Pharmacological analysis of contractile effects of eletriptan and sumatriptan on human isolated blood vessels
Introduction
Sumatriptan, the first of a new class of compounds with an agonist action at 5-HT1B/1D receptors, is effective in the acute treatment of migraine and cluster headaches (Saxena and Tfelt-Hansen, 2000). The high efficacy profile as well as some shortcomings (low oral bioavailability, high headache recurrence and chest symptoms) has prompted the development of several second-generation triptans, including eletriptan. Eletriptan displays a higher affinity than sumatriptan for the 5-HT1B (pKi: 8.00 and 7.37, respectively) as well as 5-HT1D (pKi: 8.94 and 8.04, respectively) receptor (Napier et al., 1999). Like sumatriptan, eletriptan constricts porcine carotid arteriovenous anastomoses in vivo (Willems et al., 1998) and canine saphenous vein and basilar artery in vitro (Gupta et al., 1999) and inhibits c-fos expression in trigeminal nucleus caudalis following stimulation of the superior sagittal sinus in the cat (Goadsby and Hoskin, 1999). Oral administration of the highest dose of eletriptan (80 mg) has been shown to be superior to sumatriptan (100 mg) in the treatment of migraine in three head-to-head clinical trials Goadsby et al., 2000, Saxena and Tfelt-Hansen, 2000.
It is now generally accepted that the therapeutic action of sumatriptan and other triptans is mainly due to constriction of dilated intra- and extra-cranial blood vessels, although other mechanisms interfering with the trigeminovascular system may also be involved De Vries et al., 1999a, Saxena and Tfelt-Hansen, 2000. Indeed, the triptans potently contract human isolated middle meningeal Longmore et al., 1998, Razzaque et al., 1999, temporal (Verheggen et al., 1996), middle cerebral Hamel and Bouchard, 1991, Jansen et al., 1992 and basilar (Parsons et al., 1998) arteries. However, albeit less profound, the triptans also have the ability to contract non-cranial blood vessels, such as human isolated pulmonary (MacLean et al., 1996) and coronary Connor et al., 1989, Chester et al., 1990, MaassenVanDenBrink et al., 1998 arteries. Constriction of these blood vessels may lead to cardiovascular adverse events, including myocardial ischaemia and infarction in predisposed individuals Kelly, 1995, O'Connor and Gladstone, 1995, Ottervanger et al., 1997, Main et al., 1998.
In the present study, we have investigated the contractile effects of eletriptan, in comparison to those of sumatriptan, on human isolated blood vessels used as models with relevance to therapeutic efficacy (middle meningeal artery), coronary adverse events (coronary artery) and peripheral vasoconstriction (saphenous vein). Furthermore, we used the competitive 5-HT1B/1D receptor antagonist N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR125743) Domenech et al., 1997, Pauwels, 1997 in an attempt to characterise the 5-HT receptors mediating contractions to eletriptan and sumatriptan.
Section snippets
Human isolated middle meningeal artery
Human middle meningeal arteries were obtained from 10 patients (four males, six females; age 30–69 years) undergoing craniotomy at the neurosurgical unit of the University Hospital ‘Dijkzigt’, Erasmus University Medical Centre, Rotterdam. During the surgical procedure, a part of the skull is temporarily removed and the dura matter, together with a small piece of the middle meningeal artery, is intentionally cut to obtain access to the brain. This piece of the artery was placed in a plastic tube
Human middle meningeal artery
Both eletriptan and sumatriptan contracted the middle meningeal artery in a concentration dependent manner (up to 10 μM) and with similar maxima (Emax: 94±8% and 106±17% of contraction to 1 μM prostaglandin F2α, respectively), potency (pEC50: 7.34±0.13 and 6.91±0.17, respectively) and Hill slopes (0.86±0.20 and 1.27±0.80, respectively) (Fig. 1; Table 1). However, in contrast to sumatriptan, the highest concentration of eletriptan (100 μM) induced a marked vasorelaxation, which was not affected
Discussion
In the present study, we investigated the effects of eletriptan and sumatriptan on the human isolated middle meningeal artery as a model for anti-migraine activity, and coronary artery and saphenous vein as models for peripheral vascular side-effect potential. In addition, the role of 5-HT1B/1D receptors in the vasoconstrictor responses to the two triptans was evaluated using GR125743, a potent and competitive 5-HT1B/1D receptor antagonist Domenech et al., 1997, Pauwels, 1997.
Acknowledgements
The authors wish to express their gratitude to the staff of the Neurosurgery and Cardiothoracic Surgery departments, Dijkzigt Hospital Rotterdam as well as the Rotterdam Heart Valve Bank, for providing us with human blood vessels. The authors thank Dr. H. Motulsky (Graphpad Software Inc., San Diego, CA, USA) and Dr. P.G.M. Mulder (Department of Epidemiology and Biostatistics) for their help with the statistical analysis of the data.
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