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Abstract

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.

Keywords

Coronary artery human middle meningeal artery migraine myocardium saphenous vein SB-220453 sumatriptan

Introduction

Sumatriptan, an indole sulphonamide with agonist activity at 5-HT_1B/1D receptors, is highly effective in aborting attacks of migraine and cluster headache. The drug is generally well tolerated, but up to 15% of patients consistently report chest symptoms, including chest pressure, tightness and pain, often mimicking angina (1–3). Although extracardiac mechanisms have been invoked (4), chest symptoms may well be caused by coronary vasoconstriction, which has been observed after sumatriptan both in vivo (5) and in vitro (6–9). In some cases, the use of sumatriptan, like that of ergotamine (10, 11), was even associated with myocardial infarction (12, 13) and cardiac arrest (14). ‘Second generation’ sumatriptan-like anti-migraine drugs are aimed at, in addition to achieving high efficacy and long duration of action, avoiding coronary vasoconstrictor activity (15). However, these drugs also contract human isolated coronary artery and seem to have a similar coronary side-effect potential to sumatriptan (9, 16, 17).

Due to concerns about cardiac side-effects, it would be highly desirable to develop anti-migraine drugs that act via a mechanism not involving 5-HT_1B/1D receptors. Indeed, the mechanistically novel benzopyran SB-220453 (18) has no significant affinity at 5-HT_1B/1D receptors, nor does it show any activity in a large number of receptor, ion channel and enzyme assays (18). SB-220453 exhibits a high affinity for a selective, but structurally unknown binding site in the human brain (19) and may be active in the treatment of migraine via blockade of excessive cortical excitability. SB-220453 inhibits neurogenic inflammation in rat brain meninges (18), nitric oxide release associated with cortical spreading depression as well as carotid vasodilatation induced by trigeminal nerve stimulation in the cat (19, 20). In the present study, we investigated the effects of SB-220453 on a number of human isolated blood vessels (coronary artery, saphenous vein and middle meningeal artery) as well as human isolated atrial and ventricular cardiac trabeculae. Sumatriptan was used for comparison.

Methods

Preparation of tissue

Human isolated coronary artery

Right epicardial coronary arteries were obtained from six heart beating organ donors (two male, four female; age 37–63 years), who died of non-cardiac disorders (five of cerebrovascular accident, one head trauma) less than 24 h before the tissue was taken to the laboratory. Hearts, provided by the Rotterdam Heart Valve Bank (Bio Implant Services/Eurotransplant Foundation) after removal of the aortic and pulmonary valves for transplantation purposes, were stored at 0–4°C in a sterile organ-protecting solution immediately after circulatory arrest. After arrival at the laboratory, the right coronary artery was removed and placed in a cold, oxygenated (95% O₂/5% CO₂) Krebs buffer solution of the following composition (mm): NaCl 118, KCl 4.7, CaCl₂ 2.5, MgSO₄ 1.2, KH₂PO₄ 1.2, NaHCO₃ 25 and glucose 8.3; pH 7.4. The artery was kept overnight before the experiment.

On the following day, the artery was cut into segments of 3–4 mm length, excluding distinct, macroscopically visible atherosclerotic lesions. The vessel segments were mounted in 15-ml organ baths filled with oxygenated Krebs buffer solution at 37°C. After equilibration for at least 30 min and a wash every 15 min, the vessel segments were stretched to a stable tension of about 15 mN (9). Changes in tissue tension were measured using an isometric transducer (Harvard, South Nattick, MA) and recorded on a flatbed recorder (Servogor 124; Goerz, Neudorf, Austria).

Human isolated saphenous vein

Human saphenous veins were obtained post-operatively from four patients (two male, two female; 68–79 years) undergoing coronary bypass surgery. The tissue was immediately placed in cold saline and was brought to the laboratory within 15 min. Subsequently, the vein was cleaned of connective tissue and placed in a cold, oxygenated Krebs buffer solution (for composition, see above). After overnight storage, the vein was cut into segments of 3–4 mm length. The vessel segments were mounted in 15-ml organ baths filled with oxygenated Krebs buffer solution at 37°C. After equilibration for at least 30 min and a wash every 15 min, the vessel segments were stretched to a stable tension of about 10 mN, which we previously determined to be optimal for contraction measurements (21). Contractions were measured with an isometric transducer (Harvard) and recorded on a flatbed recorder (Servogor 124; Goerz).

