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Carlos M. Villalón - One of the best experts on this subject based on the ideXlab platform.
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dihydroergotamine inhibits the vasodepressor sensory cgrpergic outflow by prejunctional activation of α2 adrenoceptors and 5 ht1 receptors
Journal of Headache and Pain, 2018Co-Authors: Jair Lozanocuenca, Abimael Gonzalezhernandez, Antoinette Maassenvandenbrink, Bruno A Marichalcancino, Carlos M. VillalónAbstract:Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow. Pithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure. DHE inhibited the vasodepressor responses to electrical stimulation (0.56–5.6 Hz), without affecting those to i.v. α-CGRP (0.1–1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists Rauwolscine (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after Rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-like; 310 μg/kg) given alone, or after the combination of Rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses. DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional Rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE’s vasoconstrictor properties resulting in an increased vascular resistance.
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the role of α1 and α2 adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin pretreated pithed rats
Journal of Headache and Pain, 2017Co-Authors: Eduardo Riveramancilla, Victor H Avilesrosas, Guadalupe Manriquemaldonado, Alain H Altamiranoespinoza, Belinda Villanuevacastillo, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors results in systemic vasopressor responses, the purpose of this study was to investigate the specific role of α1- and α2-adrenoceptors mediating DHE-induced vasopressor responses using several antagonists for these receptors. For this purpose, 135 male Wistar rats were pithed and divided into 35 control and 100 pretreated i.v. with ritanserin (100 μg/kg; to exclude the 5-HT2 receptor-mediated systemic vasoconstriction). Then, the vasopressor responses to i.v. DHE (1–3100 μg/kg, given cumulatively) were determined after i.v. administration of some α1/α2-adrenoceptor antagonists. In control animals (without ritanserin pretreatment), the vasopressor responses to DHE were: (i) unaffected after prazosin (α1; 30 μg/kg); (ii) slightly, but significantly, blocked after Rauwolscine (α2; 300 μg/kg); and (iii) markedly blocked after prazosin (30 μg/kg) plus Rauwolscine (300 μg/kg). In contrast, after pretreatment with ritanserin, the vasopressor responses to DHE were: (i) attenuated after prazosin (α1; 10 and 30 μg/kg) or Rauwolscine (α2; 100 and 300 μg/kg); (ii) markedly blocked after prazosin (30 μg/kg) plus Rauwolscine (300 μg/kg); (iii) attenuated after 5-methylurapidil (α1A; 30–100 μg/kg), L-765,314 (α1B; 100 μg/kg), BMY 7378 (α1D; 30–100 μg/kg), BRL44408 (α2A; 100–300 μg/kg), imiloxan (α2B; 1000–3000 μg/kg) or JP-1302 (α2C; 1000 μg/kg); and (iv) unaffected after the corresponding vehicles (1 ml/kg). These results suggest that the DHE-induced vasopressor responses in ritanserin-pretreated pithed rats are mediated by α1- (probably α1A, α1B and α1D) and α2- (probably α2A, α2B and α2C) adrenoceptors. These findings could shed light on the pharmacological profile of the vascular side effects (i.e. systemic vasoconstriction) produced by DHE and may lead to the development of more selective antimigraine drugs devoid vascular side effects.
