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Notes: The article briefly describes the innervation of the human cerebral circulation by nerve fibers containing neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gent-related peptide (CGRP). The neuropeptides in human cerebral arteries were characterized by radioimmunoassay in combination with HPLC. These neuropeptides mediate contraction (NPY) and dilatation (VIP, SP, CGRP). In conjunction with spontaneous attacks of migraine or cluster headache, release of CGRP is seen. With the associated symptoms of nasal congestion and rhinorrhea, VIP is released. Successful treatment may abort the peptide release in parallel with disappearance of headache.

Notes: Chronic paroxysmal hemicrania (CPH) is a rare headache syndrome of short-lasting attacks of pain, characterized clinically by trigemino-parasympathetic activation. The features of the headache are severe attacks of pain that generally last no more than minutes in association with autonomic activation, such as lacrimation or rhinorrhea. We report a patient fulfilling International Headache Society guidelines for the diagnosis of CPH in whom levels of calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) were elevated in the cranial circulation during attacks. Moreover, successful treatment of the problem with indomethacin leads to normalization of the levels of both CGRP and VIP. Given that similar neuropeptide changes are seen in cluster headache the data suggest a shared underlying pathophysiology between CPH and cluster headache.

Notes: The functional role of the trigeminal system has been addressed in experiments on the cortical surface of alpha-chloralose anaesthetized cats. Application of calcitonin gene-related peptide (CGRP) caused a concentration-dependent increase in arteriolar calibre by 38 ± 5% (n = 8) with an IC50 of 2 nM. Cerebral veins did not relax upon CGRP administration (n = 12). Substance P (SP) was less potent but showed dilatation of both arterioles (21 ± 4%) and veins (16 ± 4%). The cerebrovascular trigeminal system was investigated after chronic (14 days) surgical lesion of the trigeminal nerve with the concomitant disappearance of perivascular CGRP/SP immunoreactive nerves. The cortical arteriolar responses to subarachnoid microinjections of acidic (pH 6.8) and basic CSF (pH 7.6) as well as noradrenaline (10−4 M), neuropeptide Y (10−7 M), prostaglandin F2x (10−6 M) barium chloride (10−4 M, and autologous blood (5 μ1) were examined in anaesthetized cats with lesions of the trigeminal nerve, and were compared with their effects in sham-operated animals. The magnitude of the vasodilator and vasoconstrictor responses to these agents was unaffected by trigeminal lesions. However, duration of the vasoconstriction produced by basic CSF, but not the vasodilatation to acidic CSF, was markedly prolonged by trigeminal lesions (from 0.8 ± 0.1 min to 2.2 ± 0.3 min, p 〈 0.01). Also, the vasoconstrictor responses to noradrenaline, prostaglandin F2x, barium chloride, and autologous blood were significantly prolonged, while the maximum contractile effect to each agent was similar in lesioned as in sham-operated controls. The effects of CGRP, SP, and neurokinin A (NKA) have been examined on isolated cerebral arteries in vitro. Different CGRP analogues induced a strong relaxation with no difference in Imax (85–96%) or pD2 values (8.65–9.12). NKA induced a stronger relaxation than SP (Imax 33% and 13%, respectively). SP was more potent than NKA (pD2:8.7 and 7.7, respectively). Capsaicin, a substance which selectively causes the release of stored sensory neuropeptides (CGRP, SP, NKA), caused in vitro relaxation of precontracted arteries. This relaxation was not affected by the neurokinin blocker spantide, but shifted towards higher capsaicin concentrations by the CGRP antagonist CGRP8–37. Thus, in this preparation CGRP rather than a neurokinin (SP/NKA) is responsible for the capsaicin-induced dilatations.

Notes: Alpha-adrenergic mechanisms have frequently been implied in migraine pathophysiology. We have examined the noradrenaline reactivity of isolated human temporal arteries removed from six migraine sufferers (not during attack) and from six patients without migraine operated for intracranial disorders. Noradrenaline constricted these vessels in a concentration-dependent manner, the response being altered by phentolamine 10−8 M to 10−6 M. There was no statistically significant difference between migraine patients and controls with respect to maximal contractile force (Emax) or pD2 (negative logarithm of the concentration eliciting half maximal force). The pA2 value for phentolamine was 8.3 in vessels from controls and 7.6 in arteries from migraine sufferers. The small difference between migraine patients and controls was not statistically significant. We obtained clear evidence of alpha-adrenergic receptors in human temporal arteries but their sensitivity was independent of the migraine disorder.

