http://repub.eur.nl/res/aut/15125/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/33425/ 2011-06-01T00:00:00Z We have previously shown that 5-HT1Breceptors inhibit prejunctionally the rat vasodepressor CGRPergic sensory outflow. Since 5-HT1receptors comprise 5-HT1A, 5-HT1B, 5-HT1Dand 5-HT1Ffunctional subtypes, this study has further investigated the role of 5-HT1A, 5-HT1Dand 5-HT1Freceptor subtypes in the inhibition of the above vasodepressor sensory outflow. Pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by 5-HT1receptor agonists. Then electrical spinal stimulation (T9-T12) or i.v. bolus injections of exogenous α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The electrically-induced vasodepressor responses remained unchanged during infusions of the 5-HT1Areceptor agonists 8-OH-DPAT and NN-DP-5-CT. In contrast, these responses were inhibited by the agonists sumatriptan (5-HT1A/1B/1D/1F), indorenate (5-HT1A), PNU-142633 (5-HT1D) or LY344864 (5-HT1F), which did not affect the vasodepressor responses to exogenous CGRP (implying a prejunctional sensory-inhibition). When analysing the effects of antagonists: (i) 310 μg/kg (but not 100 μg/kg) GR127935 (5-HT1A/1B/1D/1F) abolished the inhibition to sumatriptan, indorenate, PNU-142633 or LY344864; (ii) 310 μg/kg SB224289 (5-HT1B) or BRL15572 (5-HT1D) failed to block the inhibition to sumatriptan or PNU-142633, whereas SB224289 + BRL15572 partly blocked the inhibition to sumatriptan; and (iii) 10 μg/kg WAY100635 (5-HT1A) failed to block the inhibition to indorenate. These results suggest that 5-HT1F, but not 5-HT1Aor 5-HT1D, receptor subtypes inhibit the vasodepressor sensory CGRPergic outflow although, admittedly, no selective 5-HT1Freceptor agonist is available yet. The pharmacological profile of these receptors resembles that shown in rat dorsal root ganglia by molecular biology techniques. http://repub.eur.nl/res/pub/23048/ 2011-03-01T00:00:00Z Testosterone induces vasorelaxation through non-genomic mechanisms in several isolated blood vessels, but no study has reported its effects on the canine basilar artery, an important artery implicated in cerebral vasospasm. Hence, this study has investigated the mechanisms involved in testosterone-induced relaxation of the canine basilar artery. For this purpose, the vasorelaxant effects of testosterone were evaluated in KCl- and/or PGF 2α-precontracted arterial rings in vitro in the absence or presence of several antagonists/inhibitors/blockers; the effect of testosterone on the contractile responses to CaCl2 was also determined. Testosterone (10-180 μM) produced concentration-dependent relaxations of KCl- or PGF2α-precontracted arterial rings which were: (i) unaffected by flutamide (10 μM), dl-aminoglutethimide (10 μM), actinomycin D (10 μM), cycloheximide (10 μM), SQ 22,536 (100 μM) or ODQ (30 μM); and (ii) significantly attenuated by the blockers 4-aminopyridine (KV; 1 mM), BaCl2 (KIR; 30 μM), iberiotoxin (BKCa2+; 20 nM), but not by glybenclamide (KATP; 10 μM). In addition, testosterone (31, 56 and 180 μM) and nifedipine (0.01-1 μM) produced a concentration-dependent blockade of the contraction to CaCl 2 (10 μM to 10 mM) in arterial rings depolarized by 60 mM KCl. These results, taken together, show that testosterone relaxes the canine basilar artery mainly by blockade of voltage-dependent Ca2+ channels and, to a lesser extent, by activation of K+ channels (KIR, KV and BKCa2+). This effect does not involve genomic mechanisms, production of cAMP/cGMP or the conversion of testosterone to 17β-estradiol. http://repub.eur.nl/res/pub/33710/ 2011-03-01T00:00:00Z Currently available drugs for the acute treatment of migraine, i.e. ergot alkaloids and triptans, are cranial vasoconstrictors. Although cranial vasoconstriction is likely to mediate-at least a part of-their therapeutic effects, this property also causes vascular side-effects. Indeed, the ergot alkaloids and the triptans have been reported to induce myocardial ischemia and stroke, albeit in extremely rare cases, and are contraindicated in patients with known cardiovascular