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postjunctional α2c adrenoceptors mediate vasoconstriction in rat tail artery influence of precontraction and temperature on vasoreactivity
Naunyn-schmiedebergs Archives of Pharmacology, 2010Co-Authors: Florian Jantschak, David Centurion, Carlos M. Villalón, Alexander M Popp, Raik A Hofmann, Heinz H. PertzAbstract:The isolated rat tail artery (RTA) represents an in vitro model of the cutaneous circulation. We have characterised the postjunctional α2-adrenoceptor subtype mediating vasoconstriction to the α2-adrenoceptor (α2-AR) agonist UK14304 in RTA. In non-precontracted arterial rings at 32°C, a physiological temperature for the RTA, UK14304 elicited only slight contractions which were markedly enhanced after precontraction with serotonin (5-HT; 10–50 nM). Under the condition of elevated vascular tone, the contractile UK14304 response was competitively antagonised by MK912 (pA2 = 10.05 ± 0.07), Rauwolscine (pA2 = 8.82 ± 0.06), yohimbine (pA2 = 8.45 ± 0.04), WB4101 (pA2 = 8.05 ± 0.05), BRL44408 (pA2 = 7.20 ± 0.04), ARC239 (pA2 = 6.90 ± 0.05) and prazosin (pA2 = 6.80 ± 0.05). Schild regressions were linear and had slopes of unity. Affinities (pA2) for MK912, Rauwolscine, yohimbine and WB41104 were in the same range as binding data (pKD) for these drugs at α2C-ARs of rat cerebral cortex. In addition, the presence of α2C-ARs was confirmed by Western blotting. In experiments to study the influence of temperature on vasoreactivity, UK14304-induced contractions did not differ at 37°C, 32°C or 27°C and were similarly blocked by Rauwolscine (apparent pA2 = 8.73–8.90). After rapid cooling (from 37°C to 27°C), the maximal UK14304 response was enhanced only in precontracted arteries; antagonism by Rauwolscine was the same before and after cooling (apparent pA2 = 8.80–8.90). The enhancement of the maximal UK14304 response was abolished by rewarming to 37°C. It is concluded that α2C-ARs predominantly mediated vasoconstriction in RTAs at any temperature tested. Since α2C-ARs may be involved in Raynaud’s phenomenon, the isolated RTA represents a convenient in vitro bioassay to test novel compounds for the treatment of this syndrome.
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Pharmacological characterization of the inhibition by moxonidine and agmatine on the cardioaccelerator sympathetic outflow in pithed rats
European Journal of Pharmacology, 2009Co-Authors: Luis E. Cobos-puc, Carlos M. Villalón, Antoinette Maassenvandenbrink, Jair Lozano-cuenca, Martha B. Ramírez-rosas, Araceli Sánchez-lópez, Gómez-díaz B, David CenturionAbstract:Abstract This study analysed the inhibition produced by the agonists moxonidine (imidazoline I1 receptors > α2-adrenoceptors) and agmatine (endogenous ligand of imidazoline I1/I2 receptors), 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 I1 receptors] or BU224 (2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride; 300 µg/kg; imidazoline I2 receptors) 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 I1 receptors.
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pharmacological profile of the inhibition by dihydroergotamine and methysergide on the cardioaccelerator sympathetic outflow in pithed rats
European Journal of Pharmacology, 2009Co-Authors: Jair Lozanocuenca, Heinz H. Pertz, Araceli Sanchezlopez, David Centurion, Luis E Cobospuc, Enriqueta Munozislas, Abimael Gonzalezhernandez, Carlos M. VillalónAbstract:Abstract The present study set out to analyse the pharmacological profile of the inhibitory responses induced by the antimigraine agents dihydroergotamine (DHE) and methysergide on the tachycardic responses to preganglionic sympathetic stimulation in pithed rats. For this purpose, 132 male Wistar normotensive rats were pithed and prepared to: (i) selectively stimulate the preganglionic (C7–T1) cardiac sympathetic outflow; or (ii) receive intravenous (i.v.) bolus injections of exogenous noradrenaline. Electrical sympathetic stimulation or exogenous noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. Moreover, i.v. continuous infusions of DHE (1.8, 3.1 and 5.6 µg/kg.min) or methysergide (100, 300 and 1000 µg/kg.min) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using physiological saline or antagonists (given as i.v. bolus injections), the cardiac sympatho-inhibition induced by either DHE (3.1 µg/kg.min) or methysergide (300 µg/kg.min) was: (1) unaffected by saline (1 ml/kg); (2) partially blocked by the antagonists Rauwolscine (300 µg/kg; α2) or N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1,-biphenyl]-4-carboxamide hydrochloride monohydrate (GR127935, 300 µg/kg; 5-HT1B/1D); and (3) completely antagonised by the combination Rauwolscine plus GR127935. These antagonists, at doses high enough to completely block their respective receptors, failed to modify the sympathetically-induced tachycardic responses per se. The above results, taken together, suggest that the cardiac sympatho-inhibition induced by DHE (3.1 µg/kg.min) and methysergide (300 µg/kg.min) may be mainly mediated by stimulation of both α2-adrenoceptors and 5-HT1B/1D receptors.
David Centurion - One of the best experts on this subject based on the ideXlab platform.