Human isolated middle meningeal artery

Human middle meningeal arteries were obtained from 10 patients (three male, seven female; 30–71 years) undergoing craniotomy during neurosurgical procedures. In such patients, a part of the skull is temporarily removed to gain access to the brain and a small redundant portion of a branch of the middle meningeal artery is usually found attached to the dural sheath covering the removed piece of the skull. After careful removal from the dura mater, this arterial piece was placed in cold saline and brought to the laboratory immediately. Upon arrival at the laboratory, the artery was cleaned of connective tissue and was placed in cold oxygenated Krebs buffer solution of the following composition (mm): NaCl 119, KCl 4.7, CaCl₂ 1.25, MgSO₄ 1.2, KH₂PO₄ 1.2, NaHCO₃ 25 and glucose 11.1; pH 7.4. Vessel segments of 4 mm length were mounted in 10-ml organ baths filled with oxygenated Krebs buffer solution at 37°C. After equilibration for at least 30 min and a wash every 15 min, the vessel segments were stretched to a stable tension of about 4 mN (22, 23). Contractions of the artery were measured with an isometric force displacement transducer and recorded using the IOX 1.103 software (both EMKA Technology, Paris, France).

Because endogenous prostaglandin synthesis frequently caused spontaneous increases in baseline tension in pilot experiments, the cyclo-oxygenase inhibitor indomethacin (0.1 μm) was added to the Krebs solution. The experiments were performed within 2 h after surgery.

Human atrial and ventricular cardiac trabeculae

As described above (coronary artery section), hearts were obtained from five heart beating organ donors (two male, three female; age 36–57 years), who died of non-cardiac disorders (all cerebrovascular accident). Immediately after arrival at the laboratory, right atrial and left ventricular trabeculae of approximately 1 mm thickness were carefully dissected and mounted in a 15-ml organ bath in the same Krebs buffer solution as used for the coronary artery and saphenous vein. The trabeculae were paced at 1 Hz using electrical field stimulation (5 ms, 15–20 V) delivered by a Grass S6 Square Wave Stimulator (Quincy, MA). Resting tension was set to 0.75 mN and 2.0 mN for atrial and ventricular tissue, respectively. Changes in contraction were recorded with a Harvard force transducer on a flatbed recorder (Servogor 124; Goerz). The preparation was allowed to stabilize during 1 h with a wash every 15 min (24).

Experimental protocol

Human isolated coronary artery and saphenous vein

Segments were exposed to K⁺ (30 mm) twice to ‘prime’ the tissue for stable contractions. The functional integrity of the endothelium was verified by observing relaxation to substance P (1 nm, coronary artery) or bradykinin (1 μm, saphenous vein; substance P is nearly inactive in this blood vessel) after precontraction with prostaglandin F _2α (1 μm). After washout, the tissue was exposed to K⁺ (100 mm) to determine the maximal contractile response to K⁺. After a 30-min incubation period, a concentration response curve to sumatriptan (dissolved in distilled water or dimethylsulfoxide (DMSO)) or SB-220453 (dissolved in DMSO) was constructed. In four of the experiments in coronary artery, a concentration response curve to these agonists was also constructed after a 30-min incubation with the stable thromboxane A₂ analogue U46619 (3–10 nm, the lowest concentration, determined in half logarithmic steps, eliciting a contraction ≥10% of K⁺-induced contraction). A paired parallel set-up (i.e. all compounds were tested in different segments obtained from the same artery) was used for coronary artery experiments. In the saphenous vein, a paired parallel crossover design was used (i.e. similar as in coronary artery, but in addition a second concentration response curve was constructed to SB-220453 after sumatriptan, or to sumatriptan after SB-220453 after a 30–60-min washout period). Contractions were expressed as a percentage of contraction to 100 mm K⁺.

Human isolated middle meningeal artery

Since the addition of K⁺ frequently increased basal tone (unpublished observations), vessel segments were exposed to prostaglandin F _2α (0.1 μm) two to three times to ‘prime’ the tissue for stable contractions. Subsequently, the segments were contracted with prostaglandin F _2α (1 μm) and the functional integrity of endothelium was assessed by observing relaxation to substance P (10 nm). Due to the limited number of vessel segments that could be obtained from one patient, middle meningeal artery experiments were performed in an unpaired design, i.e. concentration response curves to sumatriptan (dissolved in distilled water) or SB-220453 (dissolved in DMSO) were constructed in different arterial segments, which were in most cases obtained from different patients. In addition, a concentration response curve to sumatriptan (dissolved in DMSO) was constructed following a 30–60 min washout period after the concentration response curve to SB-220453. Contractions were expressed as a percentage of contraction to 1 μm prostaglandin F _2α.