risk factors. In view of these limitations, novel antimigraine drugs devoid of vascular (side) effects are being explored. Currently, calcitonin gene-related peptide (CGRP) receptor antagonists, which do not have direct vasoconstrictor effects, are under clinical development. Other classes of drugs, such as 5-HT1Freceptor agonists, glutamate receptor antagonists, nitric oxide synthase inhibitors, VPAC/PAC receptor antagonists and gap junction modulators, have also been proposed as potential targets for acute antimigraine drugs. Although these prospective drugs do not directly induce vasoconstriction, they may well induce indirect vascular effects by inhibiting or otherwise modulating the responses to endogenous vasoactive substances. These indirect vascular effects might contribute to the therapeutic efficacy of the previously mentioned compounds, but may alternatively also lead to vascular side-effects. As described in the current review, some of the prospective antimigraine drugs with a proposed non-vascular mechanism of action may still have direct or indirect vascular effects. http://repub.eur.nl/res/pub/31542/ 2011-02-01T00:00:00Z Objective: We pharmacologically characterized pituitary adenylate cyclase-activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC1, VPAC2and PAC1receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries. Methods: Concentration response curves to PACAP38, PACAP27, VIP and the VPAC1receptor agonist ([Lys15,Arg16,Leu27]-VIP[1-7]- GRF[8-27]) were constructed in the absence or presence of the PAC1receptor antagonist PACAP6-38 or the VPAC1receptor antagonist, PG97269. mRNA expression was measured using qPCR. Results: PACAP38 was less potent than VIP in both arteries. Both peptides had lower potency and efficacy in meningeal than in coronary arteries, while mRNA expression of VPAC1receptor was more pronounced in meningeal arteries. PACAP6-38 reduced the Emaxof PACAP27, while PG97269 right-shifted the VIP-induced relaxation curve only in the coronary arteries. Conclusion: The direct vasodilatory effect of VIP and PACAP might be less relevant than the central effect of this compound in migraine pathogenesis. http://repub.eur.nl/res/pub/20120/ 2010-07-01T00:00:00Z Background and purpose: During migraine, trigeminal nerves may release calcitonin gene-related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate (LY466195) glutamate receptors affected dural vasodilatation induced by α-CGRP, capsaicin and periarterial electrical stimulation in rats, using intravital microscopy. Experimental approach: Male Sprague-Dawley rats were anaesthetized and the overlying bone was thinned to visualize the dural artery. Then, vasodilator responses to exogenous (i.v. α-CGRP) and endogenous (released by i.v. capsaicin and periarterial electrical stimulation) CGRP were elicited in the absence or presence of the above antagonists. Key results: α-CGRP, capsaicin and periarterial electrical stimulation increased dural artery diameter. Ketamine and MK801 inhibited the vasodilator responses to capsaicin and electrical stimulation, while only ketamine attenuated those to α-CGRP. In contrast, GYKI52466 only attenuated the vasodilatation to exogenous α-CGRP, while LY466195 did not affect the vasodilator responses to endogenous or exogenous CGRP. Conclusions and implications: Although GYKI52466 has not been tested clinically, our data suggest that it would not inhibit migraine via vascular mechanisms. Similarly, the antimigraine efficacy of LY466195 seems unrelated to vascular CGRP-mediated pathways and/or receptors. In contrast, the cranial vascular effects of ketamine and MK801 may represent a therapeutic mechanism, although the same mechanism might contribute, peripherally, to cardiovascular side effects. http://repub.eur.nl/res/pub/24352/ 2009-08-15T00:00:00Z This study analysed the inhibition produced by the agonists moxonidine (imidazoline I1receptors > α2-adrenoceptors) and agmatine (endogenous ligand of imidazoline I1/I2receptors), using B-HT 933 (6-ethyl-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepin-2-amine dihydrochloride; α2-adrenoceptors) for comparison, on the rat cardioaccelerator sympathetic outflow. