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

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 per se 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.

Effect of pituitary adenylate cyclase-activating polypeptide-27 on cerebral hemodynamics in healthy volunteers: A 3T MRI study.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has emerged as an important signaling peptide in migraine pathogenesis. Recently, we have shown that the less-abundant PACAP isoform, PACAP27, induced migraine and headache in patients equipotently to PACAP38. The present study examined the effect of PACAP27 on cerebral hemodynamics in healthy volunteers using high resolution magnetic resonance angiography (MRA). Eighteen healthy volunteers received infusion of PACAP27 (10 pmol/kg/min) or placebo over 20 min and were scanned repeatedly in fixed intervals for 5 h in a double-blind, randomized, placebo-controlled study. The circumference of extra-intracerebral arteries was measured and compared with PACAP38 data. We found significant dilation of middle meningeal artery (MMA) (p = 0.019), superficial temporal artery (p = 0.001) and external carotid artery (p = 0.039) after PACAP27 infusion compared to placebo. Whereas the middle cerebral artery (MCA) (p = 0.011) and internal carotid artery (ICA) (pICAcervical = 0.015, pICAcerebral = 0.019) were constricted. No effects on basilar artery (p = 0.708) and cavernous portion of ICA were found. Post hoc analyses revealed significant larger area under the curve for MMA after PACAP38 compared to PACAP27 (p = 0.033). We also found that PACAP27 induced headache in nine out of twelve (75%) volunteers and one (17%) after placebo. In conclusion, PACAP27 induced headache and dilated extracerebral arteries (>5 h) and slightly constricted MCA in healthy volunteers. Post hoc analysis of PACAP38 data compared with PACAP27 showed that PACAP isoforms dilates MMA with significantly different magnitude.

Erenumab (AMG 334), a monoclonal antagonist antibody against the canonical CGRP receptor, does not impair vasodilatory or contractile responses to other vasoactive agents in human isolated cranial arteries.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is a neuronal transmitter present in intracranial sensory nerves, where it is involved in migraine pathophysiology as well as other biological functions. Recently, the fully human monoclonal antibody erenumab (AMG 334), which targets the canonical calcitonin gene-related peptide receptor, showed significant prophylactic efficacy and favourable safety in phase II and III clinical trials for episodic and chronic migraine and is now approved for migraine prevention in several countries. OBJECTIVE: Given that calcitonin gene-related peptide can mediate vasodilation, we investigated the effect of erenumab on vasoactive responses in the presence or absence of various vasodilatory and vasocontractile mediators in a model using isolated human cerebral and meningeal arteries. METHODS: Ring segments of human isolated cerebral and meningeal arteries were mounted in a sensitive myograph. On arterial segments pre-contracted with 30 mM potassium chloride, vasoactive responses to calcitonin gene-related peptide were studied in the presence of different concentrations of erenumab. At the maximal tested inhibitory concentration of erenumab (100 nM), functional arterial relaxation in response to nicardipine or substance P, and the contractile responses to sumatriptan and dihydroergotamine were examined. RESULTS: 30 mM potassium chloride produced a stable contraction of the vessel segments and calcitonin gene-related peptide induced a concentration-dependent relaxation. We observed that (i) erenumab had no direct contractile or relaxant effects per se (by itself), (ii) pre-treatment with erenumab antagonized the calcitonin gene-related peptide-induced relaxation in a competitive manner, (iii) the relaxant responses to nicardipine or substance P were unaffected in the presence of erenumab and (iv) the contraction induced by sumatriptan or dihydroergotamine was not modified by erenumab. CONCLUSION: Our findings demonstrate that erenumab, while not associated with vasoactive properties per se, specifically inhibits calcitonin gene-related peptide-induced relaxation of cranial arteries without impacting vasodilatory responses or contractile responses of endogenous or pharmacological vasoactive compounds.

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

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.

Clinical importance of the posterior meningeal artery: a review of the literature.

