Antoinette MaassenVanDenBrink

Coronary Side-Effect Potential of Current and Prospective Antimigraine Drugs

BACKGROUND The antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan). METHODS AND RESULTS Concentration-response curves to the antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (Emax) and the concentration eliciting 50% of Emax (EC50). The EC50 values were related to maximum plasma concentrations (Cmax) reported in patients, obtaining Cmax/EC50 ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting antimigraine drugs to assess their disappearance from the receptor biophase. Compared with sumatriptan, all drugs were more potent (lower EC50 values) in contracting the coronary artery but had similar efficacies (Emax <25% of K+-induced contraction). The Cmax of avitriptan was 7- to 11-fold higher than its EC50 value, whereas those of the other drugs were <40% of their respective EC50 values. The contractile responses to ergotamine and dihydroergotamine persisted even after repeated washings, but those to the other drugs declined rapidly after washing. CONCLUSIONS All current and prospective antimigraine drugs contract the human coronary artery in vitro, but in view of low efficacy, these drugs are unlikely to cause myocardial ischemia at therapeutic plasma concentrations in healthy subjects. In patients with coronary artery disease, however, these drugs must remain contraindicated. The sustained contraction by ergotamine and dihydroergotamine seems to be an important disadvantage compared with sumatriptan-like drugs.

Animal models of migraine: looking at the component parts of a complex disorder.

Animal models of human disease have been extremely helpful both in advancing the understanding of brain disorders and in developing new therapeutic approaches. Models for studying headache mechanisms, particularly those directed at migraine, have been developed and exploited efficiently in the last decade, leading to better understanding of the potential mechanisms of the disorder and of the action for antimigraine treatments. Model systems employed have focused on the pain‐producing cranial structures, the large vessels and dura mater, in order to provide reproducible physiological measures that could be subject to pharmacological exploration. A wide range of methods using both in vivo and in vitro approaches are now employed; these range from manipulation of the mouse genome in order to produce animals with human disease‐producing mutations, through sensitive immunohistochemical methods to vascular, neurovascular and electrophysiological studies. No one model system in experimental animals can explain all the features of migraine; however, the systems available have begun to offer ways to dissect migraines component parts to allow a better understanding of the problem and the development of new treatment strategies.

Vasoconstriction by in situ formed angiotensin II: role of ACE and chymase

OBJECTIVE To assess the importance, for vasoconstriction, of in situ angiotensin (Ang) II generation, as opposed to ang II delivery to AT receptors via the organ bath fluid. METHODS Ang I and II concentration-response curves in human and porcine coronary arteries (HCAs, PCAs) were constructed in relation to estimates of the clearances of Ang I and II (ClAngI, ClAngII) from the organ bath and the release of newly formed Ang II (RAngII) into the bath fluid. HCAs were from 25 heart valve donors (age 5-54 years), and PCAs from 14 pigs (age 3 months). RESULTS Ang I- and II-evoked constrictions were inhibited by the AT1 receptor antagonist, irbesartan, and were not influenced by the AT2 receptor antagonist, PD123319. In HCAs Ang II was only three times more potent than Ang I, wheres, in the experiments with Ang I, comparison of ClAngI with ClAngII and RAngII indicated that most of the arterially produced Ang II did not reach the bath fluid. Also in PCAs Ang I and II showed similar potency. In HCAs both the ACE inhibitor, captopril, and the chymase inhibitor, chymostatin, inhibited Ang I-evoked vasoconstriction, while only chymostatin had a significant effect on ClAngI. In PCAs Ang I-evoked vasoconstriction was almost completely ACE-dependent. CONCLUSIONS This study points towards the functional importance of in situ ACE- and chymase-dependent Ang II generation, as opposed to Ang II delivery via the circulation. It also indicates that functionally relevant changes in local Ang I-II conversion are not necessarily reflected by detectable changes in circulating Ang II.

Basic mechanisms of migraine and its acute treatment.

