Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hipertensão/induzido quimicamente , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/efeitos adversos , Adulto , Idoso , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Paclitaxel/uso terapêuticoRESUMO
Previous work showed that axotomy-induced deafferentation of the placode-derived visceral afferent neurons of the nodose ganglion altered their expression of some neuropeptides and tyrosine hydroxylase. The present studies were designed to selectively evaluate the loss of axonal transport on the numbers of vasoactive intestinal polypeptide, tyrosine hydroxylase, and calcitonin gene-related peptide mRNA-containing and immunoreactive neurons in the nodose ganglion of the adult rat. Vinblastine (0.15 mM) application to the cervical vagus nerve was used to block axonal transport between ganglionic perikarya and peripheral targets. In situ hybridization histochemistry with 35S-labeled oligonucleotide probes was used to both quantify the number of mRNA-containing neurons and to assess the density of mRNA expression per neuron, and immunocytochemistry was used to visualize the number of immunoreactive neurons. The efficacy of vinblastine to inhibit axonal transport was verified by evaluating the build-up of calcitonin gene-related peptide immunoreactive in the vagus nerve immediately rostral to the site of drug application. The absence of vinblastine-induced neuronal damage was verified by the relative absence of degenerating nerves in the vagus nerve caudal to the site of drug application. Vinblastine treatment of the vagus nerve increased the numbers of vasoactive intestinal peptide mRNA-containing neurons and vasoactive intestinal peptide-immunoreactive neurons in the nodose ganglion at three, seven and 14 days, and increased the numbers of calcitonin gene-related peptide mRNA-containing and calcitonin gene-related peptide-immunoreactive neurons in the nodose ganglion at one, three and seven days. The average labeling density of vasoactive intestinal peptide mRNA-containing neurons was also increased following vinblastine treatment. Vinblastine treatment of the cervical vagus nerve, however, led to the appearance of low-labeling density calcitonin gene-related peptide mRNA-neurons and resulted in reduction of the average labeling density for calcitonin gene-related peptide mRNA-containing neurons. In contrast, application of vinblastine to the cervical vagus nerve, decreased the number of tyrosine hydroxylase mRNA-containing and tyrosine hydroxylase-immunoreactive neurons in the nodose ganglion. In summary, inhibition of the axoplasmic transport between the periphery and the visceral sensory perikarya appeared to alter vasoactive intestinal peptide, calcitonin gene-related peptide, and tyrosine hydroxylase expression and content in visceral sensory neurons of the nodose ganglion. These data suggest the presence of an axonally transported influence on the regulation of neuropeptide and neurotransmitter enzyme synthesis in mature placode-derived visceral sensory neurons.
Assuntos
Transporte Axonal/fisiologia , Neurônios Aferentes/metabolismo , Neuropeptídeos/biossíntese , Gânglio Nodoso/metabolismo , RNA Mensageiro/biossíntese , Tirosina 3-Mono-Oxigenase/biossíntese , Nervo Vago/fisiologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/biossíntese , Imuno-Histoquímica , Hibridização In Situ , Masculino , Neurônios Aferentes/efeitos dos fármacos , Gânglio Nodoso/citologia , Gânglio Nodoso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Radioisótopos de Enxofre , Nervo Vago/efeitos dos fármacos , Peptídeo Intestinal Vasoativo/biossíntese , Vimblastina/farmacologiaRESUMO
Serotonin-1A (5-HT1A) binding sites were previously localized in several regions of the ventral medulla associated with neural regulation of the cardiovascular system. Some of these binding sites were associated with serotonergic neurons of the ventral medulla. The purpose of these studies was to assess and characterize hypotensive responses to a 5-HT1A agonist, (8-hydroxy-dipropylaminotetraline, 8-OH-DPAT), administered to the ventral medulla of the rat, to correlate the responsive ventral medullary sites with the distribution of 3H-8-OH-DPAT binding sites, and to assess the role of serotonergic systems in mediating the hypotensive responses. Ventral medullary application of 8-OH-DPAT caused dose-related reductions in mean arterial pressure and heart rate which were mediated by the autonomic nervous system. The hypotensive response to 8-OH-DPAT was attenuated by pretreatment with the 5-HT1A antagonists, spiperone or NAN-190. Microinjections of 8-OH-DPAT into ventral medullary structures revealed that 8-OH-DPAT responsive sites included the raphe pallidus, the parapyramidal region, and the rostral ventrolateral medulla. The role of serotonergic terminals in mediating the responses of 8-OH-DPAT was evaluated in animals pretreated with the serotonin nerve toxin, 5,7-dihydroxytryptamine (5,7-DHT). Cardiovascular responses to ventral medullary application of 8-OH-DPAT were unaffected by the selective depletion of serotonin. Thus, whereas the hypotensive responses elicited by 8-OH-DPAT in the raphe pallidus and parapyramidal region may involve serotonergic neurons, other non-serotonergic sites (e.g. the rostral ventrolateral medulla) can mediate the hypotensive actions of 8-OH-DPAT.
