Vasoreactivity of the intracranial internal carotid artery
Jan Erik Hardebo
Departments of Medical Cell Research and Neurology, University of Lurid, Lurid, Sweden Cephalalgia
Hardebo JE. Vasoreactivity of the intracranial internal carotid artery. Cephalalgia 1992;12:280-3. Oslo. ISSN 0333-1024 The vasoreactivity of the intracranial segment of the internal carotid artery to transmitters, present in the perivascular sympathetic, parasympathetic and sensory nerves, as well as to other vasoactive agents of relevance for headache, was tested in man and monkey. The total arterial segment from both species is equipped with contractile receptors for noradrenaline, serotonin, prostaglandin F2a, ergotamine and sumatriptan. Further, the total arterial segment dilated upon exposure to calcitonin gene-related peptide in both species. Other vascoactive transmitters, acetylcholine, substance P and neurokinin A, caused only weak dilatation, restricted to the proximal extracavernous segment in the monkey. The findings are discussed in relation to the pathogenesis and treatment of cluster headache. • Catecholamines, cranial arteries, headache, neuropeptides, serotonin Jan Erik Hardebo, Department of Medical Cell Research, Biskopsgatan 5, S-223 62 Lund, Sweden. Received 13 April 1992, accepted 2 July 1992
Sympathetic fibers to the cerebral vessels originate in the superior cervical ganglion and run as the internal carotid nerve along the internal carotid artery (ICA). Immediately after entering the skull cavity fibers diverge to form a terminal plexus in the intracranial ICA wall (1, 2). Parasympathetic fibers reach the intracranial ICA with rami orbitales from the sphenopalatine ganglion, and with the greater deep petrosal nerve from a ganglion along the greater superficial petrosal nerve, and possibly the otic ganglion (3, 4). Sensory fibers reach the human intracranial ICA within the cavernous sinus through short branches from the ophthalmic trigeminal division (3-5), with a contribution from the maxillary division, at least in the monkey (5). The present study is an investigation of whether this innervation controls local vasoactivity. Transmitters known to be present in these nerves were applied to isolated segments of the intracranial ICA from monkey and man, and their effects on vascular tone were measured. In addition, reactivity to other vasoactive agents of relevance to vascular headache were tested. Methods
The intracranial ICA from four squirrel monkeys (Saimiri sciureus) and four humans (male, aged 39-54 years) was dissected out on one side and divided into 4 mm long segments, comprising the proximal extracavernous and the proximal, intermediate and distal intracavernous segments. The monkeys were killed under anesthesia with alphaxalone-alphadolone acetate 14 mg/kg im and thiopental 10 mg/kg iv. The human material was obtained at the Pathologic Institute, Lurid, within 20 h of death. The vessels were kept in an aerated Krebs-Ringer buffer solution (millimolar composition NaCl 118, KCl 4.5, CaCl2 ´ 2H2O 1.5, MgSO4 ´ 7H2O 1.2, NaHCO3 25, KH2PO4 1.0 and glucose 6.0), and within 30 min of dissection the vessel segments were mounted on two L-shaped metal holders in an aerated organ bath containing the buffer solution at pH 7.35 and 37.0°C (6). After mounting, the vessels were subjected to a passive load of 4.0 mN (monkey) and 8 mN (man) and were allowed to stabilize for 90 min. The passive load applied was of a magnitude that would give maximum contraction of the vessels to a maximally depolarizing potassium solution (all NaCl was replaced by KCl), as tested in separate experiments. Increasing concentrations of the various constrictors were added stepwise to obtain full concentration-response curves. Relaxations to various dilators were studied at an active tone induced by prostaglandin F2a 10-5 M. The following agents were used: acetylcholine chloride (Sigma), bradykinin (Peninsula), calcitonin gene-related peptide (Peninsula), ergotamine tartrate (Sandoz), neurokinin A (Peninsula), noradrenaline hydrochloride (Sigma), prostaglandin F2a (Amoglandin; Astra), serotonin creatinine sulphate (Sigma), substance P (Peninsula), sumatriptan succinate (Glaxo) and vasoactive intestinal polypeptide (Peninsula). All agents were dissolved in saline except ergotamine, for which a stem solution was made by the aid of a few drops of glacial acetic acid. Results
All segments of the intracranical ICA from monkey and man constricted upon exposure to a depolarizing potassium solution, noradrenaline, serotonin, sumatriptan, ergotamine, and prostaglandin F2a The maximum contraction (Emax) and the concentration at which half maximum contraction occurred (EC50)
did not differ significantly between the different segments, and the values are therefore grouped together for each species (Table 1, Fig. 1). The vessels reacted to sumatriptan at a lowest concentration of 3 ´ 10-8 M in both species. All ICA segments from the four monkeys and three of the men dilated to a modest and similar extent upon exposure to calcitonin gene-related peptide (10-10 - 3 ´ 10-7 M), with a mean EC50 value for all segments of 7.1 ± 2.2 ´ 10-9 M in monkey and 8.5 ± 2.4 ´ 10-9 M in man (Fig. 2). Substance P (10-10 - 3 ´ 10-7 M) caused a minor dilatation in the extracavernous segments from two of the monkeys (5 and 7% of precontractile tone, starting at 10-8 M) but did not affect tone in the cavernous segments in monkey or any of the segments in man. Likewise, neurokinin A ( 10-10 - 3 ´ 10-7 M) slightly relaxed the extracavernous segment from one of the monkeys (7%, starting at 10-8 M), but was without effect in all other vessel segments from monkey and man. Acetylcholine ( 10-7 -3´