Notes: The cerebral circulation is invested by a rich network of neuropeptide Y (NPY) and noradrenaline containing sympathetic nerve fibers in arteries, arterioles and veins. However, the nerve supply of vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) containing fibers is sparse. While noradrenaline and NPY cause vasoconstriction, VIP, SP and CGRP are potent vasodilators. Stimulation of the trigeminal ganglion in cat and man elicits release of SP and CGRP. Subjects with spontaneous attacks of migraine show release of CGRP in parallel with headache. Cluster headache patients have release of CGRP and VIP during bouts. Treatment with sumatriptan aborts headache in migraine and cluster headache as well as the concomitant peptide release.

Notes: Vasoactive factors produced and released by the endothelium exert a powerful influence on vascular tone in the cerebral circulation. Impaired endothelium-dependent responses, such as decreased production of endothelium-derived relaxing factors, and/or release of endothelium-derived contractile factors may give rise to different pathophysiological conditions. Among the endothelium-derived contractile factors the endothelins have recently received particular attention. Endothelin-1 is the major isoform in the endothelin family, which also includes endothelin-2 and endothelin-3. Endothelin-1 is synthesized within the endothelium of cerebral vessels, whereas both endothelin-1 and endothelin-3 in addition have been identified in neurons and glia. Recent electrophysiological work has suggested a neuromodulatory role for these peptides, but at present the general interest is mainly focused on their vasoactive role. Physiological stimuli such as hypoxia, anoxia, and hemodynamic shear stress will stimulate the endothelial endothelin production. In the brain, at least two types of specific subreceptors have been cloned; ETA receptors, exclusively associated with blood vessels and ETB receptors also found on glial, epithelial, and ependymal cells. The endothelins seem so far to be the most potent vasoconstrictors yet identified. The circulating plasma levels of immunoreactive endothelin are low. Since more than 80% of the total amount released from endothelial cells seems to be secreted towards the underlying smooth muscle, endothelins have been ascribed a local vasoregulatory role. Endothelins are believed to be involved in several of our most common cerebrovascular diseases and the present review comments on their possible pathophysiological role in subarachnoid haemorrhage, cerebral ischemia, and migraine.

Notes: A rich supply of nerve fibers containing neuropeptide Y-like (NPY-LI) and tyrosine hydroxylase-like immunoreactivity was seen in human cerebral arteries, arterioles and veins. Only a sparse supply of vasoactive intestinal polypeptide (VIP-LI), substance P (SP-LI), and calcitonin gene-related peptide (CGRP-LI) was demonstrated in the walls of human cerebral vessels. In isolated ring segments of human cerebral arteries, NPY and noradrenaline caused vasoconstriction but did not potentiate each other. VIP, peptide histidine methionine, SP, neurokinin A, and CGRP relaxed arteries precontracted by prostaglandin F2a. The degree of innervation and the vasomotor responses are discussed in relation to migraine pathophysiology.

Notes: Contraction induced by 124 mM potassium followed the depolarization of smooth-muscle cells and activation of potential-operated calcium channels in human temporal arteries. The contraction elicited consisted of two phases, one rapid and one slowly developing stable phase; both were affected by the two calcium entry blockers flunarizine and nimodipine but at significantly different concentrations. In calcium-free medium 124 mM potassium resulted in a weak contraction. Addition of calcium caused a concentration-dependent contraction that was attenuated by the calcium entry blockers at concentrations comparable to those inhibiting the second phase. The results suggested that in human temporal arteries flunarizine and nimodipine act as calcium entry blockers; there was good correlation with the therapeutic plasma concentration for nimodipine but not for flunarizine.

Notes: The vasomotor effects of calcilonin gene-related peptide (CGRP) analogues have been studied in circular segments of fresh human cereoral arteries obtained at neurosurgical operations using a sensitive in vitro system. Human a-CGRP, human b-CGRP, rat a-CGRP and rat b-CGRP induced strong and potent relaxation of precontracted circular vessel segments. The Imax (maximum relaxant effect) to human calcitonin was low and the pD2 (concentration for half maximum effect) 7.7 was much lower than that of CGRP. The CGRP-1, antagonist human a-CGRP8–37 blocked the response to human a-CGRP but not to human b-CGRP, while the putative antagonist [Tyr]CGRP28–37 did not. Capsaicin (10−15 - 10−8 M) caused relaxation of the cerebral arteries by 22% of precontract on. Pre-treatment with 10−6 M human a-CGRP8–37 inhibited this relaxation. Human a-CGRP increased the cyclic AMP content of human cerebral arteries in a concentration-dependent manner. This increase in adenylyl cyclase activity was blocked by human a-CGRP8–37. The results suggest that CGRP-1 receptors coupled to adenylyl cyclase are present in human cerebral arteries.