Publications by authors named "Eloísa Rubio-Beltran"

21 Publications

  • Page 1 of 1

Selective PDE1 inhibition ameliorates vascular function, reduces inflammatory response, and lowers blood pressure in ageing animals.

J Pharmacol Exp Ther 2021 Jun 7. Epub 2021 Jun 7.

Erasmus MC, Netherlands

Diminished nitric oxide - cGMP -mediated relaxation plays a crucial role in cardiovascular ageing, leading to decreased vasodilation, vascular hypertrophy and stiffening, and ultimately cardiovascular dysfunction. Ageing is the time-related worsening of physiological function due to complex cellular and molecular interactions, and is at least partly driven by DNA damage. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice provides us an efficient tool to accelerate vascular ageing, explore mechanisms, and test potential treatments. Previously we identified the cGMP-degrading enzyme phosphodiesterase 1 as a potential treatment target in vascular ageing. In the present study, we studied the effect of acute and chronic treatment with ITI-214, a selective phosphodiesterase 1 inhibitor on vascular ageing features in mice. Compared to wild-type mice, mice at the age of 14 weeks showed decreased reactive hyperemia, diminished endothelium-dependent and -independent responses of arteries in organ baths, carotid wall hypertrophy, and elevated circulating levels of inflammatory cytokines. Acute ITI-214 treatment in organ baths restored the arterial endothelium-independent vasodilation in mice. An 8-week treatment with 100 mg/kg/d ITI-214 improved endothelium-independent relaxation in both aorta and coronary arteries, at least partly restored the diminished reactive hyperemia, lowered the systolic and diastolic blood pressure, normalized the carotid hypertrophy, and ameliorated inflammatory responses exclusively in mice. These findings suggest PDE1 inhibition would provide a powerful tool for nitric oxide - cGMP augmentation and have significant therapeutic potential to battle arteriopathy related to ageing. The findings implicate the key role of PDE1 in vascular function and might be of clinical importance for prevention of mortalities and morbidities related to vascular complications during ageing, as well as for progeria patients that show a high risk of cardiovascular disease.
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http://dx.doi.org/10.1124/jpet.121.000628DOI Listing
June 2021

Dietary salt modifies the blood pressure response to renin-angiotensin inhibition in experimental chronic kidney disease.

Am J Physiol Renal Physiol 2021 04 15;320(4):F654-F668. Epub 2021 Feb 15.

Division of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Chronic kidney disease contributes to hypertension, but the mechanisms are incompletely understood. To address this, we applied the 5/6th nephrectomy rat model to characterize hypertension and the response to dietary salt and renin-angiotensin inhibition. 5/6th nephrectomy caused low-renin, salt-sensitive hypertension with hyperkalemia and unsuppressed aldosterone. Compared with sham rats, 5/6th nephrectomized rats had lower Na/H exchanger isoform 3, Na-K-2Cl cotransporter, Na-Cl cotransporter, α-epithelial Na channel (ENaC), and Kir4.1 levels but higher serum and glucocorticoid-regulated kinase 1, prostasin, γ-ENaC, and Kir5.1 levels. These differences correlated with plasma renin, aldosterone, and/or K. On a normal-salt diet, adrenalectomy (0 ± 9 mmHg) and spironolactone (-11 ± 10 mmHg) prevented a progressive rise in blood pressure (10 ± 8 mmHg), and this was enhanced in combination with losartan (-41 ± 12 and -43 ± 9 mmHg). A high-salt diet caused skin Na and water accumulation and aggravated hypertension that could only be attenuated by spironolactone (-16 ± 7 mmHg) and in which the additive effect of losartan was lost. Spironolactone also increased natriuresis, reduced skin water accumulation, and restored vasorelaxation. In summary, in the 5/6th nephrectomy rat chronic kidney disease model, salt-sensitive hypertension develops with a selective increase in γ-ENaC and despite appropriate transporter adaptations to low renin and hyperkalemia. With a normal-salt diet, hypertension in 5/6th nephrectomy depends on angiotensin II and aldosterone, whereas a high-salt diet causes more severe hypertension mediated through the mineralocorticoid receptor. Chronic kidney disease (CKD) causes salt-sensitive hypertension, but the interactions between dietary salt and the renin-angiotensin system are incompletely understood. In rats with CKD on a normal-salt diet targeting aldosterone, the mineralocorticoid receptor (MR) and especially angiotensin II reduced blood pressure. On a high-salt diet, however, only MR blockade attenuated hypertension. These results reiterate the importance of dietary salt restriction to maintain renin-angiotensin system inhibitor efficacy and specify the MR as a target in CKD.
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http://dx.doi.org/10.1152/ajprenal.00603.2020DOI Listing
April 2021

Changing levels of sex hormones and calcitonin gene-related peptide (CGRP) during a woman's life: Implications for the efficacy and safety of novel antimigraine medications.

