RESUMO
Purine nucleosides (adenosine) and nucleotides such as adenosine mono/di/triphosphate (AMP/ADP/ATP) may produce complex cardiovascular responses. For example, adenosine-5'-(ß-thio)-diphosphate (ADPßS; a stable synthetic analogue of ADP) can induce vasodilatation/vasodepressor responses by endothelium-dependent and independent mechanisms involving purinergic P2Y receptors; however, the specific subtypes participating in these responses remain unknown. Therefore, this study investigated the receptor subtypes mediating the blood pressure changes induced by intravenous bolus of ADPßS in male Wistar rats in the absence and presence of central mechanisms with the antagonists MRS2500 (P2Y1), PSB0739 (P2Y12), and MRS2211 (P2Y13). For this purpose, 120 rats were divided into 60 anaesthetised rats and 60 pithed rats, and further subdivided into four groups (n = 30 each), namely: (a) anaesthetised rats, (b) anaesthetised rats with bilateral vagotomy, (c) pithed rats, and (d) pithed rats continuously infused (intravenously) with methoxamine (an α1-adrenergic agonist that restores systemic vascular tone). We observed, in all four groups, that the immediate decreases in diastolic blood pressure produced by ADPßS were exclusively mediated by peripheral activation of P2Y1 receptors. Nevertheless, the subsequent increases in systolic blood pressure elicited by ADPßS in pithed rats infused with methoxamine probably involved peripheral activation of P2Y1, P2Y12, and P2Y13 receptors.
RESUMO
5-Hydroxytryptamine (5-HT), or serotonin, plays a crucial role as a neuromodulator and/or neurotransmitter of several nervous system functions. Its actions are complex, and depend on multiple factors, including the type of effector or receptor activated. Briefly, 5-HT can activate: (i) metabotropic (G-protein-coupled) receptors to promote inhibition (5-HT1, 5-HT5) or activation (5-HT4, 5-HT6, 5-HT7) of adenylate cyclase, as well as activation (5-HT2) of phospholipase C; and (ii) ionotropic receptor (5-HT3), a ligand-gated Na+/K+ channel. Regarding blood pressure regulation (and beyond the intricacy of central 5-HT effects), this monoamine also exerts direct postjunctional (on vascular smooth muscle and endothelium) or indirect prejunctional (on autonomic and sensory perivascular nerves) effects. At the prejunctional level, 5-HT can facilitate or preclude the release of autonomic (e.g., noradrenaline and acetylcholine) or sensory (e.g., calcitonin gene-related peptide) neurotransmitters facilitating hypertensive or hypotensive effects. Hence, we cannot formulate a specific impact of 5-HT on blood pressure level, since an increase or decrease in neurotransmitter release would be favoured, depending on the type of prejunctional receptor involved. This review summarizes and discusses the current knowledge on the prejunctional mechanisms involved in blood pressure regulation by 5-HT and its impact on some vascular-related diseases.
RESUMO
Calcitonin gene-related peptide (CGRP), an endogenous neuropeptide released from perivascular sensory nerves, exerts a powerful vasodilatation. Interestingly, adenosine triphosphate (ATP) stimulates the release of CGRP by activation of prejunctional P2X2/3 receptors, and adenosine 5'-O-2-thiodiphosphate (ADPßS), a stable adenosine diphosphate (ADP) analogue, produces vasodilator/vasodepressor responses by endothelial P2Y1 receptors. Since the role of ADP in the prejunctional modulation of the vasodepressor sensory CGRPergic drive and the receptors involved remain unknown, this study investigated whether ADPßS inhibits this CGRPergic drive. Accordingly, 132 male Wistar rats were pithed and subsequently divided into two sets. In set 1, ADPßS (5.6 and 10 µg/kg·min) inhibited the vasodepressor CGRPergic responses by electrical stimulation of the spinal T9-T12 segment. This inhibition by ADPßS (5.6 µg/kg·min) was reverted after i.v. administration of the purinergic antagonists MRS2500 (300 µg/kg; P2Y1) or MRS2211 (3000 µg/kg; P2Y13), but not by PSB0739 (300 µg/kg; P2Y12), MRS2211 (1000 µg/kg; P2Y13) or the KATP blocker glibenclamide (20 mg/kg). In set 2, ADPßS (5.6 µg/kg·min) failed to modify the vasodepressor responses to exogenous α-CGRP. These results suggest that ADPßS inhibits CGRP release in perivascular sensory nerves. This inhibition, apparently unrelated to activation of ATP-sensitive K+ channels, involves P2Y1 and probably P2Y13, but not P2Y12 receptors.