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pharmacological analysis of the cardiac sympatho inhibitory actions of moxonidine and agmatine in pithed spontaneously hypertensive rats
European Journal of Pharmacology, 2016Co-Authors: Luis E Cobospuc, Araceli Sanchezlopez, David CenturionAbstract:Abstract This study shows that in spontaneously hypertensive rats (SHR) of 14-weeks-old, the sympathetically-induced, but not noradrenaline-induced tachycardic response are higher than age-matched Wistar normotensive rats. Furthermore, in SHR the sympathetically-induced tachycardic response was: (1) unaffected by moxonidine (3 μg/kg min); (2) partially inhibited by B-HT 933 (30 μg/kg min), both at the lowest doses; and (3) completely inhibited by the highest doses of B-HT 933 (100 μg/kg min), moxonidine (10 μg/kg min) or agmatine (1000 and 3000 μg/kg min) while the noradrenaline-induced tachycardic responses remained unaffected by the above compounds, except by 3000 μg/kg min agmatine. In SHR, 300 μg/kg Rauwolscine failed to block the sympatho-inhibition to 100 μg/kg min B-HT 933 or 10 μg/kg min moxonidine, but 1000 μg/kg Rauwolscine abolished, partially antagonized, and did not modify the sympatho-inhibition to the highest doses of B-HT 933, moxonidine, and agmatine, respectively, 3000 μg/kg AGN 192403 or 300 μg/kg BU224 given alone had no effect in the moxonidine- or agmatine-induced sympatho-inhibition, and the combination Rauwolscine plus AGN 192403 but not plus BU224, abolished the sympatho-inhibition to the highest doses of moxonidine and agmatine. In conclusion, the sympathetically-induced tachycardic responses in SHR are inhibited by moxonidine and agmatine. The inhibition of moxonidine is mainly mediated by prejunctional α 2 -adrenoceptors and to a lesser extent by I 1 -imidazoline receptors, while the inhibition of agmatine is mediated by prejunctional α 2 -adrenoceptors and I 1 -imidazoline receptors at the same extent. Notwithstanding, the inhibitory function of α 2 -adrenoceptors seems to be altered in SHR compared with Wistar normotensive rats.
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postjunctional α2c adrenoceptors mediate vasoconstriction in rat tail artery influence of precontraction and temperature on vasoreactivity
Naunyn-schmiedebergs Archives of Pharmacology, 2010Co-Authors: Florian Jantschak, David Centurion, Carlos M. Villalón, Alexander M Popp, Raik A Hofmann, Heinz H. PertzAbstract:The isolated rat tail artery (RTA) represents an in vitro model of the cutaneous circulation. We have characterised the postjunctional α2-adrenoceptor subtype mediating vasoconstriction to the α2-adrenoceptor (α2-AR) agonist UK14304 in RTA. In non-precontracted arterial rings at 32°C, a physiological temperature for the RTA, UK14304 elicited only slight contractions which were markedly enhanced after precontraction with serotonin (5-HT; 10–50 nM). Under the condition of elevated vascular tone, the contractile UK14304 response was competitively antagonised by MK912 (pA2 = 10.05 ± 0.07), Rauwolscine (pA2 = 8.82 ± 0.06), yohimbine (pA2 = 8.45 ± 0.04), WB4101 (pA2 = 8.05 ± 0.05), BRL44408 (pA2 = 7.20 ± 0.04), ARC239 (pA2 = 6.90 ± 0.05) and prazosin (pA2 = 6.80 ± 0.05). Schild regressions were linear and had slopes of unity. Affinities (pA2) for MK912, Rauwolscine, yohimbine and WB41104 were in the same range as binding data (pKD) for these drugs at α2C-ARs of rat cerebral cortex. In addition, the presence of α2C-ARs was confirmed by Western blotting. In experiments to study the influence of temperature on vasoreactivity, UK14304-induced contractions did not differ at 37°C, 32°C or 27°C and were similarly blocked by Rauwolscine (apparent pA2 = 8.73–8.90). After rapid cooling (from 37°C to 27°C), the maximal UK14304 response was enhanced only in precontracted arteries; antagonism by Rauwolscine was the same before and after cooling (apparent pA2 = 8.80–8.90). The enhancement of the maximal UK14304 response was abolished by rewarming to 37°C. It is concluded that α2C-ARs predominantly mediated vasoconstriction in RTAs at any temperature tested. Since α2C-ARs may be involved in Raynaud’s phenomenon, the isolated RTA represents a convenient in vitro bioassay to test novel compounds for the treatment of this syndrome.
