RESUMO
BACKGROUND: Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors characterized by hemodynamic instability, caused by the paroxysmal release of catecholamines. Patients may develop cardiovascular complications in the perioperative phase due to the massive release of catecholamines, particularly during anesthetic induction and surgical manipulation of the tumor. The aim of this retrospective study was to evaluate the risk factors involved in perioperative hemodynamic instability in patients who underwent surgery for chromaffin tumors. METHODS: Forty patients (median age 55 [36.50-64.50]) undergone surgery for PHEO/abdominal PGL from January 2011 to December 2016 at the AOU Careggi (Florence, Italy) were retrospectively evaluated. Systolic, diastolic, and mean blood pressure were considered at baseline and during surgery. Patients with blood pressure steadily < 140/90 mmHg before surgery were considered "adequately prepared". A preoperative therapy with doxazosin, a selective alpha-1 blocker, was started in all patients for at least 14 days prior to the surgery. The presence of hemodynamic instability was reported. RESULTS: Comparing males and females, a significant difference in doxazosin daily dose (p = 0.018), systolic blood pressure (p = 0.048), and in the proportion of adequately prepared patients (p = 0.031) emerged. A positive correlation between preoperative daily dose of doxazosin, tumor size (B = 0.60, p < 0.001), and urinary normetanephrine levels (B = 0.64, p < 0.001) was also observed. Hemodynamic instability occurred in 30.0% of patients. The absence of adequate preparation (p = 0.012) before surgery, urinary normetanephrine levels (NMNur p = 0.039), and surgery time (minutes) (p = 0.021) resulted as risk factors of hemodynamic instability in our series. The use of intraoperative drugs was higher in patients with hemodynamic instability (p < 0.001). A pre-surgical SBP level of > 133 mmHg (OR = 6 CI95% 1.37-26.20, p = 0.017) and an intraoperative SBP and MBP levels of > 127 mmHg (OR = 28.80 CI95% 2.23-371.0, p = 0.010) and > 90 mmHg (OR = 18.90 CI95% 1.82-196.0, p = 0.014), respectively, were identified as effective thresholds to recognize patients at higher risk of HI. CONCLUSIONS: A preoperative therapy with alpha-blockers is useful, but not sufficient to avoid surgical risks. Patients with higher pre-surgical levels of NMNur, pre-surgical SBP > 133 mmHg, and/or intraoperative SBP > 127 mmHg and MBP > 90 mmHg, should be carefully monitored. A multidisciplinary approach is indispensable to optimize the management of PHEOs/abdominal PGLs in order to reduce surgical complications.
Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Doenças Vasculares , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Feocromocitoma/cirurgia , Feocromocitoma/patologia , Estudos Retrospectivos , Doxazossina/farmacologia , Normetanefrina/farmacologia , Paraganglioma/cirurgia , Paraganglioma/patologia , Hemodinâmica , Neoplasias das Glândulas Suprarrenais/cirurgia , Neoplasias das Glândulas Suprarrenais/patologia , Catecolaminas/farmacologiaRESUMO
Certain catecholamine metabolites exert significant pharmacological effects. Herein, we evaluated the pharmacological activities of catecholamine metabolites in the rat thoracic aorta, prostate, and spleen to determine whether these metabolites affect the contractile functions of smooth muscle tissue via direct action on α-adrenoceptors and α-adrenoceptor subtypes. Among the catecholamine metabolites examined, normetadrenaline and metadrenaline (10-4 M each) produced relatively strong contractions in the rat thoracic aorta. Maximum aortic contractions induced by normetadrenaline (≈70% of phenylephrine (3 × 10-7 M)-induced contractions) and metadrenaline (≈45%) were significantly smaller than those induced by phenylephrine (≈95%). Normetadrenaline and metadrenaline (10-4 M each) inhibited phenylephrine (3 × 10-7 M)-induced aortic contractions, which were not affected by propranolol (10-6 M), by 5-20%. Normetadrenaline- and metadrenaline (3 × 10-5 M each)-induced aortic contractions were strongly inhibited by prazosin (10-8 M; an α1-adrenoceptor antagonist) and BMY 7378 (10-8-10-7 M; a selective α1D-adrenoceptor antagonist). Metadrenaline (3 × 10-5 M)-induced aortic contractions were also significantly inhibited by silodosin (10-9 M; a selective α1A-adrenoceptor antagonist). Normetadrenaline and metadrenaline (3 × 10-5 M each) caused silodosin (10-9 M)-sensitive prostate contractions but did not cause a prominent spleen contraction. Maximum prostate contractions induced by metadrenaline (≈100% of phenylephrine (3 × 10-5 M)-induced contractions) were nearly identical to those induced by phenylephrine (≈100%) but were significantly larger than those induced by normetadrenaline (≈80%). These findings suggest that normetadrenaline and metadrenaline act as a partial α1D/α1A-adrenoceptor agonist and partial α1D-adrenoceptor/full α1A-adrenoceptor agonist, respectively, functioning as adrenaline system stabilizers in α1D/α1A-adrenoceptor-abundant smooth muscle tissues.
