Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities.

Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ETA+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg-1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H2O2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H2O2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ETA+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H2O2-mediated coronary vasodilation.

Cold extremities in migraine: a marker for vascular dysfunction in women.

BACKGROUND AND PURPOSE: Migraine is recognized as a vascular risk factor, especially in women. Presumably, migraine, stroke and cardiovascular events share pathophysiological mechanisms. Self-reported cold extremities were investigated as a marker for vascular dysfunction in migraine. Secondly, it was hypothesized that suffering from cold extremities affects sleep quality, possibly exacerbating migraine attack frequency. METHODS: In this case-control study, a random sample of 1084 migraine patients and 348 controls (aged 22-65 years) from the LUMINA migraine cohort were asked to complete questionnaires concerning cold extremities, sleep quality and migraine. RESULTS: A total of 594 migraine patients and 199 controls completed the questionnaires. In women, thermal discomfort and cold extremities (TDCE) were more often reported by migraineurs versus controls (odds ratio 2.3, 95% confidence interval 1.4-3.7; P < 0.001), but not significantly so in men (odds ratio 2.5, 95% confidence interval 0.9-6.9; P = 0.09). There was no difference in TDCE comparing migraine with or without aura. Female migraineurs who reported TDCE had higher attack frequencies compared to female migraineurs without TDCE (4 vs. 3 attacks per month; P = 0.003). The association between TDCE and attack frequency was mediated by the presence of difficulty initiating sleep (P = 0.02). CONCLUSION: Women with migraine more often reported cold extremities compared with controls, possibly indicating a sex-specific vascular vulnerability. Female migraineurs with cold extremities had higher attack frequencies, partly resulting from sleep disturbances. Future studies need to demonstrate whether cold extremities in female migraineurs are a predictor for cardiovascular and cerebrovascular events.

A human trigeminovascular biomarker for antimigraine drugs: A randomised, double-blind, placebo-controlled, crossover trial with sumatriptan.

Current antimigraine drugs are believed, besides their direct vasoconstrictive effect, to inhibit calcitonin gene-related peptide (CGRP) release from trigeminal nerve endings during migraine. Objective The objective of this report is to establish a biomarker for the CGRP-interfering effect of antimigraine drugs. Methods We quantified the effect of sumatriptan on the trigeminal nerve-mediated rise in forehead dermal blood flow (DBF), induced by capsaicin application (0.6 mg/ml) and electrical stimulation (0.2-1.0 mA), in a randomised, double-blind, placebo-controlled, crossover study in healthy male ( n = 11, age ± SD: 29 ± 8 years) and female ( n = 11, 32 ± 7 years) individuals. Results DBF responses to capsaicin were attenuated by sumatriptan (ΔDBF, mean ± SEM: 82 ± 18 AU, p = 0.0002), but not by placebo (ΔDBF: 21 ± 12 AU, p = 0.1026). Conclusion We demonstrated that sumatriptan inhibits increases in DBF, induced by the release of, most likely, CGRP. Thus, our model may be used as a biomarker to establish the trigeminovascular effects of (potential) antimigraine drugs, such as CGRP receptor antagonists or antibodies directed against CGRP or its receptor.

A human capsaicin model to quantitatively assess salivary CGRP secretion.