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Pharmacological characterization of the inhibition by moxonidine and agmatine on the cardioaccelerator sympathetic outflow in pithed rats
European Journal of Pharmacology, 2009Co-Authors: Luis E. Cobos-puc, Carlos M. Villalón, Antoinette Maassenvandenbrink, Jair Lozano-cuenca, Martha B. Ramírez-rosas, Araceli Sánchez-lópez, Gómez-díaz B, David CenturionAbstract:Abstract This study analysed the inhibition produced by the agonists moxonidine (imidazoline I1 receptors > α2-adrenoceptors) and agmatine (endogenous ligand of imidazoline I1/I2 receptors), 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 I1 receptors] or BU224 (2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride; 300 µg/kg; imidazoline I2 receptors) 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 I1 receptors.
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pharmacological profile of the inhibition by dihydroergotamine and methysergide on the cardioaccelerator sympathetic outflow in pithed rats
European Journal of Pharmacology, 2009Co-Authors: Jair Lozanocuenca, Heinz H. Pertz, Araceli Sanchezlopez, David Centurion, Luis E Cobospuc, Enriqueta Munozislas, Abimael Gonzalezhernandez, Carlos M. VillalónAbstract:Abstract The present study set out to analyse the pharmacological profile of the inhibitory responses induced by the antimigraine agents dihydroergotamine (DHE) and methysergide on the tachycardic responses to preganglionic sympathetic stimulation in pithed rats. For this purpose, 132 male Wistar normotensive rats were pithed and prepared to: (i) selectively stimulate the preganglionic (C7–T1) cardiac sympathetic outflow; or (ii) receive intravenous (i.v.) bolus injections of exogenous noradrenaline. Electrical sympathetic stimulation or exogenous noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. Moreover, i.v. continuous infusions of DHE (1.8, 3.1 and 5.6 µg/kg.min) or methysergide (100, 300 and 1000 µg/kg.min) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using physiological saline or antagonists (given as i.v. bolus injections), the cardiac sympatho-inhibition induced by either DHE (3.1 µg/kg.min) or methysergide (300 µg/kg.min) was: (1) unaffected by saline (1 ml/kg); (2) partially blocked by the antagonists Rauwolscine (300 µg/kg; α2) or N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1,-biphenyl]-4-carboxamide hydrochloride monohydrate (GR127935, 300 µg/kg; 5-HT1B/1D); and (3) completely antagonised by the combination Rauwolscine plus GR127935. These antagonists, at doses high enough to completely block their respective receptors, failed to modify the sympathetically-induced tachycardic responses per se. The above results, taken together, suggest that the cardiac sympatho-inhibition induced by DHE (3.1 µg/kg.min) and methysergide (300 µg/kg.min) may be mainly mediated by stimulation of both α2-adrenoceptors and 5-HT1B/1D receptors.
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pharmacological characterization of ergotamine induced inhibition of the cardioaccelerator sympathetic outflow in pithed rats
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Luis E Cobospuc, Martha B Ramirezrosas, Tilo Gornemann, Heinz H. Pertz, Jair Lozanocuenca, Araceli Sanchezlopez, Carlos M. Villalón, David CenturionAbstract:Ergotamine inhibits the sympathetically-induced tachycardia in pithed rats. The present study identified the pharmacological profile of this response. Male Wistar rats were pithed and prepared to stimulate the preganglionic (C7–T1) cardiac sympathetic outflow. Intravenous continuous infusions of ergotamine dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using several antagonists, the sympatho-inhibition to ergotamine was: (1) partially blocked by Rauwolscine (α2), haloperidol (D1/2-like) or Rauwolscine plus GR127935 (5-HT1B/1D); (2) abolished by Rauwolscine plus haloperidol; and (3) unaffected by either saline or GR127935. In animals systematically pretreated with haloperidol, this sympatho-inhibition was: (1) unaffected by BRL44408 (α2A), partially antagonized by MK912 (α2C); and (3) abolished by BRL44408 plus MK912. These antagonists failed to modify the sympathetically induced tachycardic responses per se. Thus, the cardiac sympatho-inhibition by ergotamine may be mainly mediated by α2A/α2C-adrenoceptors, D2-like receptors and, to a lesser extent, by 5-HT1B/1D receptors.