Maturitas 2021 Mar 6;145:73-77. Epub 2021 Jan 6.

Div. of Pharmacology, Dept. of Internal Medicine, Erasmus University Medical Centre, PO Box 2040, 3000 CA Rotterdam, the Netherlands. Electronic address:

Migraine is a neurovascular disorder that is three times more prevalent in women than in men and represents a large socio-economic burden. Therefore, the development of new preventive medications is an urgent matter. Currently, calcitonin gene-related peptide (CGRP), a neuropeptide released from trigeminal fibres, is an important target for migraine treatment. Accordingly, antibodies directed against CGRP or its receptor, as well as small-molecule CGRP receptor antagonists, have been developed for the prophylactic and acute treatment of migraine. Results from clinical phase III trials show a significant decrease in migraine days and relatively mild side-effects. However, CGRP is not only present in the trigeminal nerve, but it is also abundant in perivascular nerve fibres. Moreover, CGRP levels and hormones vary between sexes and during different life stages, and hormones affect CGRP, with a seemingly greater role for CGRP in females. In this review we discuss whether these aspects could be associated with differences in response and efficacy of drugs interfering with the CGRP pathway. Furthermore, CGRP has been described as playing a protective role in ischemic events, and CGRP seems to play a larger role in cardiac ischemic events in female patients. As cardiovascular risk is increased in female migraine patients and also increases significantly in females after menopause, further research into the risk of blocking CGRP in these patients is needed.
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http://dx.doi.org/10.1016/j.maturitas.2020.12.012DOI Listing
March 2021

Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction.

Clin Sci (Lond) 2020 04;134(7):727-746

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (EC-KO) mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared with wild-type (WT). EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared with WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BP. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.
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http://dx.doi.org/10.1042/CS20190124DOI Listing
April 2020

Lasmiditan inhibits calcitonin gene-related peptide release in the rodent trigeminovascular system.

Pain 2020 05;161(5):1092-1099

Division of Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

Migraine headache pathophysiology involves trigeminovascular system activation, calcitonin gene-related peptide (CGRP) release, and dysfunctional nociceptive transmission. Triptans are 5-HT1B/1D/(1F) receptor agonists that prejunctionally inhibit trigeminal CGRP release, but their vasoconstrictor properties limit their use in migraine patients with cardiovascular disease. By contrast, lasmiditan is a novel antimigraine and selective 5-HT1F receptor agonist devoid of vasoconstrictor properties. On this basis, this study has investigated the modulation of trigeminal CGRP release by lasmiditan. For this purpose, we have comparatively analysed the inhibition of several components of the trigeminovascular system induced by lasmiditan and sumatriptan through: ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion, and trigeminal nucleus caudalis of mice; and in vivo dural vasodilation in the rat closed-cranial window model induced by endogenous (electrical stimulation and capsaicin) and exogenous CGRP. The ex vivo release of CGRP was similarly inhibited by sumatriptan and lasmiditan in all trigeminovascular system components. In vivo, intravenous (i.v.) lasmiditan or higher doses of sumatriptan significantly attenuated the vasodilatory responses to endogenous CGRP release, but not exogenous CGRP effects. These data suggest that lasmiditan prejunctionally inhibits CGRP release in peripheral and central trigeminal nerve terminals. Because lasmiditan is a lipophilic drug that crosses the blood-brain barrier, additional central sites of action remain to be determined.
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http://dx.doi.org/10.1097/j.pain.0000000000001801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170441PMC
May 2020

Increased Mortality and Vascular Phenotype in a Knock-In Mouse Model of Retinal Vasculopathy With Cerebral Leukoencephalopathy and Systemic Manifestations.

Stroke 2020 01 6;51(1):300-307. Epub 2019 Dec 6.

From the Department of Neurology (I.A.M., G.M.T., M.J.H.W., A.M.J.M.v.d.M.), Leiden University Medical Center, the Netherlands.