BACKGROUND: Capsaicin induces the release of calcitonin gene-related peptide (CGRP) via the transient receptor potential channel V1 (TRPV1). The CGRP response after capsaicin application on the tongue might reflect the "activation state" of the trigeminal nerve, since trigeminal CGRP-containing vesicles are depleted on capsaicin application. We tested (i) the quantitative CGRP response after oral capsaicin application; (ii) the optimal concentration of red chili homogenate; and (iii) the day-to-day variability in this response. METHODS: Saliva was collected for two consecutive days after oral application of eight capsaicin dilutions (red chili homogenates) of increasing concentrations in 13 healthy individuals. Effects of homogenate concentration were assessed. Consecutively, saliva was sampled after application of vehicle and undiluted homogenates. RESULTS: CGRP secretion (pg/ml) increased dose-dependently with homogenate concentration (p < 0.001). CGRP levels were highest after application of nondiluted homogenate (vs. baseline: 13.3 (5.0) vs. 9.7 (2.9); p = 0.003, as was total CGRP secretion in five minutes (pg) with undiluted (vs. baseline): 89.2 (44.1) vs. 14.1 (2.8); p < 0.001. The dose-dependent response in CGRP was not affected by day (p = 0.14) or day*concentration (p = 0.60). Increase in CGRP (undiluted - baseline; pg/ml) did not differ between measurements on dose-finding (p = 0.67) and follow-up days (p = 0.46). CONCLUSION: Oral application of red chili homogenate is well tolerated and causes a dose-dependent CGRP release in saliva, without day-to-day effects in this response. This model could be used to noninvasively study the activation state of the trigeminal nerve innervating salivary glands.

Development of an experimental model to study trigeminal nerve-mediated vasodilation on the human forehead.

BACKGROUND: During migraine, trigeminal sensory nerve terminals release calcitonin gene-related peptide (CGRP), inducing nociception and vasodilation. Applied on the skin, capsaicin activates the transient receptor potential vanilloid type 1 (TRPV1) channel and releases CGRP from sensory nerve terminals, thus increasing dermal blood flow (DBF). Using capsaicin application and electrical stimulation of the forehead skin, a trigeminal nerve-innervated dermatome, we aimed to develop a model to measure trigeminal nerve-mediated vasodilation in humans. METHODS: Using laser Doppler imaging, forehead DBF responses to application of capsaicin (0.06 mg/ml and 6.0 mg/ml) and saline, with and without iontophoresis, were studied in healthy subjects. The within-subject coefficient of variation (WCV) of repeated DBF measurements was calculated to assess reproducibility. RESULTS: Maximal DBF responses to 6.0 mg/ml capsaicin with and without iontophoresis did not differ (Emax 459 ± 32 and 424 ± 32 arbitrary units (a.u.), WCV 6 ± 4%). In contrast, DBF responses to 0.06 mg/ml capsaicin were significantly larger with than without iontophoresis (Emax 307 ± 60 versus 187 ± 21 a.u., WCV 21 ± 13%). Saline with iontophoresis significantly increased DBF (Emax: 245 ± 26 a.u, WCV 11 ± 8%), while saline application without iontophoresis did not affect DBF. CONCLUSION: Topical application of capsaicin and electrical stimulation induce reproducible forehead DBF increases and therefore are suitable to study trigeminal nerve-mediated vasodilation in humans.

Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model.

BACKGROUND AND PURPOSE: During migraine, trigeminal nerves may release calcitonin gene-related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate (LY466195) glutamate receptors affected dural vasodilatation induced by alpha-CGRP, capsaicin and periarterial electrical stimulation in rats, using intravital microscopy. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were anaesthetized and the overlying bone was thinned to visualize the dural artery. Then, vasodilator responses to exogenous (i.v. alpha-CGRP) and endogenous (released by i.v. capsaicin and periarterial electrical stimulation) CGRP were elicited in the absence or presence of the above antagonists. KEY RESULTS: alpha-CGRP, capsaicin and periarterial electrical stimulation increased dural artery diameter. Ketamine and MK801 inhibited the vasodilator responses to capsaicin and electrical stimulation, while only ketamine attenuated those to alpha-CGRP. In contrast, GYKI52466 only attenuated the vasodilatation to exogenous alpha-CGRP, while LY466195 did not affect the vasodilator responses to endogenous or exogenous CGRP. CONCLUSIONS AND IMPLICATIONS: Although GYKI52466 has not been tested clinically, our data suggest that it would not inhibit migraine via vascular mechanisms. Similarly, the antimigraine efficacy of LY466195 seems unrelated to vascular CGRP-mediated pathways and/or receptors. In contrast, the cranial vascular effects of ketamine and MK801 may represent a therapeutic mechanism, although the same mechanism might contribute, peripherally, to cardiovascular side effects.