Assuntos
Pressão Sanguínea/fisiologia , Bulbo/metabolismo , Receptores de Serotonina/fisiologia , 5,7-Di-Hidroxitriptamina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Bloqueio Nervoso Autônomo , Sítios de Ligação , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Microinjeções , Ratos , Ratos Sprague-Dawley , Antagonistas da SerotoninaRESUMO
The presence of 5-hydroxytryptamine (5-HT)1C/2 binding sites in autonomic regions of the thoracic spinal cord and their role in the regulation of sympathetic outflow to the cardiovascular system were examined. Light microscopic receptor autoradiography was used to visualize the binding of the 5-HT1C/2 ligand, [125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [( 125I]DOI). In thoracic spinal cord, a discrete and preferential localization of specific [125I]DOI binding sites was found in the intermediolateral cell column. To determine the mean arterial pressure (MAP) and heart rate (HR) effects resulting from activation of 5-HT1C/2 receptors in spinal cord, DOI and alpha-methyl-5-HT were administered intrathecally (i.t.) to anesthetized, artificially ventilated rats. DOI (1-100 micrograms) caused initial decreases followed by increases in MAP and HR, whereas alpha-methyl-5-HT (1-30 micrograms) only decreased MAP and HR. The distribution of [125I]DOI after i.t. administration and the effects of a peripherally administered 5-HT1C/2 antagonist 6-methyl-1-(1-methylethyl)-ergoline-8 beta-carboxylic acid, 2-hydroxyl-1-methyl propyl ester and maleate salt (LY53857) showed that the pressor effects of i.t. DOI were due to peripheral leakage and suggested that the depressor effects were due to a spinal site of action. The depressor effects of DOI were prevented by peripheral administration of phentolamine. Pretreatment with i.t. administration of 5-HT1C/2 antagonists (LY53857, ketanserin and mianserin) did not block the depressor or bradycardic effects of i.t. administration of DOI. Only LY53857 was effective in blocking the depressor effects of i.t. administration of alpha-methyl-5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Sistema Cardiovascular/inervação , Serotonina/fisiologia , Medula Espinal/efeitos dos fármacos , Anfetaminas/metabolismo , Anfetaminas/farmacologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiologia , Autorradiografia , Sítios de Ligação , Injeções Espinhais , Masculino , Ratos , Ratos Endogâmicos , Receptores de Serotonina/metabolismo , Receptores de Serotonina/fisiologia , Serotonina/análogos & derivados , Serotonina/metabolismo , Serotonina/farmacologia , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Medula Espinal/fisiologia , Medula Espinal/ultraestrutura , Sistema Nervoso Simpático/fisiologiaRESUMO
Local spinal cord vasomotor effects of 3 substance P (SP) antagonists were studied in the rat following intrathecal (IT) administration. Each SP antagonist (3.3 nmol) increased spinal cord vascular resistance and reduced blood flow. A LH-RH antagonist analog (10 nmol) of similar molecular weight and which also contained multiple D-Trp residues did not cause spinal cord vasoconstriction. The vasoconstrictor action of the SP antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP [( D-Arg]-SP) was unaffected by pretreatment with a stable SP receptor agonist (5 nmol IT). Given evidence for a cerebral vasodilator action of TRH agonists, the effects of TRH (IV) and a stable TRH analog (MK-771, IT) on [D-Arg]-SP-induced vasoconstriction were also assessed. Neither TRH nor MK-771 prevented the [D-Arg]-SP-induced vasoconstriction. However, TRH (IV) but not MK-771 (IT) partially opposed [D-Arg]-SP-induced reduction in thoracic spinal cord blood flow. Thus, SP antagonists cause spinal cord vasoconstriction by a non-SP receptor mediated phenomenon. In addition, the attenuation of SP-antagonist-induced neuropathological changes previously reported with IV. TRH administration is likely due to less severe consequences of vasoconstriction in the presence of a higher initial baseline blood flow rather than direct prevention of the vasoconstriction.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Medula Espinal/irrigação sanguínea , Substância P/análogos & derivados , Substância P/antagonistas & inibidores , Hormônio Liberador de Tireotropina/farmacologia , Vasoconstrição/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Masculino , Dados de Sequência Molecular , Ratos , Ratos Endogâmicos , Valores de Referência , Fluxo Sanguíneo Regional/efeitos dos fármacos , Relação Estrutura-Atividade , Substância P/farmacologia , Resistência Vascular/efeitos dos fármacosRESUMO
Cardiovascular and regional hemodynamic effects of the intrathecal (i.t.) administration of a thyrotropin-releasing hormone (TRH) analog, MK-771 (L-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide), were studied in rats. MK-771 (0.01-5.0 micrograms i.t.) caused dose-related increases in mean arterial pressure (MAP) and heart rate (HR). TRH (10 micrograms i.t.), but not TRH-free acid, produced similar cardiovascular effects. The MAP response to MK-771 (i.t.) remained primarily intact after cervical spinal cord transection, whereas the HR response was attenuated (37% of control). The MAP response to MK-771 was blocked by peripheral administration of pentolinium or phentolamine, and was partially attenuated by adrenalectomy. The HR response was reduced by pentolinium or atropine. Assessment of changes in regional blood flow and vascular resistance with the radioactive microsphere technique showed that MK-771 increased total peripheral resistance and vasoconstricted cutaneous, skeletal muscle, adrenal, renal and intestinal vascular beds. Cardiac output and stroke volume were not altered. MK-771 had no effect on vascular resistance locally or in other central nervous system structures. However, blood flow was elevated by MK-771 in spinal cord and brain. These data show that TRH receptor activation in the thoracic spinal cord, presumably in the intermediolateral cell column, elevated MAP by increased sympathetic activity to the peripheral vasculature and the adrenals. However, the HR response to TRH receptor activation required a supra-spinal component and was mediated in part by vagal inhibition.