The posterior meningeal artery, which arises from the vertebral artery, is a critical artery in neurological lesions. However, a comprehensive review of the importance of the posterior meningeal artery is currently lacking. In this study, we used the PubMed database to perform a review of the literature on the posterior meningeal artery to increase our understanding of its role in vascular lesions. The posterior meningeal artery provides the main blood supply to the paramedial and medial portions of the dura covering the cerebellar convexity. The posterior meningeal artery is often involved in dural arteriovenous fistulas occurring near the posterior fossa, and the posterior meningeal artery can be the path for transarterial embolisation or a path through which to monitor the degree of dural arteriovenous fistula embolisation. In posterior circulation ischaemia and moyamoya disease, the posterior meningeal artery can form transdural anastomoses with pial arteries at the surface of the brain, and these can help prevent ischemia. The posterior meningeal artery can also develop aneurysms, most of which are traumatic pseudoaneurysms; patients should therefore be treated in a timely manner or followed up carefully in cases of rebleeding. In addition, during a craniotomy, the posterior meningeal artery should be protected intraoperatively to avoid damaging any transdural anastomosis that may be present. In addition, when the posterior meningeal artery is the main feeding artery of an intracranial tumour, that artery is a satisfactory path for preoperative embolisation. Briefly, the posterior meningeal artery is a very important artery in neurosurgery.

Posterior meningeal artery DMSO injection resulting in reproducible asystole prior to Onyx therapy of a dural arteriovenous fistula: a previously undescribed variant of the trigeminocardiac reflex or a new phenomenon?

We describe a case of reproducible asystole during endovascular treatment of a posterior fossa dural arteriovenous fistula. Catheterisation of the posterior meningeal artery, a branch of the vertebral artery in this patient, followed by dimethyl sulfoxide injection prior to Onyx administration resulted in two episodes of asystole.To the best of our knowledge, this is the first reported case of asystole occurring during endovascular intervention in the posterior meningeal artery. This may represent a previously undescribed variant of the trigemino-cardiac reflex (TGCR) caused by chemical stimulation of small areas of trigeminally innervated posterior fossa dura. Alternatively, this may represent a newly identified phenomenon with chemical stimulation of regions of posterior fossa dura innervated by branches of the vagus nerve leading to increased parasympathetic activity and resultant asystole.In either case, it is important to recognise the potential for such episodes in this vascular territory to allow case planning and management.

Comparison of the vasodilator responses of isolated human and rat middle meningeal arteries to migraine related compounds.

BACKGROUND: Migraine attacks occur spontaneously in those who suffer from the condition, but migraine-like attacks can also be induced artificially by a number of substances. Previously published evidence makes the meninges a likely source of migraine related pain. This article investigates the effect of several vasodilators on meningeal arteries in order to find a connection between the effect of a substance on a meningeal vessel and its ability to artificially induce migraine. METHODS: A myograph setup was used to test the vasodilator properties of the substances acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil, prostaglandin E2 (PGE2), pituitary adenylate cyclase activating peptide-38 (PACAP-38), calcitonin gene-related peptide (CGRP) and NaCl buffer on meningeal arteries from human and rat. An unpaired t-test was used to statistically compare the mean Emax(%) at the highest concentration of each substance to the Emax(%) of NaCl buffer. RESULTS: In the human experiments, all substances except PACAP-38 had an Emax (%) higher than the NaCl buffer, but the difference was only significant for SNP and CGRP. For the human samples, clinically tested antimigraine compounds (sumatriptan, telcagepant) were applied to the isolated arteries, and both induced a significant decrease of the effect of exogenously administrated CGRP. In experiments on rat middle meningeal arteries, pre-contracted with PGF2α, similar tendencies were seen. When the pre-contraction was switched to K+ in a separate series of experiments, CGRP and sildenafil significantly relaxed the arteries. CONCLUSIONS: Still no definite answer can be given as to why pain is experienced during an attack of migraine. No clear correlation was found between the efficacy of a substance as a meningeal artery vasodilator in human and the ability to artificially induce migraine or the mechanism of action. Vasodilatation could be an essential trigger, but only in conjunction with other unknown factors. The vasculature of the meninges likely contributes to the propagation of the migrainal cascade of symptoms, but more research is needed before any conclusions can be drawn about the nature of this contribution.

Modelling headache and migraine and its pharmacological manipulation.