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. Sympathetic stimulation or noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. I.v. continuous infusions of moxonidine (3 and 10 μg/kg min), agmatine (1000 and 3000 μg/kg min) and B-HT 933 (30 and 100 μg/kg min) inhibited the tachycardic responses to sympathetic stimulation, but not those to noradrenaline. The cardiac sympatho-inhibition by either moxonidine (3 μg/kg min) or B-HT 933 (30 μg/kg min) was not modified by i.v. injections of saline or the antagonists AGN192403 [(±)-2-endo-Amino-3-exo-isopropylbicyclo[2.2.1]heptane hydrochloride; 3000 μg/kg; imidazoline I1receptors] or BU224 (2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride; 300 μg/kg; imidazoline I2receptors) and abolished by rauwolscine (300 μg/kg; α2-adrenoceptors). At the same doses of these compounds, the sympatho-inhibition to moxonidine (10 μg/kg min) and agmatine (1000 μg/kg min) was: (1) not modified by saline, AGN192403 or BU224; (2) partially blocked by rauwolscine or the combination of rauwolscine plus BU224; and (3) abolished by the combination of rauwolscine plus AGN192403. These results demonstrate that the cardiac sympatho-inhibition to: (1) 3 μg/kg min moxonidine or 30 μg/kg min B-HT 933 involves α2-adrenoceptors; and (2) 10 μg/kg min moxonidine or 1000 μg/kg min agmatine involves α2-adrenoceptors and imidazoline I1receptors. http://repub.eur.nl/res/pub/24351/ 2009-08-01T00:00:00Z Migraine is a neurovascular disorder associated with trigeminal activation, vasodilatation and trigeminal release of calcitonin gene-related peptide (CGRP). The antimigraine properties of triptans may be due to: i) vasoconstriction of the carotid arterial bed via 5-HT1Breceptors; and ii) inhibition of CGRP release from trigeminal nerves, via 5-HT1B/1Dreceptors. This study investigated the effects of intrathecally administered sumatriptan (a 5-HT1B/1Dreceptor agonist) and PNU-142633 (a 5-HT1Dreceptor agonist) on the canine external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine. For this purpose, 42 mongrel dogs were anaesthetised with sodium pentobarbitone and, subsequently, vagosympathectomized. The animals were prepared to measure arterial blood pressure, heart rate and external carotid blood flow; the thyroid artery was cannulated for infusion of agonists. 1-min intracarotid (i.c.) continuous infusions of capsaicin, α-CGRP and acetylcholine produced dose-dependent increases in external carotid blood flow without affecting arterial blood pressure or heart rate. These vasodilator responses remained unaffected after intrathecal (i.t.) administration of physiological saline (0.5 ml) or PNU-142633 (300-1000 μg); in contrast, i.t. sumatriptan (300-1000 μg) significantly inhibited the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine. Furthermore, i.t. administration of SB224289 (a 5-HT1Breceptor antagonist), but not of BRL15572 (a 5-HT1Dreceptor antagonist), abolished the above inhibition by sumatriptan. These results suggest that sumatriptan-induced inhibition of the external carotid vasodilatation to capsaicin involves a central mechanism mainly mediated by 5-HT1Breceptors. http://repub.eur.nl/res/pub/29113/ 2008-11-01T00:00:00Z Blood vessels may either constrict or dilate in response to 5-HT, the response being dependent on the species, the vascular bed studied and the condition (healthy or diseased) of the subject studied. Vasoconstriction may be mediated by 5-HT2A, but, in a variable proportion, also by 5-HT1Breceptors. The expression and function of 5-HT1Breceptors is likely to be increased in disease states such as hypertension, cerebrovascular disease and variant angina pectoris. Contractile responses mediated by 5-HT1Breceptors may be increased in blood vessels with damaged endothelium, but may also be augmented in the presence of low concentrations of other vasoconstrictors such as thromboxane A2, endothelin-1, prostaglandin F2α, angiotensin II, histamine, noradrenaline, phenylephrine