Background and Purpose- Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant small vessel disease caused by C-terminal frameshift mutations in the gene that encodes the major mammalian 3' to 5' DNA exonuclease. RVCL-S is characterized by vasculopathy, especially in densely vascularized organs, progressive retinopathy, cerebral microvascular disease, white matter lesions, and migraine, but the underlying mechanisms are unknown. Methods- Homozygous transgenic RVCL-S knock-in mice expressing a truncated Trex1 (three prime repair exonuclease 1) protein (similar to what is seen in patients) and wild-type littermates, of various age groups, were subjected to (1) a survival analysis, (2) in vivo postocclusive reactive hyperemia and ex vivo Mulvany myograph studies to characterize the microvascular and macrovascular reactivity, and (3) experimental stroke after transient middle cerebral artery occlusion with neurological deficit assessment. Results- The mutant mice show increased mortality starting at midlife (=0.03 with hazard ratio, 3.14 [95% CI, 1.05-9.39]). The mutants also show a vascular phenotype as evidenced by attenuated postocclusive reactive hyperemia responses (across all age groups; F[1, 65]=5.7, =0.02) and lower acetylcholine-induced relaxations in aortae (in 20- to 24-month-old mice; RVCL-S knock-in: E: 37±8% versus WT: E: 65±6%, =0.01). A vascular phenotype is also suggested by the increased infarct volume seen in 12- to 14-month-old mutant mice at 24 hours after infarct onset (RVCL-S knock-in: 75.4±2.7 mm versus WT: 52.9±5.6 mm, =0.01). Conclusions- Homozygous RVCL-S knock-in mice show increased mortality, signs of abnormal vascular function, and increased sensitivity to experimental stroke and can be instrumental to investigate the pathology seen in patients with RVCL-S.
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http://dx.doi.org/10.1161/STROKEAHA.119.025176DOI Listing
January 2020

Characterisation of the calcitonin gene-related peptide receptor antagonists ubrogepant and atogepant in human isolated coronary, cerebral and middle meningeal arteries.

Cephalalgia 2020 04 1;40(4):357-366. Epub 2019 Nov 1.

Department of Internal Medicine, Institute of Clinical Sciences, Lund University Hospital, Lund, Sweden.

Background: Migraine has been associated with a dysfunctional activation of the trigeminovascular system. Calcitonin gene-related peptide, a neuropeptide released from the trigeminal nerve fibres, has an important role in the pathophysiology of migraine and is a current therapeutic target for migraine treatment.

Methods: We examined the effects of two novel calcitonin gene-related peptide receptor antagonists, ubrogepant and atogepant, on the relaxations induced by α calcitonin gene-related peptide in human isolated middle meningeal, cerebral and coronary arteries. Furthermore, the contractile responses to atogepant and ubrogepant were studied and compared to the responses elicited by zolmitriptan in proximal and distal human coronary arteries.

Results: In intracranial arteries, both blockers antagonized the calcitonin gene-related peptide-induced relaxations more potently when compared to the inhibition observed in distal human coronary arteries, with atogepant showing a higher potency. When analysing their antagonistic profile in HCA, ubrogepant showed a competitive antagonist profile, while atogepant showed a non-competitive one. Neither of the gepants had vasoconstrictor effect at any of the concentrations studied in human coronary arteries, whereas zolmitriptan elicited concentration-dependent contractions.

Conclusion: ubrogepant and atogepant differentially inhibit the calcitonin gene-related peptide-dependent vasodilatory responses in intracranial arteries when compared to distal human coronary arteries. Also, both gepants are devoid of vasoconstrictive properties in human coronary arteries.
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http://dx.doi.org/10.1177/0333102419884943DOI Listing
April 2020

Characterization of binding, functional activity, and contractile responses of the selective 5-HT receptor agonist lasmiditan.

Br J Pharmacol 2019 12 7;176(24):4681-4695. Epub 2019 Nov 7.

Division of Pharmacology, Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Background And Purpose: Triptans are 5-HT receptor agonists (that also display 5-HT receptor affinity) with antimigraine action, contraindicated in patients with coronary artery disease due to their vasoconstrictor properties. Conversely, lasmiditan was developed as an antimigraine 5-HT receptor agonist. To assess the selectivity and cardiovascular effects of lasmiditan, we investigated the binding, functional activity, and in vitro/in vivo vascular effects of lasmiditan and compared it to sumatriptan.