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 alphaCGRP were greater in distal coronary arteries (i.d. 600-1000 microm; E(max) = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E(max) = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E(max) = 11 +/- 3%), and coronary arterioles (i.d. 200-300 microm; E(max) = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 microM) antagonized alphaCGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 microM telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alphaCGRP 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.

The effect of maternal ketanserin treatment on foetal 5-HT receptor function in umbilical cord artery of pre-eclamptic patients.

BACKGROUND: Maternal treatment with the 5-HT(2A) receptor antagonist ketanserin (KT) in pre-eclamptic patients is associated with a high placental transmission of KT, resulting in pharmacologically active levels of KT in the umbilical cord artery (UCA) and the neonate. Prolonged exposure to a 5-HT receptor antagonist may influence the functionality of foetal 5-HT receptors and compromise foetal development. OBJECTIVE: To study whether exposure to KT influences the characteristics of foetal 5-HT receptors, functional studies were performed on 5-HT(2A) and 5-HT(1B/1D) receptors in UCA from pre-eclamptic patients treated with KT. METHODS: UCAs were obtained, immediately after delivery, from pre-eclamptic patients (n = 7), treated antenatally with intravenous KT. Pre-eclamptic patients (n = 13), not treated with KT (non-KT), were included as a control group. Segments of UCA were prepared and mounted in tissue baths and isometric force changes were determined. Cumulative concentration response curves to 5-HT and to the 5-HT(1B/1D )receptor agonist sumatriptan were constructed in the absence or presence of the 5-HT(2A) receptor antagonist KT or the 5-HT(1B/1D) receptor antagonist GR125743, respectively. RESULTS: All UCA segments showed contractile responses to both 5-HT and sumatriptan, and the concentration response curves showed a rightward shift with increasing concentrations of KT and GR125743, respectively, indicating the presence of functional 5-HT(2A) and 5-HT(1B/1D) receptors in the foetal tissue. No significant differences were found in maximum response (E(max))(expressed in percent of response on 100 mM KCl) or potency (pEC(50)) of 5-HT in both groups (E(max) = 141 +/- 7.7%, pEC(50) = 7.67 +/- 0.26 in KT-treated group and E(max) = 162 +/- 12.6%, pEC(50) = 7.69 +/- 0.14 in non-KT treated group, respectively). No significant differences were found in the potency of the antagonist KT in both study groups (pK(b) = 7.65 +/- 0.31 in KT group and 7.46 +/- 0.17 in non-KT group, respectively). Similarly, with sumatriptan, no significant differences were found between KT-treated patients and non-KT treated patients (E(max) = 142 +/- 16.2 and 140 +/- 14.7%, respectively, pEC(50) = 6.17 +/- 0.37 and 6.41 +/- 0.28 respectively, pK(b) of GR125743 = 7.83 +/- 0.48 and 8.43 +/- 0.29, respectively). CONCLUSION: Foetal exposure to KT in pre-eclamptic patients does not seem to influence the functional characteristics of 5-HT(2A) and 5-HT(1B/1D) receptors in the UCA.

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 migraine's component parts to allow a better understanding of the problem and the development of new treatment strategies.

Donitriptan, but not sumatriptan, inhibits capsaicin-induced canine external carotid vasodilatation via 5-HT1B rather than 5-HT1D receptors.