or KCl. Such an augmentation, however, is not a generalized phenomenon, since it does not occur in all vascular beds and is not always induced by all substances mentioned above. Whereas the augmentation seems to depend on increased levels of the second messengers involved, the exact mechanism is not yet completely clear. The augmentation of 5-HT1Breceptor-mediated contractions may be of relevance in pathophysiological conditions such as variant angina and preeclampsia, where the development of 5-HT1Breceptors seems to be expedited. Further, augmentation of 5-HT1Breceptor-mediated contractions may be an important determinant in the case of chest symptoms experienced as a side effect of antimigraine drugs. http://repub.eur.nl/res/pub/14798/ 2008-10-01T00:00:00Z Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon. http://repub.eur.nl/res/pub/35487/ 2007-04-01T00:00:00Z Background. - Female sex hormones are implicated in the modulation of reactivity of a wide range of blood vessels under physiological as well as pathological conditions. Migraine, a neurovascular syndrome, is 3 times more prevalent in women during their reproductive period than in men. Objective. - This study sets out to investigate the effects of the female sex steroids, 17β-estradiol and progesterone (separately and in combination) on vasoactive responses to calcitonin gene-related peptide (CGRP), acetylcholine, and 5-hydroxytryptamine (5-HT) in rat isolated mesenteric, caudal, and basilar arteries. Methods. - Female Sprague-Dawley rats were ovariectomized (Day 0) and 7 days later subcutaneously implanted with pellets releasing over a 21-day period 17β-estradiol (0.25 mg), progesterone (50 mg), their combination, or placebo. On days 25-28, the animals were killed, arteries isolated and mounted in Mulvany myographs, and cumulative concentration response curves to CGRP, acetylcholine, and 5-HT were constructed. Results. - The relaxant responses to CGRP were significantly potentiated in mesenteric and caudal arteries from rats treated with 17β-estradiol as compared to the placebo-treated rats. Acetylcholine-induced relaxations were potentiated in the caudal artery from rats treated with the combination of 17β-estradiol and progesterone, as compared to that from placebo-treated rats. The 5-HT-induced contractions in the 3 arteries were not significantly different in efficacy or potency. Conclusion. - Our results show that 17β-estradiol potentiates CGRP-induced relaxations in the mesenteric and caudal arteries, while the combination treatment enhances acetylcholine-induced relaxations in the caudal artery. Although these in vitro experiments have been carried out in rats and a direct extrapolation to migraine in humans is not possible, our results may provide a new avenue to study the effects of sex steroids on vascular reactivity. http://repub.eur.nl/res/pub/31787/ 2007-03-01T00:00:00Z Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 μM), the neurokinin NK1receptor antagonist L-733060 (0.5 μM), the voltage-sensitive calcium channel blocker ruthenium red (100 μM), the TRPV1 receptor antagonist capsazepine (5 μM), the nitric oxide synthetase inhibitor Nω-nitro-l-arginine methyl ester HCl (l-NAME; 100 μM), the gap junction blocker 18α-glycyrrhetinic acid (10 μM), as well as the RhoA kinase inhibitor Y-27632 (1 μM). Further, we also used the K+channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 μM)+apamin (0.1 μM) and iberiotoxin (0.5 μM)+apamin (0.1 μM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) α-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK1, NO, vanilloid receptors, voltage-sensitive calcium channels, K+channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism. http://repub.eur.nl/res/pub/35596/ 2007-02-01T00:00:00Z Objective. - To compare the contractile responses to α-adrenergic receptor agonists and 5-HT in the rat carotid artery after ovariectomy and subsequent hormone replacement with 17β-estradiol, progesterone, or the combination of 17β-estradiol and progesterone. Background. - The prevalence of migraine is higher in women