Abimael Gonzalezhernandez - One of the best experts on this subject based on the ideXlab platform.
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dihydroergotamine inhibits the vasodepressor sensory cgrpergic outflow by prejunctional activation of α2 adrenoceptors and 5 ht1 receptors
Journal of Headache and Pain, 2018Co-Authors: Jair Lozanocuenca, Abimael Gonzalezhernandez, Antoinette Maassenvandenbrink, Bruno A Marichalcancino, Carlos M. VillalónAbstract:Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow. Pithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure. DHE inhibited the vasodepressor responses to electrical stimulation (0.56–5.6 Hz), without affecting those to i.v. α-CGRP (0.1–1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists Rauwolscine (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after Rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-like; 310 μg/kg) given alone, or after the combination of Rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses. DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional Rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE’s vasoconstrictor properties resulting in an increased vascular resistance.
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pharmacological profile of the inhibition by dihydroergotamine and methysergide on the cardioaccelerator sympathetic outflow in pithed rats
European Journal of Pharmacology, 2009Co-Authors: Jair Lozanocuenca, Heinz H. Pertz, Araceli Sanchezlopez, David Centurion, Luis E Cobospuc, Enriqueta Munozislas, Abimael Gonzalezhernandez, Carlos M. VillalónAbstract:Abstract The present study set out to analyse the pharmacological profile of the inhibitory responses induced by the antimigraine agents dihydroergotamine (DHE) and methysergide on the tachycardic responses to preganglionic sympathetic stimulation in pithed rats. For this purpose, 132 male Wistar normotensive rats were pithed and prepared to: (i) selectively stimulate the preganglionic (C7–T1) cardiac sympathetic outflow; or (ii) receive intravenous (i.v.) bolus injections of exogenous noradrenaline. Electrical sympathetic stimulation or exogenous noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. Moreover, i.v. continuous infusions of DHE (1.8, 3.1 and 5.6 µg/kg.min) or methysergide (100, 300 and 1000 µg/kg.min) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using physiological saline or antagonists (given as i.v. bolus injections), the cardiac sympatho-inhibition induced by either DHE (3.1 µg/kg.min) or methysergide (300 µg/kg.min) was: (1) unaffected by saline (1 ml/kg); (2) partially blocked by the antagonists Rauwolscine (300 µg/kg; α2) or N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1,-biphenyl]-4-carboxamide hydrochloride monohydrate (GR127935, 300 µg/kg; 5-HT1B/1D); and (3) completely antagonised by the combination Rauwolscine plus GR127935. These antagonists, at doses high enough to completely block their respective receptors, failed to modify the sympathetically-induced tachycardic responses per se. The above results, taken together, suggest that the cardiac sympatho-inhibition induced by DHE (3.1 µg/kg.min) and methysergide (300 µg/kg.min) may be mainly mediated by stimulation of both α2-adrenoceptors and 5-HT1B/1D receptors.
Antoinette Maassenvandenbrink - One of the best experts on this subject based on the ideXlab platform.
