Assessment of anti-migraine potential of a novel alpha-adrenoceptor agonist S19014: effects on porcine carotid and regional haemodynamics and human coronary artery.

Taking into account the drawbacks associated with the use of triptans, attempts are being made to explore other avenues for the treatment of migraine. Recently, it has been shown that both alpha1- and alpha2-adrenoceptors mediate the constriction of porcine carotid arteriovenous anastomoses, which has effectively served as an experimental model predictive of anti-migraine activity. The present study investigated the effects of a novel alpha-adrenoceptor agonist S19014 (spiro[(1,3-diazacyclopent-1-ene)-5 : 2'-(4',5'-dimethylindane)] fumarate) on carotid and systemic haemodynamics in anaesthetized pigs, and on human isolated coronary arteries. Increasing doses of S19014 (1-30 micro g/kg, i.v.) produced a dose-dependent initial short-lasting vasopressor response and a decrease of total carotid blood flow and conductance. The carotid blood flow and conductance changes were exclusively due to constriction of carotid arteriovenous anastomoses (capillary blood flow increased) and were accompanied by an increase in arterio-jugular venous oxygen saturation difference. Whereas prazosin (100 micro g/kg, i.v.) was ineffective, rauwolscine (300 micro g/kg, i.v.) attenuated the responses to S19014. The compound did not much affect the distribution of cardiac output to peripheral organs when compared with the vehicle group. Furthermore, S19014 only slightly contracted the human isolated coronary artery and its contractions, contrary to those of sumatriptan, were not increased in blood vessels pre-contracted with U46619. These results suggest that (i) the systemic and carotid vascular effects of S19014 are mainly mediated by alpha2-adrenoceptors, and (ii) S19014 could be effective in the treatment of migraine with an improved cardiovascular tolerance.

Human isolated coronary artery contraction to sumatriptan characterised by the selective 5-HT1B/1D receptor antagonist GR55562.

The antimigraine drug, sumatriptan, contracts the human coronary artery both in vivo and in vitro. Because sumatriptan has been associated with cardiac side effects, it is important to characterise the receptor involved in sumatriptan-induced coronary artery contraction. Using the agonists sumatriptan and 5-carboxamidotryptamine and the selective 5-HT1B/1D receptor antagonist GR55562, we have investigated the involvement of 5-HT1B/1D receptors in the contraction of the human isolated coronary artery. Contractions to sumatriptan (pEC50: 6.1+/-0.2, maximal effect: 21+/-4% of 100 mM K+-induced contraction) were competitively antagonised by GR55562. The pA2 of GR55562 (7.40+/-0.16) was in accord with its reported affinity at the human 5-HT1B receptor. Since the contractions to 5-carboxamidotryptamine did not reach a maximum with the highest concentration used (10 microM), pEC50 values could not be calculated for Schild analysis. However, using the pEC10%/K+ values (negative logarithm of the concentration needed to induce 10% of the contraction to 100 mM K+), GR55562 proved a less potent antagonist against 5-carboxamidotryptamine than against sumatriptan. These results show that sumatriptan contracts the human isolated coronary artery via 5-HT1B/1D receptors, most probably the 5-HT1B subtype. 5-Carboxamidotryptamine may contract the human isolated coronary artery, at least partly, via a novel yet to be characterised, receptor.

Human isolated coronary artery contraction to sumatriptan: a post hoc analysis.

A post hoc analysis was performed on concentration response curves to sumatriptan in 62 human isolated coronary arteries. We determined whether donor-related clinical characteristics (age, sex, cause of death) and properties of the coronary artery (functional endothelial integrity, muscle mass) were related to the potency and efficacy of sumatriptan in contracting the human isolated coronary artery. The efficacy of sumatriptan was inversely related to the functional integrity of the vessel endothelium. Thus, contrary to expectation, coronary artery constriction to sumatriptan seems to be more pronounced in patients with nondiseased coronary arteries where the endothelium is intact. Nevertheless, in view of the high coronary reserve in these patients, myocardial ischemia after the use of sumatriptan is unlikely to occur, whereas in patients with coronary artery disease even a small contraction may be deleterious.

BMS-181885, a 5-HT1B/1D receptor ligand, in experimental models predictive of antimigraine activity and coronary side-effect potential.