Similarities between laboratory animals and humans in anatomy and physiology of the cephalic nociceptive pathways have allowed scientists to create successful models that have significantly contributed to our understanding of headache. They have also been instrumental in the development of novel anti-migraine drugs different from classical pain killers. Nevertheless, modelling the mechanisms underlying primary headache disorders like migraine has been challenging due to limitations in testing the postulated hypotheses in humans. Recent developments in imaging techniques have begun to fill this translational gap. The unambiguous demonstration of cortical spreading depolarization (CSD) during migraine aura in patients has reawakened interest in studying CSD in animals as a noxious brain event that can activate the trigeminovascular system. CSD-based models, including transgenics and optogenetics, may more realistically simulate pain generation in migraine, which is thought to originate within the brain. The realization that behavioural correlates of headache and migrainous symptoms like photophobia can be assessed quantitatively in laboratory animals, has created an opportunity to directly study the headache in intact animals without the confounding effects of anaesthetics. Headache and migraine-like episodes induced by administration of glyceryltrinitrate and CGRP to humans and parallel behavioural and biological changes observed in rodents create interesting possibilities for translational research. Not unexpectedly, species differences and model-specific observations have also led to controversies as well as disappointments in clinical trials, which, in return, has helped us improve the models and advance our understanding of headache. Here, we review commonly used headache and migraine models with an emphasis on recent developments.

Cranioselectivity of sumatriptan revisited: pronounced contractions to sumatriptan in small human isolated coronary artery.

BACKGROUND: Initial concerns about the coronary side-effect potential of the anti-migraine drug sumatriptan and second-generation triptans initiated cranioselectivity studies using proximal human coronary arteries. However, myocardial ischaemia may originate from both large and small human coronary arteries. METHODS: We investigated the contractions to sumatriptan in proximal (internal diameter 2-3 mm), distal (internal diameter 1,000-1,500 µm) and small (internal diameter 500-1,000 µm) human epicardial coronary arteries and compared these with contractions in the human middle meningeal artery. Concentration response curves to sumatriptan in human coronary arteries were constructed in the absence or presence of the 5-hydroxytryptamine1B (5-HT1B) receptor antagonist SB224289 and the 5-HT1D receptor antagonist BRL15572. The effect of sumatriptan on increased cyclic adenosine monophosphate (cAMP) levels induced by forskolin in proximal and distal coronary artery segments was investigated using a biochemical assay. Western blotting was used to analyse the 5-HT1B receptor density in the human arteries. RESULTS: Contractions in the proximal human coronary artery were significantly smaller than those in the human meningeal artery, as we showed previously. In contrast, contractions to sumatriptan in distal and small human coronary arteries were not different from those in the human meningeal artery. The 5-HT1B receptor antagonist SB224289, but not the 5-HT1D receptor antagonist BRL15572, inhibited the contraction induced by sumatriptan in the coronary arteries. Moreover, in distal, but not in proximal, coronary arteries, sumatriptan inhibited the increase in cAMP levels induced by forskolin. Contrary to our expectations, the 5-HT1B receptor expression was more pronounced in the proximal human coronary artery than in the distal and small human coronary artery. CONCLUSIONS: Based on functional experiments in distal and small human coronary arteries, contractions to sumatriptan are not as cranioselective as previously assumed. However, the vast clinical experience with sumatriptan and other triptans has proven that these drugs are cardiovascularly safe when contraindications are taken into account.

Clinical importance of the middle meningeal artery.

Middle meningeal artery (MMA)is an important branch which supplies among others cranial dura mater. It directly attaches to the cranial bones (is incorporated into periosteal layer of dura mater), favors common injuries in course of head trauma. This review describes available data on the MMA considering its varability, or treats specific diseases or injuries where the course of MMA may have clinical impact.

Olvanil acts on transient receptor potential vanilloid channel 1 and cannabinoid receptors to modulate neuronal transmission in the trigeminovascular system.

The transient receptor potential vanilloid channel 1 (TRPV1) is a nociceptive transducer located on nociceptive neurons. TRPV1 channels located on peripheral neurons mainly transduce the sense of heat and are also activated by low pH or capsaicin. The role of centrally located TRPV1 channels is not fully understood. Likewise their importance in pain syndromes of central origin, such as migraine, is not known. Experimental data suggest a relationship to migraine. However, experimental studies with TRPV1 receptor antagonists indicate that the receptor may not be a useful target for new acute migraine treatments. Any potential role for the receptor in the chronification of migraine has not been investigated. The present study aimed at analyzing the use of the TRPV1 channel as a target to desensitize trigeminal neurons and thereby inhibit neuronal activity in the trigeminocervical complex. The TRPV1 receptor agonist olvanil was used for desensitization because, as compared with capsaicin, it is non-noxious and lacks capsaicin's pungency and CGRP release potential. We further investigated a possible effect of olvanil on cannabinoid (CB(1)) receptors, as an interaction between both receptor systems has been described previously. The results show that olvanil dose-dependently inhibited spontaneous and stimulus-induced activity within the trigeminocervical complex, whereas it had no effect on CSD susceptibility. We further demonstrated that the inhibiting effect of olvanil is mediated by vanilloid and cannabinoid receptor systems, thereby using the synergistic effects this dual mechanism offers. Curiously, TRPV1 receptor agonism may have anti-nociceptive properties through central mechanisms that would be of considerable interest to elucidate.

Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers.

AIM: To explore a possible relationship between vasodilatation and delayed headache we examined the effect of pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) on the middle meningeal artery (MMA) and middle cerebral artery (MCA) using high resolution magnetic resonance angiography (MRA). METHODS: In a double-blind, randomized, placebo-controlled study 14 healthy volunteers were scanned repeatedly after infusion (20 min) of 10 pmol/kg/min PACAP38 or placebo. In addition, four participants were scanned following subcutaneous sumatriptan (6 mg). RESULTS: We found significant dilatation of the MMA (p = 0.00001), but not of the MCA (p = 0.50) after PACAP38. There was no change after placebo (p > 0.40). Vasodilatation (range 16-23%) lasted more than 5 h. Sumatriptan selectively contracted the MMA by 12.3% (p = 0.043). CONCLUSION: PACAP38-induced headache is associated with prolonged dilatation of the MMA but not of the MCA. Sumatriptan relieves headache in parallel with contraction of the MMA but not of the MCA.

Effects of heating coagulation of middle meningeal artery on plasma CGRP level and c-fos expression in migraine rat triggered by nitroglycerin.

Current theory or hypothesis relevant to migraine indicates that trigeminovascular system plays a pivotal role in the pathophysiology of migraine. Particularly, release of neuropeptide and induction of c-fos like immunoreactivity (c-fos LI) within trigeminal nucleus caudalis neurons are regarded as activation markers of trigeminovascular system. In the present study, we set up a rat model for migraine triggered by nitroglycerin (NTG) and coagulated the middle meningeal artery by heating. Using this model, we determined the plasma calcitonin gene-related peptide (CGRP) level as well as the expression of c-fos in trigeminal nucleus caudalis of rats. We found that NTG led to markedly increase in plasma CGRP level and c-fos expression in trigeminal nucleus caudalis compared with the isotonic saline-treated group (P < 0.05). More importantly, heat coagulation of middle meningeal artery could decrease plasma CGRP level and c-fos expression in trigeminal nucleus caudalis (P < 0.05). Heat coagulation of middle meningeal artery may ameliorate sufferings of rat induced by NTG and play an important role in restraining the release of CGRP as well as the activation of neurons in trigeminal nucleus caudalis in rats following NTG infusion.

Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery.

OBJECTIVE: We pharmacologically characterized pituitary adenylate cyclase-activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC(1), VPAC(2) and PAC(1) receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries. METHODS: Concentration response curves to PACAP38, PACAP27, VIP and the VPAC(1) receptor agonist ([Lys15,Arg16,Leu27]-VIP[1-7]-GRF[8-27]) were constructed in the absence or presence of the PAC(1) receptor antagonist PACAP6-38 or the VPAC(1) receptor antagonist, PG97269. mRNA expression was measured using qPCR. RESULTS: PACAP38 was less potent than VIP in both arteries. Both peptides had lower potency and efficacy in meningeal than in coronary arteries, while mRNA expression of VPAC(1) receptor was more pronounced in meningeal arteries. PACAP6-38 reduced the E(max) of PACAP27, while PG97269 right-shifted the VIP-induced relaxation curve only in the coronary arteries. CONCLUSION: The direct vasodilatory effect of VIP and PACAP might be less relevant than the central effect of this compound in migraine pathogenesis.

Temporal profile of vascular changes induced by systemic nitroglycerin in the meningeal and cortical districts.