Migraine is a neurovascular disorder characterized by recurrent unilateral headaches accompanied by nausea, vomiting, photophobia and phonophobia. Current theories suggest that the initiation of a migraine attack involves a primary event in the central nervous system (CNS), probably involving a combination of genetic changes in ion channels and environmental changes, which renders the individual more sensitive to environmental factors; this may, in turn, result in a wave of cortical spreading depression (CSD) when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Early PET studies have suggested the involvement of a migraine active region in the brainstem. Migraine headache is associated with trigeminal nerve activation and calcitonin gene-related peptide (CGRP) release from the trigeminovascular system. Administration of triptans (5-HT(1B/1D) receptor agonists) causes the headache to subside and the levels of CGRP to normalize. Moreover, administration of CGRP receptor antagonists aborts the headache. Recent immunohistochemical and pharmacological results suggest that the trigeminal system has receptors for CGRP; further, 5-HT(1B/1D) receptors, which inhibit the action of CGRP in pain transmission when activated, have been demonstrated. This offers an explanation for the treatment response. The present review provides an updated analysis of the basic mechanisms involved in the pathophysiology of migraine and the various pharmacological approaches (including 5-HT(1B/1D) receptor agonists, CGRP receptor antagonists and glutamate receptor antagonists) that have shown efficacy for the acute treatment of this disorder.

5-HT1B Receptor Polymorphism and Clinical Response to Sumatriptan

The 5‐HT1 receptor agonist, sumatriptan, is highly effective in the treatment of migraine. Some patients, however, do not respond or experience recurrence of the headache. In addition, some patients report chest symptoms after sumatriptan. We investigated whether these different responses could be attributed to genetic diversity of the 5‐HT1B receptor, which most likely mediates the therapeutic action and the coronary side effects of sumatriptan. Allele frequencies of two polymorphisms in the 5‐HT1B receptor gene (G861C and T‐261G) were investigated in migraine patients with consistently good response to sumatriptan (n=14), with no response (n=12), with recurrence of the headache (n=12), with chest symptoms (n=13), and in patients without chest symptoms (n=27). Allele frequencies (G:0.74; C:0.26 at nt 861 and T:0.39; G:0.61 at nt ‐261) did not differ between patient groups, indicating that genetic diversity of the 5‐HT1B receptor does not seem to be involved in the different clinical responses to sumatriptan.

Augmented contraction of the human isolated coronary artery by sumatriptan: a possible role for endogenous thromboxane.