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Functional Characterization of the Prejunctional Receptors Mediating the Inhibition by Ergotamine of the Rat Perivascular Sensory Peptidergic Drive
2019Co-Authors: Abimael González-hernández, Antoinette Maassenvandenbrink, Jair Lozano-cuenca, Bruno A. Marichal-cancino, Carlos M. VillalónAbstract:Calcitonin gene-related peptide (α-CGRP) released from perivascular sensory nerves induces decreases in diastolic blood pressure (DBP). Experimentally, this can be shown by spinal thoracic (T9–T12) electrical stimulation of these afferent fibers. Because ergotamine inhibits these neurogenic vascular responses and displays affinity for monoaminergic receptors that inhibit neurotransmitter release, we investigated whether this ergotamine-induced inhibition results from activation of serotonin 5-HT1B/1D, dopamine D2-like, and α2-adrenergic receptors. Wistar rats were pithed and, under autonomic ganglion blockade, received intravenous infusions of methoxamine followed by ergotamine (0.1–3.1 μg kg–1 min–1). Thoracic T9–T12 electrical stimulation or an intravenous bolus of α-CGRP resulted in decreases in DBP. Ergotamine inhibited the electrically induced, but not α-CGRP-induced, responses. The vasodilator sensory inhibition by 3.1 μg of ergotamine kg–1 min–1 was resistant to simultaneous blockade of 5-HT1B/1D, D2-like, and α2-adrenergic receptors upon addition of antagonists GR127935, haloperidol, and Rauwolscine. Moreover, the inhibition by 0.31 μg of ergotamine kg–1 min–1 was unaltered by GR127935 and haloperidol, partly blocked by GR127935 and Rauwolscine or Rauwolscine and haloperidol, and abolished by GR127935, haloperidol, and Rauwolscine. These findings imply that prejunctional 5-HT1B/1D, D2-like, and α2-adrenergic receptors mediate the sensory inhibition induced by 0.31 μg of ergotamine kg–1 min–1, whereas larger doses may involve other receptors. Thus, ergotamine’s ability to inhibit the perivascular sensory peptidergic drive may result in facilitation of its systemic vasoconstrictor properties
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dihydroergotamine inhibits the vasodepressor sensory cgrpergic outflow by prejunctional activation of α2 adrenoceptors and 5 ht1 receptors
Journal of Headache and Pain, 2018Co-Authors: Jair Lozanocuenca, Abimael Gonzalezhernandez, Antoinette Maassenvandenbrink, Bruno A Marichalcancino, Carlos M. VillalónAbstract:Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow. Pithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure. DHE inhibited the vasodepressor responses to electrical stimulation (0.56–5.6 Hz), without affecting those to i.v. α-CGRP (0.1–1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists Rauwolscine (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after Rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-like; 310 μg/kg) given alone, or after the combination of Rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses. DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional Rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE’s vasoconstrictor properties resulting in an increased vascular resistance.
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Additional file 1: of Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors
2018Co-Authors: Abimael González-hernández, Antoinette Maassenvandenbrink, Jair Lozano-cuenca, Bruno Marichal-cancino, Carlos VillalónAbstract:Figure S1. Effect per se of i.v. bolus injections of: (a) saline (1 ml/kg); (b) Rauwolscine (310 μg/kg); (c) GR127935 (31 μg/kg); or (d) haloperidol (310 μg/kg) given separately; as well as the combinations (e) Rauwolscine plus GR127935 (310 and 31 μg/kg, respectively); (f) Rauwolscine plus haloperidol (310 μg/kg each); or (g) GR127935 plus haloperidol (31 and 310 μg/kg, respectively) on the electrically-induced vasodepressor responses produced during an i.v. continuous infusion of methoxamine (20 μg/kg. min) (n = 5 for each group). No significant effects were produced after administration of compounds (P > 0.05). (PDF 881 kb
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the role of α1 and α2 adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin pretreated pithed rats
Journal of Headache and Pain, 2017Co-Authors: Eduardo Riveramancilla, Victor H Avilesrosas, Guadalupe Manriquemaldonado, Alain H Altamiranoespinoza, Belinda Villanuevacastillo, Antoinette Maassenvandenbrink, Carlos M. VillalónAbstract:Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors results in systemic vasopressor responses, the purpose of this study was to investigate the specific role of α1- and α2-adrenoceptors mediating DHE-induced vasopressor responses using several antagonists for these receptors. For this purpose, 135 male Wistar rats were pithed and divided into 35 control and 100 pretreated i.v. with ritanserin (100 μg/kg; to exclude the 5-HT2 receptor-mediated systemic vasoconstriction). Then, the vasopressor responses to i.v. DHE (1–3100 μg/kg, given cumulatively) were determined after i.v. administration of some α1/α2-adrenoceptor antagonists. In control animals (without ritanserin pretreatment), the vasopressor responses to DHE were: (i) unaffected after prazosin (α1; 30 μg/kg); (ii) slightly, but significantly, blocked after Rauwolscine (α2; 300 μg/kg); and (iii) markedly blocked after prazosin (30 μg/kg) plus Rauwolscine (300 μg/kg). In contrast, after pretreatment with ritanserin, the vasopressor responses to DHE were: (i) attenuated after prazosin (α1; 10 and 30 μg/kg) or Rauwolscine (α2; 100 and 300 μg/kg); (ii) markedly blocked after prazosin (30 μg/kg) plus Rauwolscine (300 μg/kg); (iii) attenuated after 5-methylurapidil (α1A; 30–100 μg/kg), L-765,314 (α1B; 100 μg/kg), BMY 7378 (α1D; 30–100 μg/kg), BRL44408 (α2A; 100–300 μg/kg), imiloxan (α2B; 1000–3000 μg/kg) or JP-1302 (α2C; 1000 μg/kg); and (iv) unaffected after the corresponding vehicles (1 ml/kg). These results suggest that the DHE-induced vasopressor responses in ritanserin-pretreated pithed rats are mediated by α1- (probably α1A, α1B and α1D) and α2- (probably α2A, α2B and α2C) adrenoceptors. These findings could shed light on the pharmacological profile of the vascular side effects (i.e. systemic vasoconstriction) produced by DHE and may lead to the development of more selective antimigraine drugs devoid vascular side effects.