than in men, and changes in 17β-estradiol levels seem to affect the frequency of attacks in female migraineurs. However, the underlying mechanisms are not yet completely understood. Methods. - After 1 week of acclimatization (Day 0), female Sprague-Dawley rats were either sham-operated or bilateral ovariectomized. One week later (Day 7), the ovariectomized rats were subcutaneously implanted with a pellet releasing over a 21-day period either placebo, 0.25 mg 17β-estradiol, 50 mg progesterone, or the combination of the 2 hormones. Blood samples were collected on Days 0, 7, and 21 to measure plasma norepinephrine and epinephrine. On days 25 to 28, the animals were killed to isolate carotid artery and mount its segments in Mulvany myographs. Cumulative concentration response curves to α-adrenergic receptor agonists and 5-HT were constructed in the absence or presence of suitable antagonists. Results. - The potency of norepinephrine in ovariectomized rats was significantly reduced in animals treated with progesterone as compared to those with placebo. In placebo-treated ovariectomized animals there was a noticeable response mediated by α2-adrenoceptors, in contrast to that in sham-operated or ovariectomized rats treated with 17β-estradiol and progesterone, either alone or in combination. The plasma levels of norepinephrine and epinephrine were not significantly affected by either ovariectomy or the subsequent hormone replacement. The potency of 5-HT was significantly reduced in animals having circulating sex hormones as compared to that in placebo-treated ovariectomized animals. Conclusion. - Taken together, our results indicate that circulating progesterone and/or 17β-estradiol may reduce the contraction of the rat carotid artery in response to norepinephrine and 5-HT. This effect of female sex hormones might be one of the factors through which these hormones aggravate migraine in women. http://repub.eur.nl/res/pub/35617/ 2007-02-01T00:00:00Z Background. - The prevalence of migraine is 2 to 3-fold higher in females than in males, and it is intricately related to the levels of female sex hormones. These hormones may regulate the synthesis and receptor expression of calcitonin gene-related peptide (CGRP), which mediates neurogenic dural vasodilatation and is implicated in migraine pathogenesis. Objective. - To investigate the effects of the female sex steroids, 17β-estradiol and progesterone, separately and in combination, on dural vasodilatation induced by αCGRP, periarterial electrical stimulation and capsaicin in ovariectomized rats, using intravital microscopy. Methods. - Sprague-Dawley rats were ovariectomized and, 7 days later, subcutaneously implanted with 21-day release pellets of 17β-estradiol, progesterone, their combination or placebo. On day 19 to 21, the animals were anesthetized, overlying bone thinned to visualize the middle meningeal artery and vasodilator responses to αCGRP (10 to 3000 ng kg-1), periarterial electrical stimulation (25 to 125 μA) and capsaicin (0.3 to 18 μg kg-1) elicited. Results. - There were no significant differences in the vasodilator potency or efficacy of αCGRP or capsaicin in the different groups studied. In contrast, the vasodilator response to electrical stimulation was significantly higher in rats treated with 17β-estradiol (Emax:157 ± 19%) as compared to those observed after placebo treatment (Emax:93 ± 11%). Conclusion. - Our results show that, in contrast to CGRP- or capsaicin-induced dural vasodilatation, 17β-estradiol enhanced neurogenic vasodilatation, suggesting increased CGRP release from perivascular nerves. This may be one of the mechanisms through which 17β-estradiol exacerbates migraine in women. http://repub.eur.nl/res/pub/35845/ 2007-02-01T00:00:00Z Clinical evidence indicates that female sex steroids may contribute to the high prevalence of migraine in women, as well as changes in the frequency or severity of migraine attacks that are in tandem with various reproductive milestones in women's life. While female sex steroids do not seem to be involved in the pathogenesis of