Experimental Approach: Binding and second messenger activity assays of lasmiditan and other serotoninergic agonists were performed for human 5-HT , 5-HT , 5-HT , 5-ht , 5-HT , 5-HT , 5-HT , and 5-HT receptors, and the results were correlated with their potency to constrict isolated human coronary arteries (HCAs). Furthermore, concentration-response curves to lasmiditan and sumatriptan were performed in proximal and distal HCA, internal mammary, and middle meningeal arteries. Finally, anaesthetized female beagle dogs received i.v. infusions of lasmiditan or sumatriptan in escalating cumulative doses, and carotid and coronary artery diameters were measured.

Key Results: Lasmiditan showed high selectivity for 5-HT receptors. Moreover, the functional potency of the analysed compounds to inhibit cAMP increase through 5-HT receptor activation positively correlated with their potency to contract HCA. In isolated human arteries, sumatriptan, but not lasmiditan, induced contractions. Likewise, in vivo, sumatriptan decreased coronary and carotid artery diameters at clinically relevant doses, while lasmiditan was devoid of vasoconstrictor activity at all doses tested.

Conclusions And Implications: Lasmiditan is a selective 5-HT receptor agonist devoid of vasoconstrictor activity. This may represent a cardiovascular safety advantage when compared to the triptans.
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http://dx.doi.org/10.1111/bph.14832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965684PMC
December 2019

Characterisation of vasodilatory responses in the presence of the CGRP receptor antibody erenumab in human isolated arteries.

Cephalalgia 2019 Dec 8;39(14):1735-1744. Epub 2019 Jul 8.

Division of Pharmacology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Background: Migraine is associated with activation of the trigeminovascular system, release of calcitonin gene-related peptide (CGRP) and dilation of dural arteries. Novel treatments target calcitonin gene-related peptide or its receptor, which are present in all vascular beds, raising cardiovascular concerns. Erenumab is a human CGRP-receptor antibody approved for the prophylactic treatment of migraine.

Methods: We characterised the relaxant responses to CGRP in the absence and presence of erenumab (1 μM) in isolated human middle meningeal, internal mammary and (proximal and distal) coronary arteries. Furthermore, in human internal mammary arteries from cardiovascularly-compromised patients, we assessed the pharmacological specificity of erenumab by investigating whether the vasodilatory responses to acetylcholine, sodium nitroprusside, pituitary adenylate cyclase activating polypeptide-38 (PACAP), vasoactive intestinal peptide and nicardipine, along with the vasoconstrictor responses to dihydroergotamine, were modified by erenumab.

Results: Calcitonin gene-related peptide induced concentration-dependent vasodilatory responses in all vessels studied that were significantly antagonised by erenumab. In human internal mammary arteries from cardiovascularly-compromised patients, the responses to acetylcholine, sodium nitroprusside, PACAP, vasoactive intestinal peptide, nicardipine and dihydroergotamine were unaffected by erenumab.

Conclusion: Erenumab inhibits calcitonin gene-related peptide-induced vasodilatory responses in human middle meningeal arteries, human internal mammary arteries and human coronary arteries. Moreover, erenumab shows functional specificity as no interaction was observed with the relaxant responses to several vasodilators, nor the dihydroergotamine-dependent vasoconstrictor responses.
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http://dx.doi.org/10.1177/0333102419863027DOI Listing
December 2019

Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models.

Cephalalgia 2019 Oct 19;39(11):1421-1434. Epub 2019 May 19.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Background: The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine.

Objective: We aimed to explore purinergic receptors as potential anti-migraine targets.

Methods: We used the human middle meningeal artery as a proxy for the trigeminal system to screen for possible anti-migraine candidates. The human findings were followed by intravital microscopy and calcitonin gene-related peptide release measurements in rodents.

Results: We show that the purinergic P2Y13 receptor fulfills all the features of a potential anti-migraine target. The P2Y13 receptor is expressed in both the human trigeminal ganglion and middle meningeal artery and activation of this receptor causes: a) middle meningeal artery contraction ; b) reduced dural artery dilation following periarterial electrical stimulation and c) a reduction of CGRP release from both the dura and the trigeminal ganglion . Furthermore, we show that P2X3 receptor activation of the trigeminal ganglion causes calcitonin gene-related peptide release and middle meningeal artery dilation.