Assuntos
Glândulas Suprarrenais/inervação , Pressão Sanguínea , Receptores de Neurotransmissores/metabolismo , Medula Espinal/metabolismo , Sistema Nervoso Simpático/fisiologia , Hormônio Liberador de Tireotropina/análogos & derivados , Glândulas Suprarrenais/efeitos dos fármacos , Adrenalectomia , Animais , Bloqueio Nervoso Autônomo , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Injeções Espinhais , Masculino , Ratos , Ratos Endogâmicos , Receptores do Hormônio Liberador da Tireotropina , Fluxo Sanguíneo Regional , Sistema Nervoso Simpático/efeitos dos fármacos , Tiazolidinas , Hormônio Liberador de Tireotropina/administração & dosagem , Hormônio Liberador de Tireotropina/farmacologia , Resistência Vascular/efeitos dos fármacosRESUMO
Regional CNS and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P receptor agonist, [pGlu5,MePhe8,MeGly9]-substance P5-11 ([DiMe]-SP), were studied in anesthetized rats with the radioactive microsphere technique. It was previously shown that [DiMe]-SP caused a sympathetically mediated increase in mean arterial pressure (MAP) by an action within the spinal cord. In this study, [DiMe]-SP (5 and 33 nmol, i.t.) increased MAP. The 5 nmol dose increased resistance in cutaneous, renal, splanchnic, and adrenal vascular beds but decreased resistance, and increased blood flow in some skeletal muscle beds. Total peripheral resistance was unchanged. The 33 nmol dose increased resistance in each peripheral vascular bed analyzed and increased total peripheral resistance. Whereas each dose increased heart rate, stroke volume and cardiac output were unchanged with the 5 nmol dose and were reduced with the 33 nmol dose. Neither dose of [DiMe]-SP significantly altered regional brain or spinal cord blood flows. These data show that the i.t. administration of the SP agonist, [DiMe]-SP, increased vascular tone to most peripheral vascular beds whereas the low dose caused a vasodilation of skeletal muscle. These effects are consistent with the notion of a dose-related activation of SP receptors in the spinal cord affecting sympathetic outflow to the adrenals and to the vasculature.
Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Fragmentos de Peptídeos , Receptores de Neurotransmissores/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Medula Espinal/irrigação sanguínea , Substância P/análogos & derivados , Animais , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Injeções Espinhais , Masculino , Ácido Pirrolidonocarboxílico/análogos & derivados , Ratos , Ratos Endogâmicos , Receptores da Neurocinina-1 , Volume Sistólico/efeitos dos fármacos , Substância P/administração & dosagem , Substância P/farmacologia , Resistência Vascular/efeitos dos fármacosRESUMO
Regional central nervous system and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P (SP) receptor antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P ([D-Arg]-SP), were studied in anesthetized rats. It was found that [D-Arg]-SP (3.3 nmol i.t.) reduced mean arterial pressure and cardiac output due to a reduction in stroke volume. Total peripheral resistance was not altered. Whereas most vascular beds showed no alterations in vascular resistance, a renal vasoconstriction was noted. The hypotensive effect of [D-Arg]-SP was blocked by phentolamine (10 mg/kg i.v.) but not by propranolol (1 mg/kg i.v.). In the absence of changes in vascular arterial resistance due to [D-Arg]-SP, it appears that a change in venous return may contribute to the [D-Arg]-SP-induced reduction in stroke volume. These data provide evidence that a spinal cord SP system may tonically affect sympathetic neurons controlling venous, but not arterial, vasomotor tone. [D-Arg]-SP (i.t.) did not alter brain blood flow but significantly decreased blood flow in the thoracolumbar spinal cord 15 to 20 min after administration. The reduction in spinal cord flow did not appear to be responsible for the [D-Arg]-SP-induced hypotension because kainic acid (i.t.), an agent that interacts with glutamate receptors, produced similar pressor responses in the presence and absence of [D-Arg]-SP. In addition, whereas the pressor effect of low doses of a SP agonist [pGlu5, MePhe8, MeGly9]-substance P (5-11) were blocked by [D-Arg]-SP, a higher dose produced the typical pressor effect.(ABSTRACT TRUNCATED AT 250 WORDS)