migraine per se, they may modulate several mediators and/or receptor systems via both genomic and non-genomic mechanisms; these actions may be perpetuated at the central nervous system, as well as at the peripheral (neuro)vascular level. For example, female sex steroids have been shown to enhance: (i) neuronal excitability by elevating Ca2+and decreasing Mg2+concentrations, an action that may occur with other mechanisms triggering migraine; (ii) the synthesis and release of nitric oxide (NO) and neuropeptides, such as calcitonin gene-related peptide CGRP, a mechanism that reinforces vasodilatation and activates trigeminal sensory afferents with a subsequent stimulation of pain centres; and (iii) the function of receptors mediating vasodilatation, while the responses of receptors inducing vasoconstriction are attenuated. The serotonergic, adrenergic and γ-aminobutyric acid (GABA)-ergic systems are also modulated by sex steroids, albeit to a varying degree and with potentially contrasting effects on migraine outcome. Taken together, female sex steroids seem to be involved in an array of components implicated in migraine pathogenesis. Future studies will further delineate the extent and the clinical relevance of each of these mechanisms, and will thus expand the knowledge on the femininity of migraine. http://repub.eur.nl/res/pub/13200/ 2003-09-01T00:00:00Z 1. Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 microg kg-1, i.v.), a potent and selective CGRP receptor antagonist, on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone. 2. Infusions of capsaicin (0.3, 1, 3 and 10 microg kg-1 min-1, i.c.) did not alter the heart rate, but dose-dependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS. 3. Capsaicin infusion (10 microg kg-1 min-1, i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently blocked by BIBN4096BS. 4. Capsaicin infusion (10 microg kg-1 min-1, i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS. 5. The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin-induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine. http://repub.eur.nl/res/pub/31869/ 1997-07-14T00:00:00Z It has been suggested that the late hypotensive response to serotonin (5-hydroxytryptamine; 5-HT) in vagosympathectomized rats is mediated by '5-HT1-like' receptors since this effect is mimicked by 5-carboxamidotryptamine (5-CT), is not modified by cyproheptadine, ketanserin or MDL 72222, but it is blocked by met hysergide. The present study was set out to reanalyze this suggestion in terms of the classification schemes proposed in 1994 and 1996 by the NC-IUPHAR subcommittee on the classification and nomenclature of 5-HT receptors. I.v. bolus injections of 5-CT (0.01-0.3 μg · kg-1), 5-HT (1-30 μg · kg-1) and 5-methoxytryptamine (5-MeO-T; 1-30 μg · kg-1) produced dose-dependent hypotensive responses with a rank order of agonist potency: 5-CT >> 5-HT ≤ 5-methoxytryptamine with sumatriptan (30-1000 μg · kg-1) inactive. The depressor responses to 5-HT and 5-CT were not attenuated by i.v. GR127935 (300-3000 μg · kg-1) or equivalent volumes of saline. In contrast, lisuride, methiothepin, mesulergine, metergoline and clozapine dose-dependently antagonized the responses to 5-HT and 5-CT; the rank order of apparent pA2values against 5-HT and 5-CT, respectively, was: lisuride (7.7; 7.8) > methiothepin (6.8; 7.0) ≤ mesulergine (6.4; 6.6) > clozapine (5.7; 5.8); metergoline displayed variable potencies (5.6; 6.4). Except for lisuride, which also affected isoprenaline-induced hypotension, the antagonism by the other drugs was selective. Based upon the above rank order of agonist potency, the blockade by a series of drugs showing high affinity for the cloned 5-ht7receptor and the lack of blockade by GR127935, our results indicate that the 5-HT receptor mediating hypotension in vagosympathectomized rats is operationally similar to other putative 5-ht7receptors mediating vascular and non-vascular responses (e.g. relaxation of the rabbit femoral vein, canine coronary and external carotid arteries and guinea-pig ileum as well as feline tachycardia).