Atrial and ventricular cardiac trabeculae

A concentration response curve to noradrenaline (10 nm to 10 μm) was constructed to verify the viability of the tissue. Trabeculae yielding < 0.25 mN response to 10 μm noradrenaline were excluded from further analysis. After washout, a concentration response curve to sumatriptan (dissolved in distilled water or DMSO) or SB-220453 (dissolved in DMSO) was constructed. In four out of five experiments, concentration response curves were also obtained after precontraction with noradrenaline (10 μm). Since this precontraction was not always stable for a period long enough to allow construction of a complete concentration response curve (1 nm to 100 μm) to the agonists, not all concentrations were studied in these experiments. Changes in contraction were expressed as percentage of increase in contraction to 10 μm noradrenaline.

Compounds

Sumatriptan succinate was a kind gift from GlaxoWellcome (Dr H. E. Connor, Ware, UK). SB-220453 ((-)-cis-6-acetyl-4S-(3-chloro-4-fluoro-benzoylamino)3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3S-ol) was kindly provided by SmithKline Beecham (Dr A. A. Parsons, Harlow, UK). U46619 (9,11-dideoxy-11α,9α-epoxy, methanoprostaglandin F _2α), prostaglandin F _2α (Tris salt), bradykinin acetate, substance P acetate and DMSO were purchased from Sigma Chemical Co. (St Louis, MO). Indomethacin was obtained from the pharmacy of Erasmus University Medical Centre Rotterdam (Rotterdam, The Netherlands). The chemicals used for the Krebs buffer solutions were purchased from Merck (Darmstadt, Germany).

Sumatriptan was dissolved in distilled water or, where indicated, in DMSO and further diluted in distilled water. Indomethacin and SB-220453 were dissolved in DMSO and further diluted in distilled water. The other compounds were dissolved in distilled water.

Statistical analysis

Concentration response curves were analysed using GraphPad software (GraphPad Software Inc., San Diego, CA) to determine pEC₅₀ values (negative logarithm of the concentration eliciting 50% of the maximal contractile response, E_max). When a plateau in the concentration response curve was not reached, the response observed with the highest concentration used (100 μm) was considered as E_max.

At 100 μm, SB-220453 and sumatriptan (dissolved in DMSO) induced a small relaxation of the blood vessels, which was not easily quantifiable. This relaxant response, which was also observed with equivalent amounts of the solvent DMSO, has been ignored. For the experiments in the presence of U46619, the precontraction induced by U46619 was subtracted from the concentration response curves obtained with the agonists.

All data in the text and illustrations are presented as mean ± sem, with n representing the number of different subjects or, when specifically mentioned, the number of vessel segments or trabeculae. Differences between pEC₅₀ and E_max values of the compounds were evaluated with Tukey's test, once an analysis of variance (anova) for paired (coronary artery, saphenous vein, myocardial trabeculae) or unpaired data (middle meningeal artery) had revealed that the samples represented different populations. Values of P < 0.05 were considered to indicate significant differences.

Ethical approval

The Ethical Committee of the Erasmus University Medical Centre Rotterdam approved this study.

Results

Human isolated coronary artery

All coronary artery segments relaxed after substance P (1 nm). The response amounted to 48 ± 15% (range 9–107%) of the precontraction (22 ± 6 mN) to prostaglandin F _2α (1 μm). Contraction to 100 mm K⁺ was 55 ± 6 mN (n = 6).

Sumatriptan induced a concentration-dependent contraction, which was independent of the solvent (distilled water and DMSO) used; E_max, 12 ± 3% and 7 ± 1% of K⁺-induced contraction, respectively; pEC₅₀, 6.0 ± 0.2% and 6.4 ± 0.2%, respectively. The E_max of sumatriptan did not correlate to the relaxant response to substance P (Pearson's r = 0.117). SB-220453 induced no response (Fig. 1, left panel). After precontraction with U46619 (17 ± 3% of K⁺-induced contraction), the E_max to sumatriptan was substantially augmented in two out of the four experiments. However, the mean E_max (39 ± 24% for sumatriptan dissolved in distilled water and 38 ± 17% for sumatriptan dissolved in DMSO) was, as reported previously (25), not significantly different from values in these four experiments in the absence of U46619 (16 ± 3% for sumatriptan dissolved in distilled water and 9 ± 1% for sumatriptan dissolved in DMSO). The pEC₅₀ of sumatriptan in the presence of U46619 (6.7 ± 0.3 and 6.6 ± 0.3 for sumatriptan dissolved in distilled water and DMSO, respectively) was also not significantly increased, when compared with those in the absence of U46619 (6.2 ± 0.3% for sumatriptan dissolved in distilled water and 6.5 ± 0.2% for sumatriptan dissolved in DMSO). Similar to the experiments performed on vessel segments in the absence of U46619, SB-220453 failed to either contract or relax the coronary artery in the presence of U46619 (Fig. 1, right panel).