Conclusion: Both an agonist directed at the P2Y13 receptor and an antagonist of the P2X3 receptor seem to be viable potential anti-migraine therapies.
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http://dx.doi.org/10.1177/0333102419851810DOI Listing
October 2019

Nonclinical safety evaluation of erenumab, a CGRP receptor inhibitor for the prevention of migraine.

Regul Toxicol Pharmacol 2019 Aug 11;106:224-238. Epub 2019 May 11.

Amgen Research, One Amgen Center Dr., Thousand Oaks, CA, 91320, USA.

Calcitonin gene-related peptide (CGRP) and its receptor have been implicated as a key mediator in the pathophysiology of migraine. Thus, erenumab, a monoclonal antibody antagonist of the CGRP receptor, administered as a once monthly dose of 70 or 140 mg has been approved for the preventive treatment of migraine in adults. Due to the species specificity of erenumab, the cynomolgus monkey was used in the pharmacology, pharmacokinetics, and toxicology studies to support the clinical program. There were no effects of erenumab on platelets in vitro (by binding, activation or phagocytosis assays). Specific staining of human tissues with erenumab did not indicated any off-target binding. There were no erenumab-related findings in a cardiovascular safety pharmacology study in cynomolgus monkeys or in vitro in human isolated coronary arteries. Repeat-dose toxicology studies conducted in cynomolgus monkeys at dose levels up to 225 mg/kg (1 month) or up to 150 mg/kg (up to 6 months) with twice weekly subcutaneous (SC) doses showed no evidence of erenumab-mediated adverse toxicity. There were no effects on pregnancy, embryo-fetal or postnatal growth and development in an enhanced pre-postnatal development study in the cynomolgus monkey. There was evidence of placental transfer of erenumab based on measurable serum concentrations in the infants up to 3 months post birth. The maternal and developmental no-observed-effect level (NOEL) was the highest dose tested (50 mg/kg SC Q2W). These nonclinical data in total indicate no safety signal of concern to date and provide adequate margins of exposure between the observed safe doses in animals and clinical dose levels.
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http://dx.doi.org/10.1016/j.yrtph.2019.05.013DOI Listing
August 2019

Effects of two isometheptene enantiomers in isolated human blood vessels and rat middle meningeal artery - potential antimigraine efficacy.

J Headache Pain 2019 May 3;20(1):47. Epub 2019 May 3.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.

Background: Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action.

Methods: Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model.

Results: The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 μM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses.

Conclusion: The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.
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http://dx.doi.org/10.1186/s10194-019-1003-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734216PMC
May 2019

Understanding CGRP and Cardiovascular Risk.

Handb Exp Pharmacol 2019 ;255:131-140

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Increasing knowledge about the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology has led to the development of antibodies against this peptide or its receptor. However, CGRP is widely expressed throughout the body, participating not only in pathophysiological conditions but also in several physiological processes and homeostatic responses during pathophysiological events. Therefore, in this chapter, the risks of long-term blockade of the CGRP pathway will be discussed, with focus on the cardiovascular system, as this peptide has been described to have a protective role during ischemic events, and migraine patients present a higher risk of stroke and myocardial infarction.
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http://dx.doi.org/10.1007/164_2019_204DOI Listing
September 2019

PACAP38 and PAC receptor blockade: a new target for headache?

J Headache Pain 2018 Aug 7;19(1):64. Epub 2018 Aug 7.

Department of Internal Medicine, Institute of Clinical Sciences, Lund University, Lund, Sweden.

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated.Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacological targets need to be identified.Due to the ability of PACAP38 to induce migraine-like attacks, its location in structures previously associated with migraine pathophysiology and the 100-fold selectivity for the PAC receptor when compared to VIP, new attention has been drawn to this pathway and its potential role as a novel target for migraine treatment. In accordance with this, antibodies against PACAP38 (ALD 1910) and PAC receptor (AMG 301) are being developed, with AMG 301 already in Phase II clinical trials. No results have been published so far, but in preclinical studies, AMG 301 has shown responses comparable to those observed with triptans. If these antibodies prove to be effective for the treatment of migraine, several considerations should be addressed, for instance, the potential side effects of long-term blockade of the PACAP (receptor) pathway. Moreover, it is important to investigate whether these antibodies will indeed represent a therapeutic advantage for the patients that do not respond the CGRP (receptor)-antibodies.In conclusion, the data presented in this review indicate that PACAP38 and PAC receptor blockade are promising antimigraine therapies, but results from clinical trials are needed in order to confirm their efficacy and side effect profile.
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http://dx.doi.org/10.1186/s10194-018-0893-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081277PMC
August 2018

Protective effects of PACAP in ischemia.