Assuntos
Aorta Torácica/efeitos dos fármacos , Metanefrina/farmacologia , Contração Muscular/efeitos dos fármacos , Normetanefrina/farmacologia , Próstata/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Relação Dose-Resposta a Droga , Masculino , Próstata/metabolismo , Próstata/fisiologia , Ratos , Ratos WistarRESUMO
Organic cation transporter 3 (OCT3) is a corticosterone-sensitive, low-affinity, high-capacity transporter. This transporter functions, in part, to clear monoamines, including serotonin (5-HT), from the extracellular space. The central nucleus of the amygdala (CeA) is an important structure controlling fear- and anxiety-related behaviors. The CeA has reciprocal connections with brainstem nuclei containing monoaminergic systems, including serotonergic systems arising from the dorsal raphe nucleus, which are thought to play an important role in modulation of CeA-mediated behavioral responses. Organic cation transporter 3 (OCT3) is expressed in the CeA, but little is known about the role of OCT3 within the CeA in modulating serotonergic signaling. We hypothesized that inhibition of OCT3-mediated transport in the CeA during restraint stress would increase extracellular 5-HT. In Experiment 1, rats received unilateral reverse dialysis of either corticosterone or normetanephrine, which interfere with OCT3-mediated transport, into the CeA under home cage control conditions. In Experiment 2, rats received unilateral reverse dialysis of corticosterone, normetanephrine, or vehicle into the CeA, while undergoing a 40-min period of restraint stress. Infusion of these drugs had no effect on extracellular concentrations of 5-HT during home cage control conditions, but, in contrast, markedly increased extracellular concentrations of 5-HT during restraint stress, relative to vehicle-treated controls. These findings suggest a role for OCT3 in the CeA in control of serotonergic signaling during stressful conditions.
Assuntos
Núcleo Central da Amígdala/efeitos dos fármacos , Núcleo Central da Amígdala/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Serotonina/metabolismo , Estresse Psicológico/tratamento farmacológico , Animais , Ansiedade/metabolismo , Corticosterona/farmacologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Medo/fisiologia , Masculino , Microdiálise , Normetanefrina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose-response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use.
Assuntos
Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Corticosterona/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Normetanefrina/farmacologia , Fator 3 de Transcrição de Octâmero/metabolismo , Animais , Cocaína/administração & dosagem , Corticosterona/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Normetanefrina/administração & dosagem , Fator 3 de Transcrição de Octâmero/antagonistas & inibidores , Fator 3 de Transcrição de Octâmero/deficiênciaRESUMO
Two distinct norepinephrine (NE) transporter mechanisms (uptake 1 and uptake 2) regulate extracellular NE concentrations. An association has been observed between the gradual improvement in patients treated with antidepressants that inhibit the NE transporter (NET/uptake 1) and increases in urinary normetanephrine, the O-methylated NE metabolite and potent inhibitor of uptake 2. These observations led to the hypothesis that increased levels of normetanephrine, and consequently inhibition of uptake 2, may partly be responsible for the clinical efficacy of some antidepressants. To investigate this hypothesis, we employed microdialysis techniques in the rat frontal cortex to monitor extracellular changes in normetanephrine following chronic administration of the clinically effective antidepressant, venlafaxine (a serotonin (5-HT) and NE reuptake inhibitor). We evaluated the neurochemical effects of inhibiting uptake 2 alone, or in conjunction with venlafaxine, on extracellular levels of NE and 5-HT. Chronic venlafaxine administration (14 days, 10 mg/kg, s.c.) elicited significant increases in cortical NE and 5-HT while producing a non-significant trend to increase cortical levels of normetanephrine. Additional studies revealed that combining normetanephrine with venlafaxine (10 mg/kg, i.p.), at a dose of normetanephrine (10 mg/kg, i.p.) that did not produce changes in extracellular levels of NE on its own, potentiated antidepressant-induced increases in extracellular NE. We also report mouse behavioral data involving the tail suspension test that complement the neurochemical observations. These preclinical findings, taken together, suggest that inhibiting both uptake 1 and uptake 2 via venlafaxine and normetanephrine, respectively, elicits a greater increase in cortical levels of NE than inhibiting either transporter alone.