Figure 1

Concentration response curves in human isolated coronary arteries to sumatriptan (dissolved in distilled water (•) or dimethylsulfoxide (DMSO; ▪)) and SB-220453 (▵, dissolved in DMSO). Experiments were performed in the absence of U46619 (left panel, n = 6) or after precontraction with U46619 (3–10 nm; right panel, n = 4, except sumatriptan dissolved in distilled water n = 3). The precontraction induced by U46619 was 17 ± 3%, n = 15 vessel segments.

Human isolated saphenous vein

Saphenous vein segments relaxed after bradykinin (1 μm), the response amounting to 49 ± 24% (range 10–107%) of the precontraction (6 ± 3 mN) induced by prostaglandin F _2α (1 μm). Contraction to 100 mm K⁺ was 10 ± 2 mN (n = 4).

In all experiments, sumatriptan (dissolved in DMSO) induced a concentration-dependent contraction (E_max 52 ± 5%, pEC₅₀ 6.3 ± 0.1), which was unrelated to the relaxant response to bradykinin (Pearson's r =−0.081). SB-220453 did not induce a contraction in any of the concentrations used (Fig. 2). The concentration response curves to sumatriptan that were constructed after the concentration response curve to SB-220453 did not differ from those constructed before SB-220453 (E_max 59 ± 10%; pEC₅₀ 6.2 ± 0.2). Also after the concentration response curve to sumatriptan, SB-220453 failed to contract the saphenous vein.

Figure 2

Concentration response curves in human isolated saphenous vein (n = 4) to sumatriptan (▪) and SB-220453 (▵), both dissolved in dimethylsulfoxide. Whereas sumatriptan induced a concentration-dependent contraction in all experiments, SB-220453 had no effect.

Human isolated middle meningeal artery

Middle meningeal artery segments relaxed to substance P (10 nm) with 44 ± 7% (range 19–76%) of the precontraction (8 ± 2 mN) induced by prostaglandin F _2α (1 μm, n = 10).

Sumatriptan (dissolved in distilled water) induced a concentration-dependent contraction in all experiments (E_max 105 ± 18%, pEC₅₀ 6.9 ± 0.2), which was not related to the relaxant response to substance P (Pearson's r =− 0.155). SB-220453 did not induce any contraction (Fig. 3). After construction of the concentration response curves to SB-220453, the contraction to sumatriptan (dissolved in DMSO) did not differ significantly from that to sumatriptan dissolved in distilled water (E_max 101 ± 2%; pEC₅₀ 6.8 ± 0.4).

Figure 3

Concentration response curves in human isolated middle meningeal artery to sumatriptan (dissolved in distilled water, •; n = 5) and SB-220453 (▵, dissolved in dimethylsulfoxide; n = 4).

Human atrial and ventricular trabeculae

As we reported earlier (24), baseline contractile force was significantly lower in the atrial (0.64 ± 0.13 mN, n = 17 trabeculae) than in ventricular (3.04 ± 0.45 mN, n = 20 trabeculae) tissue. In both tissues, noradrenaline (10 nm to 10 μm) increased contractile force in a concentration-dependent manner. After exposure to 10 μm noradrenaline, the force of contraction increased to 2.43 ± 0.36 mN (n = 17 trabeculae) and 5.02 ± 0.43 mN (n = 20 trabeculae) in the atrial and ventricular trabeculae, respectively.

Neither SB-220453 nor sumatriptan displayed a positive inotropic effect on atrial and ventricular trabeculae (Fig. 4). At concentrations ≥10 μm, SB-220453 and sumatriptan (dissolved in DMSO) induced a negative inotropic effect in both atrial (sumatriptan 37 ± 32% of contraction to 10 μm noradrenaline, SB-220453 34 ± 29%) and ventricular (sumatriptan 18 ± 9%, SB-220453 55 ± 21%) trabeculae, which were not different for these compounds. This negative inotropic effect may be assigned to the solvent DMSO, since it was not observed with sumatriptan dissolved in distilled water (Fig. 4). After a precontraction with noradrenaline (10 μm) also, none of the compounds induced a positive inotropic effect, while a negative effect on contractility was observed at concentrations ≥10 μm of SB-220453 and sumatriptan dissolved in DMSO (data not shown).