Many acutely acting antimigraine drugs have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have investigated the effects of BMS-181885 (3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-(1,2-dioxo-4-me thyl-3-cyclobuten-3-yl)amino-1H-indole), a 5-HT1B/1D receptor ligand. In anaesthetised pigs, BMS-181885 (10, 30, 100 and 300 microg kg(-1)) decreased the total carotid blood flow and conduction, exclusively at the expense of the arteriovenous anastomotic fraction as the capillary fraction did in fact increase. The highest dose (300 microg kg(-1)) produced a reduction of 52+/-6% from the baseline arteriovenous anastomotic flow. When carotid haemodynamic changes after a single 100 microg kg(-1)dose of BMS-181885 or sumatriptan were studied at different time-points, BMS-188185 had a longer duration of action. Both BMS-181885 (pD2:7.9+/-0.1; Emax:9+/-3% of the contraction to 100 mM K+) and sumatriptan (pD2:6.3+/-0.1; Emax:28+/-8% of the contraction to 100 mM K+) contracted the human isolated coronary artery. The above results suggest that (i) the longer-lasting vasoconstrictor action of BMS-181885 on porcine carotid arteriovenous anastomoses may be related to its reported slow dissociation from 5-HT1B/1D receptor, and (ii) BMS-181885 should be able to abort migraine headaches in patients. It will be interesting to find out whether these properties are clinically important so that the drug exhibits less headache recurrence and coronary side-effects than sumatriptan.

Chromosomal localization of the 5-HT1F receptor gene: no evidence for involvement in response to sumatriptan in migraine patients.

The 5-HT1F receptor, which is present in both human vascular and neuronal tissue, may mediate the therapeutic effect and/or side-effects of sumatriptan. We investigated the chromosomal localization of the 5-HT1F receptor gene and the relation between eventually existing polymorphisms and the clinical response to sumatriptan in migraine patients. The 5-HT1F receptor gene was localized using a monochromosomal mapping panel, followed by a radiation-reduced hybrid mapping and fluorescent in situ hybridization. The results of these techniques show that the 5-HT1F receptor gene is localized at 3p12. We investigated the presence of polymorphisms by single strand conformation polymorphism analysis in 14 migraine patients who consistently responded well to sumatriptan, 12 patients who consistently experienced recurrence of the headache after initial relief, 12 patients with no response to sumatriptan, and in 13 patients who consistently experienced chest symptoms after use of sumatriptan. No polymorphisms were detected in any of the patients. We therefore conclude that genetic diversity of the 5-HT1F receptor gene is most probably not responsible for the variable clinical response to sumatriptan.

Differential effects of unilateral magnetic cortical stimulation on reaction time.

Data from patients with brain lesions suggested that the right hemisphere is involved in the intention of simple movements, while the left is involved in more complex tasks. The contributions of each hemisphere to a reaction time (RT) task were assessed with cortical magnetic stimulation in five healthy right-handed subjects. Subjects were asked to push buttons with both hands as fast as possible after a visual start stimulus. At three different delays (25, 50 and 75 ms) after the start signal, a magnetic stimulus of 20, 40 or 60% of maximum intensity was given to either the right or the left hemisphere. Delay, intensity and side of stimulation varied in random order. Repeated measures analysis of variance showed two main effects: firstly, RT was longer on the body side innervated by the stimulated than by the non-stimulated hemisphere. Thus, cortical stimulation delayed the execution of a motor task, as shown previously. Secondly, there was an interaction between side of stimulation and delay of the cortical stimulus. At a delay of 25 ms, right-sided stimulation resulted in longer RTs than left-sided stimulation. At delays of 50 and 75 ms, the reverse proved true. In both cases the effect held for both hands. According to these results, the right hemisphere is predominantly involved in the early phases of an RT task, while the left hemisphere is more involved in later phases of processing. The results show that cortical magnetic stimulation can be used to investigate differential contributions of the hemispheres to motor tasks in vivo.

Effects of avitriptan, a new 5-HT 1B/1D receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential.