J Headache Pain 2018 Mar 2;19(1):19. Epub 2018 Mar 2.

Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus MC, Rotterdam, The Netherlands.

Pituitary adenylate cyclase activating polypeptide (PACAP) is an ubiquitous peptide involved, among others, in neurodevelopment, neuromodulation, neuroprotection, neurogenic inflammation and nociception. Presence of PACAP and its specific receptor, PAC1, in the trigeminocervical complex, changes of PACAP levels in migraine patients and the migraine-inducing effect of PACAP injection strongly support the involvement of PACAP/PAC1 receptor in migraine pathogenesis. While antagonizing PAC1 receptor is a promising therapeutic target in migraine, the diverse array of PACAP's functions, including protection in ischemic events, requires that the cost-benefit of such an intervention is well investigated by taking all the beneficial effects of PACAP into account. In the present review we summarize the protective effects of PACAP in ischemia, especially in neuronal ischemic injuries, and discuss possible points to consider when developing strategies in migraine therapy interfering with the PACAP/PAC1 receptor system.
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http://dx.doi.org/10.1186/s10194-018-0845-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834414PMC
March 2018

Is selective 5-HT receptor agonism an entity apart from that of the triptans in antimigraine therapy?

Pharmacol Ther 2018 06 17;186:88-97. Epub 2018 Jan 17.

Div. of Pharmacology, Dept. of Internal Medicine, Erasmus University Medical Center, PO Box 2040, 3000, CA, Rotterdam, The Netherlands. Electronic address:

Migraine is a neurovascular disorder that involves activation of the trigeminovascular system and cranial vasodilation mediated by release of calcitonin gene-related peptide (CGRP). The gold standard for acute migraine treatment are the triptans, 5-HT receptor agonists. Their actions are thought to be mediated through activation of: (i) 5-HT receptors in cranial blood vessels with subsequent cranial vasoconstriction; (ii) prejunctional 5-HT receptors on trigeminal fibers that inhibit trigeminal CGRP release; and (iii) 5-HT receptors in central nervous system involved in (anti)nociceptive modulation. Unfortunately, coronary arteries also express 5-HT receptors whose activation would produce coronary vasoconstriction; hence, triptans are contraindicated in patients with cardiovascular disease. In addition, since migraineurs have an increased cardiovascular risk, it is important to develop antimigraine drugs devoid of vascular (side) effects. Ditans, here defined as selective 5-HT receptor agonists, were developed on the basis that most of the triptans activate trigeminal 5-HT receptors, which may explain part of the triptans' antimigraine action. Amongst the ditans, lasmiditan: (i) fails to constrict human coronary arteries; and (ii) is effective for the acute treatment of migraine in preliminary Phase III clinical trials. Admittedly, the exact site of action is still unknown, but lasmiditan possess a high lipophilicity, which suggests a direct action on the central descending antinociceptive pathways. Furthermore, since 5-HT receptors are located on trigeminal fibers, they could modulate CGRP release. This review will be particularly focussed on the similarities and differences between the triptans and the ditans, their proposed sites of action, side effects and their cardiovascular risk profile.
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http://dx.doi.org/10.1016/j.pharmthera.2018.01.005DOI Listing
June 2018

Gender aspects of CGRP in migraine.

Cephalalgia 2019 03 30;39(3):435-444. Epub 2017 Oct 30.

1 Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Background: Migraine is two to three times more prevalent in women than in men, but the mechanisms involved in this gender disparity are still poorly understood. In this respect, calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology and, more recently, the functional interactions between ovarian steroid hormones, CGRP and the trigeminovascular system have been recognized and studied in more detail.

Aims: To provide an overview of CGRP studies that have addressed gender differences utilizing animal and human migraine preclinical research models to highlight how the female trigeminovascular system responds differently in the presence of varying ovarian steroid hormones.

Conclusions: Gender differences are evident in migraine. Several studies indicate that fluctuations of ovarian steroid hormone (mainly estrogen) levels modulate CGRP in the trigeminovascular system during different reproductive milestones. Such interactions need to be considered when conducting future animal and human experiments, since these differences may contribute to the development of gender-specific therapies.
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http://dx.doi.org/10.1177/0333102417739584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402050PMC
March 2019

Blocking CGRP in migraine patients - a review of pros and cons.