BACKGROUND AND PURPOSE: It has been suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the effects of the agonists sumatriptan (5-HT(1B/1D) water-soluble), donitriptan (5-HT(1B/1D) lipid-soluble), PNU-142633 (5-HT(1D) water-soluble) and PNU-109291 (5-HT(1D) lipid-soluble) on vasodilator responses to capsaicin, alpha-CGRP and acetylcholine in dog external carotid artery. EXPERIMENTAL APPROACH: 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone. Blood pressure and heart rate were recorded with a pressure transducer, connected to a cannula inserted into a femoral artery. A precalibrated flow probe was placed around the common carotid artery, with ligation of the internal carotid and occipital branches, and connected to an ultrasonic flowmeter. The thyroid artery was cannulated for infusion of agonists. KEY RESULTS: Intracarotid infusions of capsaicin, alpha-CGRP and acetylcholine dose-dependently increased blood flow through the carotid artery. These responses remained unaffected after intravenous (i.v.) infusions of sumatriptan, PNU-142633, PNU-109291 or physiological saline; in contrast, donitriptan significantly attenuated the vasodilator responses to capsaicin, but not those to alpha-CGRP or acetylcholine. Only sumatriptan and donitriptan dose-dependently decreased the carotid blood flow. Interestingly, i.v. administration of the antagonist, SB224289 (5-HT(1B)), but not of BRL15572 (5-HT(1D)), abolished the inhibition by donitriptan. CONCLUSIONS AND IMPLICATIONS: Our results suggest that the inhibition produced by donitriptan of capsaicin-induced external carotid vasodilatation is mainly mediated by 5-HT(1B), rather than 5-HT(1D), receptors, probably by a central mechanism.

The potential anti-migraine compound SB-220453 does not contract human isolated blood vessels or myocardium; a comparison with sumatriptan.

The mechanistically novel benzopyran derivative SB-220453, which is undergoing clinical evaluation in migraine, exhibits a high affinity for a selective, but not yet characterized, binding site in the human brain. It inhibits nitric oxide release and cerebral vasodilatation following cortical spreading depression as well as carotid vasodilatation induced by trigeminal nerve stimulation in the cat. The aim of our study was to investigate the contractile properties of SB-220453 on a number of human isolated blood vessels (coronary artery, saphenous vein and middle meningeal artery) as well as atrial and ventricular cardiac trabeculae. While sumatriptan induced marked contractions in three blood vessels investigated, SB-220453 was devoid of any effect. In atrial and ventricular cardiac trabeculae, neither SB-220453 nor sumatriptan displayed a positive or negative inotropic effect. Since SB-220453 did not contract the middle meningeal artery, we conclude that potential anti-migraine effects are not mediated via a direct cerebral vasoconstriction. The lack of activity of SB-220453 in coronary artery, saphenous vein and cardiac trabeculae demonstrates that the compound is unlikely to cause adverse cardiac side-effects.

Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels.

BACKGROUND: Eletriptan is a 5-HT(1B/1D) receptor agonist with proven efficacy in the acute treatment of migraine. OBJECTIVE: To assess the craniovascular selectivity of eletriptan and sumatriptan in blood vessels predictive of therapeutic efficacy (human middle meningeal artery) and adverse coronary side effects (human coronary artery and human saphenous vein). METHOD: The authors obtained coronary artery from organ donors (n = 9), middle meningeal artery from patients (n = 11) undergoing craniotomy, and saphenous vein from patients (n = 9) undergoing coronary bypass surgery. Concentration-response curves to eletriptan and sumatriptan were constructed to obtain measurements of efficacy (maximum contraction, E(max)) and potency (concentration eliciting 50% of E(max), EC(50)). The contraction that is likely to be induced at the maximal free plasma concentration (C(max)) was determined by calculating C(max)/EC(50) ratios and by interpolation of the concentration-response curves. RESULTS: Eletriptan and sumatriptan induced concentration-dependent contractions of meningeal artery, coronary artery, and saphenous vein. Eletriptan was less potent than sumatriptan in coronary artery, whereas both compounds had similar potency in meningeal artery and saphenous vein. However, the potency of eletriptan and sumatriptan was higher in meningeal artery than in coronary artery (86-fold for eletriptan and 30-fold for sumatriptan) or saphenous vein (66- and 25-fold). The efficacy of eletriptan and sumatriptan was similar within tissues. The predicted contraction by eletriptan (40 mg and 80 mg) and sumatriptan (100 mg) at free C(max) observed in clinical trials was similar in meningeal artery, whereas in coronary artery and saphenous vein it was lower for 40 mg eletriptan than for sumatriptan. CONCLUSIONS: At therapeutic concentrations both eletriptan and sumatriptan contract middle meningeal artery more than coronary artery. This suggests that in patients with healthy coronary arteries, they have a limited propensity to cause adverse coronary side effects. However, both drugs remain contraindicated in patients with coronary artery disease.