Assuntos
Química Encefálica/efeitos dos fármacos , Cicloexanóis/farmacologia , Normetanefrina/metabolismo , Normetanefrina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Elevação dos Membros Posteriores/métodos , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Microdiálise , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Cloridrato de VenlafaxinaRESUMO
Rat liver slices were employed as experimental model to characterise the system involved in the transport process which participates in liver tyramine uptake. The uptake of 0.4 micromol l-1of [3H]tyramine by rat liver slices was linear from 5 min up to the end of incubation. At 15 min the uptake was 4.58+/-0.18 pmol mg-1protein. The accumulation of [3H]tyramine was sensitive to temperature (69. 3+/-4.0% inhibition at 0 degrees C, P<0.001), to sodium omission replaced by 150 mmol l-1Tris or 110 mmol l-1Tris+40 mmol l-1choline (27.6+/-6.0%, P<0.01, and 24.6+/-3.8% inhibition, P<0.01, respectively), and the inhibition of Na+-K+-adenosine triphosphatase by 150 micromol l-1ouabain (20.4+/-2.6% decrease, P<0.01). Uptake of [3H]tyramine was cocaine- (10 micromol l-1) and desipramine- (1 micromol l-1) dependent (32.2+/-6.4%, P<0.05, and 31.6+/-4.0% inhibition, P<0.05, respectively). Uptake of [3H]tyramine in rat liver slices was not modified by 30 micromol l-1isoprenaline, 30 micromol l-1corticosterone, 30 micromol l-1normetanephrine and noradrenaline up to 4 micrometers at higher noradrenaline concentrations tyramine transport was diminished (P<0.05). Results achieved by incubation with increasing tyramine concentrations indicate that at the micromolar level hepatic uptake occurs by a combined passive diffusion and transport-mediated mechanism, whereas at greater tyramine concentrations passive transport predominates. These results suggest that both simple diffusion and a transport-mediated mechanism are involved in this uptake from hepatocytes, which presents features similar to those described for type 1 non-neuronal uptake systems.
Assuntos
Fígado/metabolismo , Simpatomiméticos/farmacocinética , Tiramina/farmacocinética , Corticosteroides/farmacologia , Inibidores da Captação Adrenérgica , Animais , Sobrevivência Celular/efeitos dos fármacos , Cocaína/farmacologia , Desipramina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Isoproterenol/farmacologia , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Norepinefrina/farmacocinética , Normetanefrina/farmacologia , Ratos , Ratos Wistar , Sódio/farmacologia , Temperatura , Fatores de Tempo , TrítioRESUMO
Almost all bacteria require iron for growth and virulence expression. However, Listeria spp. do not produce any siderophore for iron acquisition. Representative strains of each of the six species of Listeria were examined for their ability to use various compounds as iron suppliers in iron-restricted medium. Here we show that L. monocytogenes, L. innocua, L. ivanovii, L. welshimeri, L. seeligeri, and L. grayi were able to use exogenous siderophores and various catechol ligands, including catecholamines, to overcome growth inhibition induced by tropolone, an iron chelating agent. In contrast, no growth promoting effect was observed with normetanephrine or 4-hydroxy-3-methoxyphenylglycol-piperazine salt, which indicates that the o-diphenol function of the ligand must be free to allow iron acquisition. Furthermore, we demonstrate that catecholamines do not act through specific bacterial receptors, because no difference in growth stimulation was observed between [+]- and [-]-norepinephrine. These results show that utilization of a variety of catechol compounds to acquire iron is a general phenomenon in the genus Listeria.
Assuntos
Catecolaminas/farmacologia , Catecóis/farmacologia , Ferro/administração & dosagem , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/crescimento & desenvolvimento , Sideróforos/farmacologia , Meios de Cultura , Quelantes de Ferro/farmacologia , Cinética , Metoxi-Hidroxifenilglicol/farmacologia , Norepinefrina/química , Norepinefrina/farmacologia , Normetanefrina/farmacologia , Estereoisomerismo , Tropolona/farmacologiaRESUMO
Listeria monocytogenes is a ubiquitous potentially pathogenic organism requiring iron for growth and virulence. Although it does not produce siderophores, L. monocytogenes is able to obtain iron by using either exogenous siderophores produced by various microorganisms or natural catechol compounds widespread in the environment. In the presence of tropolone, an iron-chelating agent, growth of L. monocytogenes is completely inhibited. However, the growth inhibition can be relieved by the addition of dopamine or norepinephrine under their different isomeric forms, while the catecholamine derivatives 4-hydroxy-3-methoxyphenylglycol and normetanephrine did not relieve the inhibitory effect of tropolone. Preincubation of L. monocytogenes with chlorpromazine and yohimbine did not antagonize the growth-promoting effect of catecholamines in iron-complexed medium. In addition, norepinephrine stimulated the growth-promoting effect induced by human transferrin in iron-limited medium. Furthermore, dopamine and norepinephrine allowed 55Fe uptake by iron-deprived bacterial cells. The uptake of iron was energy dependent, as indicated by inhibition of 55Fe uptake at 0 degrees C as well as by preincubating the bacteria with KCN. Inhibition of 55Fe uptake by L. monocytogenes was also observed in the presence of Pt(II). Moreover, when assessed by a whole-cell ferric reductase assay, reductase activity of L. monocytogenes was inhibited by Pt(II). These data demonstrate that dopamine and norepinephrine can function as siderophore-like compounds in L. monocytogenes owing to their ortho-diphenol function and that catecholamine-mediated iron acquisition does not involve specific catecholamine receptors but acts through a cell-bound ferrireductase activity.