BACKGROUND: Clinical studies indicated that nitric oxide (NO) donors cause regional changes in cerebral blood flow (CBF), similar to those reported in spontaneous migraine. Systemic nitroglycerin (NTG), a NO donor, is a well-accepted experimental model of migraine. In this study we have examined the effects of NTG on the meningeal and cortical blood flow in rats. METHODS: Regional blood flow was monitored in male Sprague-Dawley rats using laser Doppler flowmetry before and after NTG/saline injection over 150 minutes. The effect of pre-treatment with Nω-nitro-L-arginine ester (L-NAME) or 7-nitroindazole (7-NI) on NTG-induced changes on blood flow was also investigated. RESULTS: In the dura NTG caused a biphasic response represented by an initial decrease in blood flow followed by a significant increase. At variance, in the cortex NTG caused only an increase in blood flow. Pre-treatment with either L-NAME or 7-NI prevented NTG-induced increase in blood flow in both districts, while only L-NAME also prevented NTG-induced decrease in dural blood flow. CONCLUSION: The present findings provide additional information on the timing of effects of NTG on blood flow at both the meningeal and cortical levels. These effects seem to be related to vasoregulatory mechanisms and/or metabolic activity in response to the synthesis of endogenous NO.

5-HT7 receptor-mediated meningeal dilatation induced by 5-carboxamidotryptamine in rats is not altered by 5-HT depletion and chronic corticosterone treatment.

Low brain serotonin levels and high circulating levels of corticosterone are features of migraine. The 5-HT7 receptor was shown to mediate dilator responses to the 5-HT1B/1D and 5-HT7 receptor agonist, 5-carboxamidotryptamine in the middle meningeal artery of rats. Here we analyzed the effect of serotonin depletion and chronic corticosterone treatment on 5-HT7 receptor-mediated dilatation induced by 5-carboxamidotryptamine in the middle meningeal artery of anesthetized rats. Two weeks before experiments, male Wistar rats received i.c.v. injections of vehicle or the neurotoxin, 5,7-dihydroxytryptamine; upon recovery, animals received a chronic s.c. treatment (2 weeks) with vehicle (1 ml/kg/day) or corticosterone (20 mg/kg/day). At the end of treatments, animals were anesthetized and prepared for recording of blood pressure and blood flow in the middle meningeal artery, and i.v. drug administration. All animals received the 5-HT1B/1D receptor antagonist GR-127935 (1 mg/kg, i.v.) alone or combined with the 5-HT7 receptor antagonist, SB-269970 (1 mg/kg, i.v.). Topical 5-carboxamidotryptamine (0.01-1000 microM) to the exposed dura mater encephala produced decreases in diastolic blood pressure, variable changes in meningeal blood flow and increases in conductance (i.e. dilatation) in the middle meningeal artery. Meningeal dilator responses to 5-carboxamidotryptamine did not differ among treatment groups. In all cases, the combined treatment with GR-127935 + SB-269970 inhibited hypotensive and meningeal dilator responses to 5- carboxamidotryptamine. Together, these data do not support the notion that 5-HT7 receptors mediating dilatation in the middle meningeal artery are regulated by low brain serotonin levels and/or chronically high circulating levels of corticosterone. Further studies are required to elucidate the potential impact of these conditions and the role of 5-HT7 receptors in migraine.

TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation.

The TRPA1 receptor is a member of the transient receptor potential (TRP) family of ion channels expressed in nociceptive neurons. TRPA1 receptors are targeted by pungent compounds from mustard and garlic and environmental irritants such as formaldehyde and acrolein. Ingestion or inhalation of these chemical agents causes irritation and burning in the nasal and oral mucosa and respiratory lining. Headaches have been widely reported to be induced by inhalation of environmental irritants, but it is unclear how these agents produce headache. Stimulation of trigeminal neurons releases CGRP and substance P and induces neurogenic inflammation associated with the pain of migraine. Here we test the hypothesis that activation of TRPA1 receptors is the mechanistic link between environmental irritants and peptide-mediated neurogenic inflammation. Known TRPA1 agonists and environmental irritants stimulate CGRP release from dissociated rat trigeminal ganglia neurons and this release is blocked by a selective TRPA1 antagonist, HC-030031. Further, TRPA1 agonists and environmental irritants increase meningeal blood flow following intranasal administration. Prior dural application of the CGRP antagonist, CGRP(8-37), or intranasal or dural administration of HC-030031, blocks the increases in blood flow elicited by environmental irritants. Together these results demonstrate that TRPA1 receptor activation by environmental irritants stimulates CGRP release and increases cerebral blood flow. We suggest that these events contribute to headache associated with environmental irritants.