J Headache Pain 2017 Sep 25;18(1):96. Epub 2017 Sep 25.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.
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http://dx.doi.org/10.1186/s10194-017-0807-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612904PMC
September 2017

Pharmacological analysis of the inhibition produced by moxonidine and agmatine on the vasodepressor sensory CGRPergic outflow in pithed rats.

Eur J Pharmacol 2017 Oct 8;812:97-103. Epub 2017 Jul 8.

Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios No. 235, Col. Granjas-Coapa, Deleg. Tlalpan, 14330 Ciudad de México, México. Electronic address:

Calcitonin gene-related peptide (CGRP) plays a role in several (patho)physiological functions, and modulation of its release is considered a therapeutic target. In this respect, electrical spinal (T--T) stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. This study investigated the role of imidazoline I and I receptors in the inhibition by moxonidine and agmatine of these vasodepressor responses. Male Wistar pithed rats (pretreated i.v. with 25mg/kg gallamine and 2mg/kg⋅min hexamethonium) received i.v. continuous infusions of methoxamine (20μg/kg⋅min) followed by physiological saline (0.02ml/min), moxonidine (1, 3, 10 or 30μg/kg⋅min) or agmatine (1000 or 3000μg/kg⋅min). Under these conditions, electrical stimulation (0.56-5.6Hz; 50V; 2ms) of the spinal cord (T-T) produced frequency-dependent vasodepressor responses which were: (i) unchanged during saline infusion; and (ii) inhibited during the above infusions of moxonidine or agmatine. Moreover, using i.v. administrations, the inhibition by 3μg/kg⋅min moxonidine or 3000μg/kg⋅min agmatine (which failed to inhibit the vasodepressor responses by α-CGRP; 0.1-1µg/kg) was: (i) unaltered after saline (1ml/kg), rauwolscine (300μg/kg; α-adrenoceptor antagonist) or BU224 (300μg/kg; imidazoline I receptor antagonist); and (ii) reversed after AGN 192403 (3000μg/kg; imidazoline I receptor antagonist). This reversion was relatively more pronounced after AGN 192403 plus rauwolscine. These blocking doses of antagonists lacked any effects on the electrically-induced vasodepressor responses. Therefore, the inhibition of the vasodepressor sensory CGRPergic outflow by moxonidine and agmatine is mainly mediated by prejunctional imidazoline I receptors on perivascular sensory nerves.
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http://dx.doi.org/10.1016/j.ejphar.2017.07.020DOI Listing
October 2017

Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-isometheptene and (R)-isometheptene in pithed rats.

J Headache Pain 2017 Dec 4;18(1):52. Epub 2017 May 4.

Department of Pharmacobiology, Cinvestav-Coapa, Czda. Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, 14330, Mexico City, Mexico.

Background: Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- isometheptene and (R)-isometheptene, and the pharmacological profile of the more potent enantiomer.

Methods: The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of isometheptene racemate, (S)-isometheptene or (R)-isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h).

Results: Compared to (R)-isometheptene, (S)-isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin.

Conclusions: The different cardiovascular effects of the isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-isometheptene (a tyramine-like action and a direct stimulation of α-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-isometheptene. Thus, (R)-isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
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http://dx.doi.org/10.1186/s10194-017-0761-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418177PMC
December 2017

Hypothalamic paraventricular nucleus stimulation enhances c-Fos expression in spinal and supraspinal structures related to pain modulation.

Neurosci Res 2015 Sep 28;98:59-63. Epub 2015 Apr 28.

Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus UNAM-Juriquilla, México. Electronic address:

The hypothalamic paraventricular nuclei (PVN) inhibits spinal nociception. Furthermore, projections from the PVN to other structures related to pain modulation exist, but a functional interaction has not yet been fully demonstrated. As an initial approach, we show here that PVN electric stimulation with the same parameters used to induce analgesia in rats enhances c-Fos expression not only in the dorsal horn of the spinal cord but also in the nucleus raphe magnus, locus coeruleus and the periaqueductal gray area. These results suggest that a functional interaction between these structures could occur, possibly to assure a mechanism of endogenous analgesia.
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http://dx.doi.org/10.1016/j.neures.2015.04.004DOI Listing
September 2015