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Pharmacological characterization of the inhibition by moxonidine and agmatine on the cardioaccelerator sympathetic outflow in pithed rats
European Journal of Pharmacology, 2009Co-Authors: Luis E. Cobos-puc, Carlos M. Villalón, Antoinette Maassenvandenbrink, Jair Lozano-cuenca, Martha B. Ramírez-rosas, Araceli Sánchez-lópez, Gómez-díaz B, David CenturionAbstract:Abstract This study analysed the inhibition produced by the agonists moxonidine (imidazoline I1 receptors > α2-adrenoceptors) and agmatine (endogenous ligand of imidazoline I1/I2 receptors), 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 I1 receptors] or BU224 (2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride; 300 µg/kg; imidazoline I2 receptors) 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 I1 receptors.
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5 ht1b receptors α2a 2c and to a lesser extent α1 adrenoceptors mediate the external carotid vasoconstriction to ergotamine in vagosympathectomised dogs
Naunyn-schmiedebergs Archives of Pharmacology, 2004Co-Authors: Luis Felipe Valdivia, David Centurion, Pramod R. Saxena, Udayasankar Arulmani, Carlos M. VillalónAbstract:It has previously been suggested that ergotamine produces external carotid vasoconstriction in vagosympathectomised dogs via 5-HT1B/1D receptors and α2-adrenoceptors. The present study has reanalysed this suggestion by using more selective antagonists alone and in combination. Fifty-two anaesthetised dogs were prepared for ultrasonic measurements of external carotid blood flow. The animals were divided into thirteen groups (n=4 each) receiving an i.v. bolus injection of, either physiological saline (0.3 ml/kg; control), or the antagonists SB224289 (300 μg/kg; 5-HT1B), BRL15572 (300 µg/kg; 5-HT1D), Rauwolscine (300 µg/kg; α2), SB224289 + BRL15572 (300 µg/kg each), SB224289 + Rauwolscine (300 µg/kg each), BRL15572 + Rauwolscine (300 µg/kg each), Rauwolscine (300 µg/kg) + prazosin (100 µg/kg; α1), SB224289 (300 µg/kg) + prazosin (100 µg/kg), SB224289 (300 µg/kg) + Rauwolscine (300 µg/kg) + prazosin (100 µg/kg), SB224289 (300 µg/kg) + prazosin (100 µg/kg) + BRL44408 (1,000 µg/kg; α2A), SB224289 (300 µg/kg) + prazosin (100 µg/kg)+ imiloxan (1,000 µg/kg; α2B), or SB224289 (300 µg/kg) + prazosin (100 µg/kg) + MK912 (300 µg/kg; α2C). Each group received consecutive 1-min intracarotid infusions of ergotamine (0.56, 1, 1.8, 3.1, 5.6, 10 and 18 µg/min), following a cumulative schedule. In saline-pretreated animals, ergotamine induced dose-dependent decreases in external carotid blood flow without affecting arterial blood pressure or heart rate. These control responses were: unaffected by SB224289, BRL15572, Rauwolscine or the combinations of SB224289 + BRL15572, BRL15572 + Rauwolscine, Rauwolscine + prazosin, SB224289 + prazosin, or SB224289 + prazosin + imiloxan; slightly blocked by SB224289 + Rauwolscine; and markedly blocked by SB224289 + Rauwolscine + prazosin, SB224289 + prazosin + BRL44408 or SB224289 + prazosin + MK912. Thus, the cranio-selective vasoconstriction elicited by ergotamine in dogs is predominantly mediated by 5-HT1B receptors as well as α2A/2C-adrenoceptor subtypes and, to a lesser extent, by α1-adrenoceptors.