Figure 4

Concentration response curves in human isolated atrial (left panel, n = 3–5) and ventricular (right panel, n = 5) trabeculae to sumatriptan (dissolved in distilled water, •, or dimethylsulfoxide (DMSO; ▪) and SB-220453 (▵, dissolved in DMSO). NA, Noradrenaline.

Discussion

Human isolated blood vessels

SB-220453 did not induce any significant contraction of the human isolated coronary artery, saphenous vein or middle meningeal artery. In contrast, sumatriptan, investigated in parallel, produced marked contractions. Since contractions to some agonists can be ‘unmasked’ or augmented in the presence of increased tension (7, 25), we also investigated the coronary artery contraction in the presence of the thromboxane A₂ analogue U46619. Indeed, the contraction to sumatriptan was augmented in two of the coronary arteries investigated (in accordance with our previous findings (25)), but even in these precontracted segments, SB-220453 failed to elicit any contraction.

In all blood vessels, a slight relaxation was observed at the highest concentration of SB-220453 and sumatriptan (both dissolved in DMSO), but not with sumatriptan dissolved in distilled water. Therefore, this relaxation may be assigned to the solvent DMSO. However, despite this relaxant response, SB-220453 did not affect the concentration response curve to sumatriptan (see Figs 2 and 3).

It is known that the presence or absence of functional endothelium can influence contractile responses in blood vessels (26, 27). In our study, the endothelial quality of the blood vessels varied, as is illustrated by the relaxation to substance P (coronary artery 9–107%, middle meningeal artery 19–76%) or bradykinin (saphenous vein 10–107%). The contraction to sumatriptan was not related to the endothelial quality, though in a large post hoc study we have previously demonstrated that coronary artery contraction to sumatriptan slightly increases with increasing functional integrity of the endothelium (26). Because in none of the blood vessels did SB-220453 induce any contraction, our results suggest that the lack of response to these compounds is not dependent on the quality of the endothelium.

It is conceivable that overnight storage of the coronary artery and saphenous vein segments may have affected responses to SB-220453. However, several arguments suggest that this was probably not the case. First, the endothelial function in the present study was similar to that reported in coronary arteries obtained directly after explantation of the heart (28, 29). Second, porcine coronary arteries display similar basic contractile as well as relaxant properties, whether investigated immediately or after 24 h storage (30). Lastly, as in coronary artery and saphenous vein, SB-220453 also failed to contract middle meningeal artery, which was studied within 2 h of surgical removal.

Atrial and ventricular cardiac trabeculae

Apart from a negative inotropic effect associated with the solvent DMSO, no inotropic response was observed with SB-220453 or sumatriptan in either atrial or ventricular cardiac trabeculae. Sumatriptan did not display any effect on cardiac trabecular contractility despite expression of both 5-HT_1B and 5-HT_1D mRNA in human atrium and ventricle (31). However, the present results are consistent with the observed lack of haemodynamic effects of sumatriptan in patients, where no negative or positive inotropic effects were demonstrated (32). These studies are also in accordance with in vitro studies performed on guinea pig (33, 34) cardiac tissue. In fact, the role of 5-HT_1B and 5-HT_1D receptors on the human heart is still poorly understood (36), although the 5-HT_1D receptor has been reported to mediate inhibition of noradrenaline release in human atrium (37).

In conclusion, our results do not provide any evidence of human blood vessel contraction or altered myocardial contractility in response to SB-220453. Since SB-220453 did not contract the middle meningeal artery, we conclude that potential therapeutic efficacy is independent of cerebral vasoconstriction. SB-220453 did not contract coronary artery, saphenous vein or cardiac trabeculae, and is therefore likely to be devoid of adverse cardiovascular side-effects observed with serotonergic agonists.

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The Potential Anti-Migraine Compound SB-220453 does not Contract Human Isolated Blood Vessels or Myocardium;A Comparison with Sumatriptan

Abstract

Keywords

Introduction

Methods

Preparation of tissue

Human isolated coronary artery

Human isolated saphenous vein

Human isolated middle meningeal artery

Human atrial and ventricular cardiac trabeculae

Experimental protocol

Human isolated coronary artery and saphenous vein

Human isolated middle meningeal artery

Atrial and ventricular cardiac trabeculae

Compounds

Statistical analysis

Ethical approval

Results

Human isolated coronary artery

Human isolated saphenous vein

Human isolated middle meningeal artery

Human atrial and ventricular trabeculae

Discussion

Human isolated blood vessels

Atrial and ventricular cardiac trabeculae

References