Several acutely acting antimigraine drugs, including ergotamine and sumatriptan, have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of avitriptan (BMS-180048; 3-[3-[4-(5-methoxy-4-pyrimidinyl)-l-piperazinyl[propyl]-N-methyl-l H-indole-5-methane-sulfonamide monofumarate), a new 5-HT 1B/1D receptor agonist. In anaesthetized pigs, avitriptan (10, 30, 100 and 300 micrograms.kg-1) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was increased. The mean +/- SEM i.v. dose of avitriptan eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was calculated to be 76 +/- 23 micrograms.kg-1 (132 +/- 40 nmol.kg-1) and the highest dose (300 micrograms.kg-1) produced a 72 +/- 4% reduction. In recent comparative experiments (DeVries et al. 1996), the mean +/- SEM ED50 (i.v.) of sumatriptan in decreasing carotid arteriovenous anastomotic blood flow was 63 +/- 17 micrograms.kg-1 (158 +/- 43 nmol.kg-1), with a reduction of 76 +/- 4% by 300 micrograms.kg-1, i.v. Both avitriptan (pD2; 7.39 +/- 0.09; Emax: 13.0 +/- 4.5% of the contraction to 100 mM K+) and sumatriptan (pD2: 6.33 +/- 0.09; Emax: 15.5 +/- 2.3% of the contraction to 100 mM K+) contracted the human isolated coronary artery. The above results suggest that avitriptan should be able to abort migraine headaches in patients, but may exhibit sumatriptan-like effects on coronary arteries. Initial clinical studies have demonstrated the therapeutic action of the drug in acute migraine.

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 microM), 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 microM) 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 2 h-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 non-selective 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.

Effects of S20749, a close analogue of sumatriptan, on porcine carotid haemodynamics and human isolated coronary artery.

Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine arteriovenous anastomoses. Sumatriptan also constricts the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of S20749 (1-[2-(dimethylamino)ethyl]-naphthalene-7-methylsulfonamide), a close analogue of sumatriptan. S20749 (30, 100, 300 and 1000 micrograms.kg-1) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was moderately increased. These changes were statistically significant with the highest two doses. S20749 moderately constricted the human isolated coronary artery (pD2: < or = 4.5: Fmax: > 11% of the contraction to 100 mM K+). The above results suggest that S20749 should be able to abort migraine headaches in patients.

Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential.

Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine carotid arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of GMC2021 (3-[2-(dimethylanimo)ethyl]-5-[(trifluoromethyl)sulfonyl]oxy][1 H]indole oxalate, a close analogue of sumatriptan. GMC2021 (30, 100, 300 and 1000 micrograms.kg-1, i.v.) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow to the skin and ears was moderately increased. The mean +/- S.E.M. dose of GMC2021 eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was found to be 1.1 +/- 0.3 mumol.kg-1 and the highest dose (1000 micrograms.kg-1) produced a 67 +/- 4% reduction. The carotid haemodynamic effects of GMC2021 were reduced by the selective 5-HT1D receptor antagonist, GR127935 (N-[methoxy-3-(4-methyl-1- piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1 , 1-biphenyl]-4-carboxamide hydrochloride), which completely antagonizes porcine carotid haemodynamic responses to sumatriptan (ED50: 0.16 mumol.kg-1, i.v.). Compared to sumatriptan (pD2: 6.12 +/- 0.15; Emax: 31.3 +/- 12.3% of contractions to 100 mM K+), GMC2021 was less potent in constricting the human isolated coronary artery (pD2: 5.45 +/- 0.2; Emax: 21.0 +/- 4.8% of contractions to 100 mM K+). The above results suggest that GMC2021 constricts carotid arteriovenous anastomoses partly by a 5-HT1D receptor and partly by another, probably novel, receptor and that GMC2021 should be able to abort migraine headaches in patients, with perhaps a less propensity for coronary side effects.

Interictal cortical hyperexcitability in migraine patients demonstrated with transcranial magnetic stimulation.

Cortical excitability to magnetic stimulation was investigated interictally in 10 patients with migraine with aura, 10 with migraine without aura and in 10 healthy volunteers. Thresholds, latencies and amplitudes of the magnetic-evoked potentials (MEPs) were measured from threshold to 100% stimulus intensity in 10% steps. Compound motor action potentials (CMAPs) evoked with supramaximal electrical stimulation of the ulnar nerve were used to calculate MEP/CMAP amplitude ratios. Thresholds and latencies of MEPs did not differ between patients and controls. MEP/CMAP amplitude ratios were significantly increased at all intensities in patients with migraine with aura (RM-ANOVA, p < 0.01) and without aura (p < 0.05) compared with controls. In migraine patients, MEP amplitudes and MEP/CMAP amplitude ratios were positively related to the frequency of migraine attacks (Spearman's r = 0.47, p < 0.01 and r = 0.56, p < 0.002, respectively). MEP parameters were not related to the side of the headache nor the aura, in either type of migraine, implying that both hemispheres are equally involved in migraine. Migraine with aura and, to a lesser extent, migraine without aura, are associated with increased interictal cortical excitability.