10-4 M) slightly relaxed the extracavernous ICA segment in three of the monkeys (4, 4 and 7%, starting at 10-5 M), but did not affect tone in the other segments in monkey or any of the segments in man. Vasoactive intestinal polypeptide and bradykinin (10-10 - 3 x 10-7 M) was without effect on tone in all vessel segments from monkey and man. Discussion
The present study demonstrates that the total intracranial segment of ICA in man and monkey is equipped with contractile adrenergic receptors to the sympathetic nerve transmitter noradrenaline, and with dilatory receptors to the sensory nerve transmitter calcitonin gene-related peptide. In monkey, the extracavernous segment in addition displays a weak dilatation upon exposure to the parasympathetic nerve transmitter acetylcholine and the sensory nerve transmitters substance P and neurokinin A. Continuous activity of the perivascular sympaTable 1. Contractile response to noradrenaline, serotonin, sumatriptan, ergotamine and prostaglandin F2a in the intracranial internal carotid artery of monkey and man. Maximum contraction (Emax) is expressed as a percentage of contraction induced by a maximally depolarizing potassium solution, and the molar concentration (M) at which half maximum contraction occurred is termed EC50. Mean ± SEM of 16 observations in four individuals of each species. Emax (%) E50 (M) Monkey Man Monkey Man Noradrenaline 88 ± 3 77 ± 4 1.9± 1.1 ´ 10-6 2.8 ± 1.4 x 10-6 Serotonin 74 ± 4 74 ± 5 5.2± 2.3 ´ 10-8 6.4 ± 1.2 x 10-8 Sumatriptan 75 ± 5 77 ± 5 3.5± 1.5 ´ 10-7 2.5 ± 1.8 x 10-7 Ergotamine 46 ± 3 42 ± 3 6.1± 2.0 ´ 10-8 6.9 ± 1.6 x 10-5 PGF2a 88 ± 6 84 ± 4 2.3± 1.4 ´ 10-6 2.1 ± 1.7 x 10-6
thetic nerves contributes to constrictor tone in the cranial arteries (7). Contractile receptors for serotonin and the serotoninID-like receptor agonist sumatriptan were also found in the intracranial ICA, as previously demonstrated in its pial arterial branches (8-10). The receptors of this arterial segment are of particular interest in migraine and cluster headache, wherein sumatriptan is an effective treatment (11, 12). Also ergotamine, which acts at both adrenergic and serotoninergic receptors (13), constricted the vessel. The intracranial ICA has been implicated in the pathogenesis of cluster headache (14, 15). The angiographic findings in cluster headache of a dilated ICA with branches at the cavernous level during pain (16, see also discussion in ref. 17), and a narrowed lumen of the proximal extracavernous ICA towards the end of an attack (16), support a sympathetic lesion at the cavernous level. Based on these findings constriction of the proximal ICA might alleviate the attack. Indeed agents with vasoconstrictor properties, such as noradrenaline (18), ergotamine and sumatriptan (11), terminate the pain of cluster headache. Also compression of the ipsilateral common carotid artery alleviates pain (19). To the contrary, vasodilators such as nitroglycerin, histamine and alcohol, initiate an attack. An inflammatory process in the cavernous sinus, its inflow veins (superior ophthalmic vein) and outflow sinuses (superior and inferior petrosal sinuses) has been found in cluster headache sufferers during active periods (17, 20). This process may be responsible for the ipsilateral sympthetic lesion observed during this time in the majority of sufferers (21-24), probably located where these fibers penetrate the cavernous sinus together with the ICA (15). A reduced tone in the ICA, in combination with a reduced outflow from the cavernous sinus due to the obliterated sinuses, may cause venous congestion in the inflamed cavernous sinus and thus the pain. Further dilatation of the ICA may exaggerate the venous congestion and thus provoke an attack, whereas constriction of the ICA-by activation of intact sympathetic fibers proximal to the lesion, or by administration of vasconstrictor agents-may terminate the attack by alleviating the load on the venous side (15). That constriction of the ICA alone explains why subcutaneous sumatriptan alleviates the attack is supported by the rapid effect (within 15 min) (11) as soon as sufficiently high circulating concentrations of the drug are reached (after a mean of 10 min) (25). The peak plasma concentration is 1.75 x 10-7 M (range 1.33-2.62 x 10-7 M) (21). The intracranial ICA has vasa vasorum (2) and is located outside the blood-brain barrier. Probably therefore almost the same concentration can be reached around serotoninID-like receptors in this arterial segment after penetration of its wall. As we found in our isolated ICA segments, a sumatriptan concentration of this magnitude causes a substantial arterial contraction. Contraction may be restricted to the ICA but also may involve the external carotid arterial tree and extracranial arteriovenous anastomosis and veins, which also constrict upon exposure to sumatriptan (8, 26). There is the potential for dilatation of the intracranial ICA if the perivascular pain fibers become activated during cluster headache attacks to release their transmitter calcitonin gene-related peptide. We have found in the present experiments that intracranial ICA is equipped throughout its length with vasodilatory receptors for this neuropeptide. The perivascular sympathetic fibers may become further impinged against bone in the carotid canal if the artery dilates initially during an attack and this adds to the sympathetic lesion. Acknowledgments.-This study was supported by grants from the Medical Faculty at Lund University, Sweden, and the Swedish Medical Research Council, no. 14X-5680. The skilful word processing of Katarina Danielson is gratefully acknowledged. I thank Professor Niels Svendgaard for permission to use tissue from monkey and Dr Norihiro Suzuki for help with human tissues. References
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