Hypertension impairs leptomeningeal collateral growth after common carotid artery occlusion: restoration by antihypertensive treatment.

Chronic mild hypoperfusion has been shown to enlarge pial collateral vessels in normal mouse brains. The purpose of this study was to clarify the effect of hypertension on pial collateral vessel development after chronic hypoperfusion using spontaneously hypertensive rats (SHR). In normotensive rats, unilateral common carotid artery (CCA) occlusion enlarged leptomeningeal collateral vessels. CCA occlusion also preserved residual cerebral blood flow (CBF) and attenuated infarct size after middle cerebral artery (MCA) occlusion 14 days later. In contrast, in SHR, CCA occlusion neither enlarged the leptomeningeal anastomosis nor showed protective effects after MCA occlusion. However, decreasing blood pressure using an angiotensin II AT1 receptor blocker restored the beneficial effect of CCA occlusion on collateral growth as well as on residual CBF and infarct size after MCA occlusion. Adaptive responses in CBF autoregulation curves observed 14 days after CCA occlusion in normotensive rats were impaired in untreated SHR, but were restored after antihypertensive treatment. In conclusion, SHR have impaired leptomeningeal collateral growth after CCA occlusion, but antihypertensive treatment restores the beneficial effect of CCA occlusion on collateral circulation.

The evolution of the meningeal vascular system in the human genus: From brain shape to thermoregulation.

OBJECTIVES: The imprints of the middle meningeal vessels make it possible to analyze vascularization in fossil specimens. The association between changes in the cortical anatomy and vascular organization raises questions about the actual physiological meaning of these features, most of all when dealing with the origin of the modern human brain. Metabolism and thermoregulation may be relevant factors in influencing morphological adaptations between brain and vessels. This study is aimed at investigating the relationships between endocranial morphology and endocranial vessels in modern humans and to analyze the pattern of heat dissipation through the endocranial surface in fossil specimens. METHODS: Through angiotomography, it is possible to make an anatomical reconstruction of the meningeal and cerebral vessels, providing information on the morphology of the endocranial vascular system. At the same time, digital modeling can be performed to investigate the relationships between the endocranial geometry and physical properties such as heat dissipation patterns in extinct hominids. RESULTS: The middle meningeal network is largely independent from the cerebral vascular system. Furthermore, in adults, the medium and upper tracts of the middle meningeal artery shows scarce or absent blood flow. Parietal bossing in modern humans involves relative cooling of the cortical surface at the supramarginal gyrus. CONCLUSIONS: The evidence does not support a thermoregulatory role for the meningeal vascular network, at least in adult normal blood flow conditions. On the other hand, biomechanical protective functions (hydraulic skeleton for shock adsorption) cannot be ruled out.

Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers.

BACKGROUND: Calcitonin gene-related peptide (CGRP) plays a fundamental role in the pathophysiology of neurovascular headaches. CGRP infusion causes headache and dilation of cranial vessels. However, it is unknown to what extent CGRP-induced vasodilation contributes to immediate head pain and whether the migraine-specific abortive drug sumatriptan, a 5-hydroxytryptamine 1B/1D agonist, inhibits CGRP-induced immediate vasodilation and headache. METHODS: We performed a double-blind, randomized, placebo-controlled, crossover study in 18 healthy volunteers. We recorded circumference changes of the middle meningeal artery (MMA) and middle cerebral artery (MCA) using magnetic resonance angiography before and after infusion (20 minutes) of 1.5 µg/min human αCGRP or placebo (isotonic saline) as well as after a 6-mg sumatriptan subcutaneous injection. RESULTS: Compared with placebo, CGRP caused significant dilation of MMA (p = 0.006) and no dilation of MCA (p = 0.69). Sumatriptan caused a marked contraction of MMA (15%-25.2%) and marginal contraction of MCA (3.9% to 5.3%). Explorative analysis revealed that sumatriptan had a more selective action on MMA compared with MCA on the CGRP day (p < 0.0001) and on the placebo day (p = 0.007). CONCLUSION: These data suggest that exogenous CGRP dilates extracranial vessels and not intracranial, and that sumatriptan exerts part of its antinociceptive action by constricting MMA and not MCA. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that IV GCRP causes dilation of the MMA but not the MCA in healthy volunteers, and that sumatriptan reverses the dilation of the MMA caused by CGRP.