Pharmacological analysis of contractile effects of eletriptan and sumatriptan on human isolated blood vessels.

Eletriptan, a second-generation triptan with high affinity for 5-HT(1B/1D) receptors, is highly effective in migraine, with or without aura. We compared the effects of eletriptan and sumatriptan on the human isolated middle meningeal and coronary arteries and saphenous vein, used as models for therapeutic efficacy and potential side effects, and have investigated the role of 5-HT(1B/1D) receptors in contractions induced by these triptans. Concentration-response curves to eletriptan and sumatriptan were constructed in the absence or presence of a selective 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-py rid yl) benzamide (GR125743). All three blood vessels constricted in response to eletriptan and sumatriptan, but the middle meningeal artery relaxed following the highest concentration (100 microM) of eletriptan. In the middle meningeal artery, GR125743 antagonised the contractions induced by both eletriptan (pEC(50): 7.34+/-0.13) and sumatriptan (pEC(50): 6.91+/-0.17) to a similar degree (pA(2): 8. 81+/-0.17 and 8.64+/-0.21, respectively). In the human coronary artery and saphenous vein, sumatriptan-induced contractions (pEC(50): 6.24+/-0.14 and 6.19+/-0.12, respectively) were also potently antagonised by GR125743 (pA(2): 8.18+/-0.27 and 8.34+/-0.12, respectively). The eletriptan-induced contractions of the human saphenous vein (pEC(50): 6.09+/-0.13) were antagonised less effectively by GR125743 (pK(B): 7.73+/-0.18), and those of the human coronary artery (pEC(50): 5.54+/-0.22) remained unaffected by GR125743 up to a concentration of 100 nM. These results suggest that (i) based on the differences in pEC(50) values, the cranioselectivity of eletriptan (63-fold) is higher than that of sumatriptan (5-fold) in coronary artery, (ii) the contractile effects of sumatriptan and eletriptan (lower concentrations) in the three blood vessels are mediated via the 5-HT(1B) receptor, and (iii) additional mechanisms seem to be involved in coronary artery and saphenous vein contractions and middle meningeal artery relaxation following high concentrations of eletriptan.

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.

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.

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.

70th Scientific Sessions of the American Heart Association.

The 70th Scientific Sessions of the American Heart Association were attended by 37,000 people, including 21,000 medical professionals. Out of 13,103 submissions, 4,300 abstracts were selected for presentation at this conference. The abstracts have been published in a supplement to Circulation (Volume 96, Number 8).

Interictal cortical excitability to magnetic stimulation in familial hemiplegic migraine.

We studied interictal cortical excitability with magnetic stimulation in controls, in patients with migraine with aura, and in patients with familial hemiplegic migraine (FHM), in which ictal hemiparesis occurs. Amplitudes (p < 0.05) and amplitude ratios (p < 0.01) revealed heightened excitability in migraine with aura when compared to controls. In patients with FHM, mean thresholds were higher (p < 0.001) and conduction times longer (p < 0.01) than in controls. In FHM, amplitudes were lower on the ictally paretic side of the body than on the other (p < 0.05). Patients with FHM may have increased interictal cortical excitability, complicated by decreased excitability of the affected side.

69th scientific sessions of the American Heart Association.

Out of more than 12,000 abstract submissions, 4359 were selected for presentation at the 69th Scientific Sessions of the American Heart Association, held in New Orleans, Louisiana, USA. The abstracts have been published in a supplement to Circulation (Volume 94, Number 8).