RESUMO
Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB1, CB2, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB1), AM630 (CB2), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoyletha-nolamide (0.1-3.1 µg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 µg/kg NIDA41020, 100 µg/kg capsazepine, or 31 µg/kg cannabidiol; (ii) unaffected by 310 µg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 µg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB1, TRPV1 and probably GPR55, but not by CB2, receptors.
Assuntos
Artérias/efeitos dos fármacos , Etanolaminas/farmacologia , Ácidos Palmíticos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Amidas , Animais , Artérias/inervação , Artérias/metabolismo , Estado de Descerebração , Estimulação Elétrica , Masculino , Norepinefrina/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Sistema Nervoso Simpático/fisiologia , Simpatomiméticos/farmacologia , Canais de Cátion TRPV/metabolismoRESUMO
ATP is a cotransmitter released with other neurotransmitters from sympathetic nerves, where it stimulates purinergic receptors. Purinergic adenosine P1 receptors (coupled to Gi/o proteins) produce sympatho-inhibition in several autonomic effectors by prejunctional inhibition of neurotransmitter release. Similarly, signalling through P2Y12 and P2Y13 receptors coupled to Gi/o proteins is initiated by the ATP breakdown product ADP. Hence, this study has pharmacologically investigated a possible role of ADP-induced inhibition of the cardioaccelerator sympathetic drive in pithed rats, using a stable ADP analogue (ADPßS) and selective antagonists for the purinergic P2Y1, P2Y12 and P2Y13 receptors. Accordingly, male Wistar rats were pithed and: (i) pretreated i.v. with gallamine (25 mg/kg) and desipramine (50 µg/kg) for preganglionic spinal (C7-T1) stimulation of the cardioaccelerator sympathetic drive (n = 78); or (ii) prepared for receiving i.v. injections of exogenous noradrenaline (n = 12). The i.v. continuous infusions of ADPßS (10 and 30 µg/kg/min) dose-dependently inhibited the tachycardic responses to electrical sympathetic stimulation, but not those to exogenous noradrenaline. The cardiac sympatho-inhibition produced by 30 µg/kg/min ADPßS was (after i.v. administration of compounds) (i) unchanged by 1-ml/kg bidistilled water or 300-µg/kg MRS 2500 (P2Y1 receptor antagonist), (ii) abolished by 300-µg/kg PSB 0739 (P2Y12 receptor antagonist) and (iii) partially blocked by 3000-µg/kg MRS 2211 (P2Y13 receptor antagonist). Our results suggest that ADPßS induces a cardiac sympatho-inhibition that mainly involves the P2Y12 receptor subtype and, probably to a lesser extent, the P2Y13 receptor subtype. These receptors may represent therapeutic targets for treating cardiovascular pathologies, including stroke and myocardial infarctions.
Assuntos
Difosfato de Adenosina/análogos & derivados , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Receptores Purinérgicos P2Y12/metabolismo , Receptores Purinérgicos P2/metabolismo , Sistema Nervoso Simpático/fisiologia , Tionucleotídeos/farmacologia , Difosfato de Adenosina/farmacologia , Animais , Masculino , Ratos , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
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.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Ergotamina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Sistema Nervoso Autônomo/fisiologia , Pressão Sanguínea/fisiologia , Antagonistas de Dopamina , Estimulação Elétrica , Haloperidol/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Ratos , Ratos Wistar , Antagonistas da Serotonina , Ioimbina/farmacologiaRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Assuntos
Di-Hidroergotamina/farmacologia , Receptores Adrenérgicos alfa 1/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Ritanserina/farmacologia , Vasoconstrição/fisiologia , Vasoconstritores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND: Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- isometheptene and (R)-isometheptene, and the pharmacological profile of the more potent enantiomer. METHODS: The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of isometheptene racemate, (S)-isometheptene or (R)-isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). RESULTS: Compared to (R)-isometheptene, (S)-isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. CONCLUSIONS: The different cardiovascular effects of the isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-isometheptene. Thus, (R)-isometheptene may represent a superior therapeutic benefit as an antimigraine agent.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Metilaminas/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Pressão Sanguínea/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Frequência Cardíaca/fisiologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Metilaminas/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Wistar , Estereoisomerismo , Sistema Nervoso Simpático/fisiologia , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêuticoRESUMO
The endocannabinoid system exhibits multiple functions in cardiovascular regulation mainly by cannabinoid (CB1 and CB2) receptors, vanilloid TRPV1 receptors and, probably, by the orphan G protein-coupled receptor 55 (GPR55). Hence, the role of these receptors was investigated in Wistar pithed rats on anandamide- and lysophosphatidylinositol (LPI)-induced inhibition of the vasopressor responses induced by preganglionic (T7-T9) stimulation of the vasopressor sympathetic outflow or i.v. bolus injections of noradrenaline. The corresponding frequency- and dose-dependent vasopressor responses were analyzed before and during i.v. continuous infusions of anandamide (CB1, CB2, TRPV1 and GPR55), JWH-015 (CB2) and LPI (GPR55) in animals receiving (i.v.) the antagonists NIDA41020 (CB1), AM630 (CB2), capsazepine (TRPV1) and/or cannabidiol (GPR55). Anandamide (0.1-3.1 µg/kg min) inhibited the vasopressor responses by electrical stimulation, but not those by noradrenaline; while LPI (5.6-10 µg/kg min) inhibited both responses. In contrast, JWH-015 (5.6-10 µg/kg min) failed to induce sympatho-inhibition. Anandamide-induced sympatho-inhibition was: (i) dose-dependently blocked by 31 and 100 µg/kg NIDA41020; (ii) slightly blocked by 310 µg/kg AM630 or 31 µg/kg cannabidiol; and (iii) unaffected by 310 µg/kg capsazepine. Moreover, LPI-induced inhibition of both vasopressor responses was blocked and abolished by 10 and 31 µg/kg cannabidiol, respectively, and weakly blocked by 100 µg/kg NIDA41020. Thus, the sympatho-inhibition by anandamide is primarily mediated by cannabinoid CB1 and, minimally, by cannabidiol-sensitive receptors. In contrast, LPI-induced inhibition of both responses seems to be mainly mediated by postjunctional cannabidiol-sensitive (presumably endothelial GPR55) receptors.
Assuntos
Ácidos Araquidônicos/farmacologia , Endocanabinoides/farmacologia , Lisofosfolipídeos/farmacologia , Norepinefrina/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Vasoconstritores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Desipramina/farmacologia , Estimulação Elétrica , Frequência Cardíaca/efeitos dos fármacos , Indóis/farmacologia , Masculino , Ratos , Ratos WistarRESUMO
It has been suggested that during a migraine attack trigeminal nerves release calcitonin gene-related peptide (CGRP), producing central nociception and vasodilatation of cranial arteries, including the extracranial branches of the external carotid artery. Since trigeminal inhibition may prevent this vasodilatation, the present study has investigated the effects of intrathecal dihydroergotamine on the external carotid vasodilatation to capsaicin, α-CGRP and acetylcholine. Anaesthetized vagosympathectomized dogs were prepared to measure blood pressure, heart rate and external carotid conductance. A catheter was inserted into the right common carotid artery for the continuous infusion of phenylephrine (to restore the carotid vascular tone), whereas the corresponding thyroid artery was cannulated for one-min intracarotid infusions of capsaicin, α-CGRP and acetylcholine (which dose-dependently increased the external carotid conductance). Another cannula was inserted intrathecally (C(1)-C(3)) for the administration of dihydroergotamine, the α(2)-adrenoceptor antagonist rauwolscine or the serotonin 5-HT(1B/1D) receptor antagonist GR127935 (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). Intrathecal dihydroergotamine (10, 31 and 100µg) inhibited the vasodilatation to capsaicin, but not that to α-CGRP or acetylcholine. This inhibition was: (i) unaffected by 10µg GR127935 or 100µg rauwolscine, but abolished by 31µg GR127935 or 310µg rauwolscine at 10µg dihydroergotamine; and (ii) abolished by the combination 10µg GR127935+100µg rauwolscine at 100µg dihydroergotamine. Thus, intrathecal (C(1)-C(3)) dihydroergotamine seems to inhibit the external carotid vasodilatation to capsaicin by spinal activation of serotonin 5-HT(1B/1D) (probably 5-HT(1B)) receptors and α(2) (probably α(2A/2C))-adrenoceptors.