1 The antimigraine drug, sumatriptan, contracts the human coronary artery and, in some patients, elicits chest symptoms (e.g. pressure and pain), particularly after subcutaneous administration. We studied the effects of the thromboxane A2 (TxA2) analogue, U46619 and endothelin‐1 on contractile responses to sumatriptan in the human isolated coronary artery as well as the role of endogenously produced TxA2 and endothelin‐1 in contractions evoked by sumatriptan. 2 In the presence of U46619 (1 and 3 nM), mean concentration‐response curves to sumatriptan in the human coronary artery were shifted vertically due to the initial contraction by U46619, but when this initial contraction was subtracted from the response to sumatriptan, no significant augmentation was observed. However, analysis of the degree of augmentation in individual arterial segments revealed that the augmentation was variable and related inversely to the Emax of sumatriptan in the absence of U46619 (r = 0.78 and 0.81 for 1 and 3 nM, respectively; P < 0.05). 3 Treatment with the TxA2 receptor antagonist, SQ30741 (100 nM), or incubation of vessel segments with aspirin (10 μm), significantly reduced responses to sumatriptan; in aspirin‐treated vessel segments, SQ30741 failed to decrease further the contractions to sumatriptan. The decrease in Emax of sumatriptan by both SQ30741 and aspirin correlated significantly with the Emax of sumatriptan without SQ30741 (r = 0.74; P < 0.01) or aspirin (r = 0.94; P < 0.01). In aspirin‐treated vessel segments, responses to sumatriptan were significantly augmented in the presence of U46619 (3 nM; P < 0.05). 4 The specificity of SQ30741 was demonstrated by its ability to antagonize coronary artery contractions to U46619 (pA2: 7.54 ± 0.30), but not endothelin‐1. Similarly, incubation with aspirin (10 μm) did not affect contractile responses to endothelin‐1, but significantly reduced TxA2 production in coronary artery segments as judged by a decrease in thromboxane B2 (TxB2) from 4.77 ± 0.98 to 1.38 ± 0.36 ng g−1 2h−1. 5 Endothelin‐1 (1 nM) did not significantly augment contractions to sumatriptan; there was also no relationship between the degree of augmentation and the control Emax of sumatriptan in the absence of endothelin‐1. Furthermore, unlike SQ30741 or aspirin, a high concentration (100 nM) of the nonselective ETA/ETB receptor antagonist, SB 209670, failed to affect contractile responses to sumatriptan. However, SB 209670 potently antagonized coronary artery contractions induced by endothelin‐1 with a pA2 of 8.84 ± 0.32. 6 Compared to control vascular segments, endothelial denudation did not reduce TxA2 production (with endothelium = 2.56 ± 1.38 vs. without endothelium = 12.32 ± 4.94 ng TxB2 g−1 2 h−1), suggesting that the production of TxA2 is not confined to the endothelium. The sumatriptan‐induced contractions were also unaffected by endothelial denudation. 7 The results of the present study suggest that endogenously produced TxA2 enhances contractions to sumatriptan in the human isolated coronary artery. Such a mechanism may play a role in causing chest symptoms after sumatriptan by potentiating coronary vascular contraction by sumatriptan in vivo.

Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries.

Introduction: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. Materials and methods: We investigated the effect of the CGRP receptor antagonist, telcagepant, on CGRP-induced cranial vasodilatation in human isolated cerebral and middle meningeal arteries. We also studied the expression of the CGRP receptor components in cranial arteries with immunocytochemistry. Concentration response curves to αCGRP were performed in human isolated cerebral and middle meningeal arteries in the absence or presence of telcagepant. Arterial slices were stained for RAMP1, CLR and actin in a double immunofluorescence staining. Results: In both arteries, we found that: (i) telcagepant was devoid of any contractile or relaxant effects per se; (ii) pretreatment with telcagepant antagonised the αCGRP-induced relaxation in a competitive manner; and (iii) immunohistochemistry revealed expression and co-localisation of CLR and RAMP1 in the smooth muscle cells in the media layer of both arteries. Conclusions: Our findings provide morphological and functional data on the presence of CGRP receptors in cerebral and meningeal arteries, which illustrates a possible site of action of telcagepant in the treatment of migraine.

Characterization of the Calcitonin Gene-Related Peptide Receptor Antagonist Telcagepant (MK-0974) in Human Isolated Coronary Arteries

The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human αCGRP were greater in distal coronary arteries (i.d. 600–1000 μm; Emax = 83 ± 7%) than proximal coronary arteries (i.d. 2–3 mm; Emax = 23 ± 9%), coronary arteries from explanted hearts (i.d. 3–5 mm; Emax = 11 ± 3%), and coronary arterioles (i.d. 200–300 μm; Emax = 15 ± 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 μM) antagonized αCGRP-induced relaxation competitively in distal coronary arteries (pA2 = 8.43 ± 0.24) and proximal coronary arteries and coronary arterioles (1 μM telcagepant, giving pKB = 7.89 ± 0.13 and 7.78 ± 0.16, respectively). αCGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.

Wiping Out CGRP: Potential Cardiovascular Risks

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.

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 VPAC1, VPAC2 and PAC1 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 VPAC1 receptor agonist ([Lys15,Arg16,Leu27]-VIP[1-7]-GRF[8-27]) were constructed in the absence or presence of the PAC1 receptor antagonist PACAP6-38 or the VPAC1 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 VPAC1 receptor was more pronounced in meningeal arteries. PACAP6-38 reduced the Emax 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.