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Pharmacological analysis of the mechanisms involved in the tachycardic and vasopressor responses to the antimigraine agent, isometheptene, in pithed rats
Life sciences, 2004Co-Authors: Luis Felipe Valdivia, David Centurion, Pramod R. Saxena, Mercedes Perusquía, Udayasankar Arulmani, Carlos M. VillalónAbstract:Abstract The present study set out to investigate the pharmacological profile of the cardiovascular responses induced by the antimigraine agent, isometheptene, in pithed rats. For this purpose, intravenous (i.v.) administration of blocking doses of the antagonists prazosin (α 1 ; 100 μg/kg), Rauwolscine (α 2 ; 300 μg/kg), the combination of prazosin (100 μg/kg) plus Rauwolscine (300 μg/kg), propranolol (β; 1000 μg/kg), ritanserin (5-HT 2 ; 100 μg/kg) or equivalent volumes of saline (1 ml/kg) were used. Isometheptene (0.03, 0.1, 0.3, 1 and 3 mg/kg, i.v.) produced dose-dependent increases in heart rate and diastolic blood pressure which were highly reproducible as they remained unaltered after saline. These tachycardic responses to isometheptene remained unaffected after prazosin, Rauwolscine, ritanserin or the combination prazosin plus Rauwolscine, but were abolished after propranolol. In contrast, the isometheptene-induced vasopressor responses were not significantly modified after the above doses of Rauwolscine, ritanserin or propranolol, but were markedly blocked after prazosin or the combination of prazosin plus Rauwolscine; the latter blockade did not significantly differ from that produced by prazosin alone. Interestingly, in rats pretreated intraperitoneally (i.p.) with reserpine (5 mg/kg; −24 h), isometheptene-induced tachycardic responses were abolished whereas the corresponding vasopressor responses were markedly attenuated and subsequently blocked by prazosin. It is concluded that isometheptene-induced tachycardic responses seem to involve only an indirect (tyramine-like action) mechanism mediated by β-adrenoceptors, whilst the corresponding vasopressor responses are mediated by a predominantly indirect (tyramine-like action), as well as a minor direct (α 1 -adrenoceptors), sympathomimetic mechanism.
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5 ht1b receptors and α2a 2c adrenoceptors mediate external carotid vasoconstriction to dihydroergotamine
European Journal of Pharmacology, 2004Co-Authors: Carlos M. Villalón, David Centurion, Pramod R. Saxena, Udayasankar Arulmani, Edwin W Willems, Luis Felipe ValdiviaAbstract:Abstract Dihydroergotamine produces external carotid vasoconstriction in vagosympathectomized dogs by 5-HT1B/1D receptors and α2-adrenoceptors. This study identified the specific subtypes involved in this response. One-minute intracarotid infusions of dihydroergotamine (5.6–10 μg/min) dose-dependently decreased external carotid blood flow without affecting blood pressure or heart rate. This response was: (1) partly blocked in dogs pretreated intravenously with the antagonists SB224289 (5-HT1B; 2,3,6,7-tetrahydro-1′-methyl-5-[2′-methyl-4′ (5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]furo[2,3-f]indole-3-spiro-4′-piperidine hydrochloride), Rauwolscine (α2), BRL44408 (α2A; 2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole) or MK912 (α2C; (2S,12bS)-1′3′-dimethylspiro(1,3,4,5′,6,6′,7,12b-octahydro-2Hbenzo[b]furo[2,3-a]quinazoline)-2,4′-pyrimidin-2′-one); (2) markedly blocked after SB224289 plus Rauwolscine; and (3) unaffected after BRL15572 (5-HT1D; 1-(3-chlorophenyl)-4-[3,3-diphenyl (2-(S,R) hydroxypropanyl) piperazine] hydrochloride) or imiloxan (α2B). Therefore, the above response involves 5-HT1B receptors and α2A/2C-adrenoceptors.
