarct risk after 12-to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta. Interpretation: Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition.

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Section: Methodsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Mulder

Vries

et al. 2020

Annals of Neurology

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“…Moreover, it is important to note that we did not measure sensory nerve activity directly, but the electrically-induced CGRP release in the systemic vasculature could be estimated indirectly by measurement of the evoked vasodepressor response, as previously established using the CGRP receptor antagonists CGRP 8–37 [ 12 ] and olcegepant [ 24 ]. Hence, the inhibition by DHE was considered sensory-inhibitory since this ergot inhibited the vasodepressor responses induced by spinal (T 9 -T 12 ) stimulation of the vasodepressor sensory CGRPergic outflow (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors

et al. 2018

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BackgroundDihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow.MethodsPithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure.ResultsDHE inhibited the vasodepressor responses to electrical stimulation (0.56–5.6 Hz), without affecting those to i.v. α-CGRP (0.1–1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-like; 310 μg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses.ConclusionDHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE’s vasoconstrictor properties resulting in an increased vascular resistance.Electronic supplementary materialThe online version of this article (10.1186/s10194-018-0869-8) contains supplementary material, which is available to authorized users.

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“…Initially, this was known as the nonadrenergic-noncholinergic (NANC) component of the vasodepressor sensory outflow [ 33 ]. To sum up, the pithed rat model is a powerful tool to investigate the role of several monoaminergic receptors in the inhibition of the perivascular sympathetic and sensory CGRPergic outflows [ 10 , 34 , 35 ]. The major advantages of the pithed rat model over other experimental approaches include, among others: (i) the exclusion of neural reflexes integrated in the CNS that allow us to study local and systemic perivascular modulation; (ii) the reproducibility of vascular responses induced pharmacologically and/or electrically (as the preparation lasts several hours); (iii) this reproducibility and long-lasting experimental protocols allow the rats to be their own controls (particularly for the sympathetic outflow) by comparing the effect of drugs before and after treatments; (iv) the relatively low cost of the model; and (v) the possibility of stimulating the autonomic (sympathetic) or sensory perivascular outflows involved in cardiovascular responses in a selective manner.…”

Section: The Rat Vasculature As a Preclinical Modelmentioning

confidence: 99%

Monoaminergic Receptors as Modulators of the Perivascular Sympathetic and Sensory CGRPergic Outflows

Marichal‐Cancino

González‐Hernández

Muñoz-Islas

et al. 2020

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: Blood pressure is a highly controlled cardiovascular parameter that normally guarantees an adequate blood supply to all body tissues. This parameter is mainly regulated by vascular peripheral resistance and is maintained by local mediators (i.e., autacoids), and by the nervous and endocrine systems. Regarding the nervous system, blood pressure can be modulated at central level by regulating the autonomic output. However, at peripheral level there exists a modulation by activation of prejunctional monoaminergic receptors in autonomic- or sensory-perivascular fibers. These modulatory mechanisms on resistance blood vessels exert an effect on the release of neuroactive substances from the autonomic or sensory fibers that modify blood pressure. Certainly, resistance blood vessels are innervated by perivascular: (i) autonomic sympathetic fibers (producing vasoconstriction mainly by noradrenaline release); and (ii) peptidergic sensory fibers [producing vasodilatation mainly by calcitonin gene-related peptide (CGRP) release]. In the last years, by using pithed rats, several monoaminergic mechanisms for controlling both the sympathetic and sensory perivascular outflows have been elucidated. Additionally, several studies have shown the functions of many monoaminergic auto-receptors and hetero-receptors expressed on perivascular fibers that modulate neurotransmitter release. On this basis, the present review: (i) summarizes the modulation of the peripheral vascular tone by adrenergic, serotoninergic, dopaminergic, and histaminergic receptors on perivascular autonomic (sympathetic) and sensory fibers, and (ii) highlights that these monoaminergic receptors are potential therapeutic targets for the development of novel medications to treat cardiovascular diseases (with some of them explored in clinical trials or already in clinical use).

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Olcegepant blocks neurogenic and non‐neurogenic CGRPergic vasodepressor responses and facilitates noradrenergic vasopressor responses in pithed rats

Cited by 21 publications

References 39 publications

Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors

Monoaminergic Receptors as Modulators of the Perivascular Sympathetic and Sensory CGRPergic Outflows

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