Assuntos
Catecolaminas/metabolismo , FMN Redutase , Ferro/metabolismo , Listeria monocytogenes/enzimologia , NADH NADPH Oxirredutases/metabolismo , Clorpromazina/farmacologia , Dopamina/farmacologia , Quelantes de Ferro/farmacologia , Metoxi-Hidroxifenilglicol/farmacologia , Norepinefrina/farmacologia , Normetanefrina/farmacologia , Tropolona/farmacologia , Ioimbina/farmacologiaRESUMO
This study examined whether the provision of norepinephrine, as would be encountered within the highly innervated gastrointestinal system, affected the growth rate of enterotoxigenic Escherichia coli (ETEC) and the expression of the K99 pilus adhesin virulence-related factor. The addition of norepinephrine to serum-containing medium resulted in a 3- to 7-fold increase in the growth rate of the K99+ ETEC strain B44 as compared to growth in vehicle supplemented medium or medium supplemented with normetanephrine, a norepinephrine metabolite that contains one more methyl group than norepinephrine. ELISA analysis revealed that K99 pilus adhesin expression was increased in norepinephrine supplemented culture as compared to normetanephrine and vehicle supplemented controls. This increase occurred from 9 to 15 hours of incubation which represented the exponential growth phase for the norepinephrine supplemented culture. These results indicate that addition of norepinephrine affects both ETEC growth and expression of a specific virulence factor.
Assuntos
Adesinas Bacterianas/biossíntese , Antígenos de Superfície/biossíntese , Toxinas Bacterianas , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Norepinefrina/farmacologia , Animais , Bovinos , Divisão Celular/efeitos dos fármacos , Enterotoxinas/biossíntese , Escherichia coli/patogenicidade , Normetanefrina/farmacologia , Virulência/efeitos dos fármacosRESUMO
The small intestine is richly innervated by the sympathetic nervous system. High concentrations of monoamines, most notably norepinephrine, are found throughout the various intestinal layers. In order to determine whether norepinephrine is capable of influencing bacterial pathogenesis, the growth and production of virulence factors in ETEC and EHEC were examined in a physiologically relevant medium utilizing very low initial bacterial inoculums to more closely mimie in vivo conditions. The growth of ETEC strain B44 and the production of the K99 pilus adhesin on a protein equivalent basis was greatly increased in the presence of norepinephrine. Growth of EHEC O157:H7 was also increased in norepinephrine containing medium as well as production of SLT-I and SLT-II. The ability of norepinephrine to increase both bacterial growth and expression of virulence factors was shown to be non-nutritional in nature. Given the abundant adrenergic innervation in the small intestine, these in vitro results suggest that the neurohumoral environment of the host may play a role in bacterial growth and expression of virulence factors.
Assuntos
Antígenos de Superfície/biossíntese , Escherichia coli O157/crescimento & desenvolvimento , Escherichia coli O157/patogenicidade , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/patogenicidade , Norepinefrina/farmacologia , Aderência Bacteriana , Proteínas de Bactérias/biossíntese , Toxinas Bacterianas/biossíntese , Intestinos/inervação , Intestinos/microbiologia , Normetanefrina/farmacologia , Toxina Shiga I , Toxina Shiga IIRESUMO
Adrenoceptors mediating contraction in ring segments of human umbilical arteries from normal term pregnancies were investigated in vitro. Contraction was elicited by (order of potency indicated): noradrenaline = the alpha 2-adrenoceptor agonist oxymetazoline >> the alpha 1-adrenoceptor agonist phenylephrine. The alpha 1-adrenoceptor antagonist prazosin antagonized the contraction elicited by noradrenaline and phenylephrine. The alpha 2-adrenoceptor antagonist rauwolscine antagonized the contraction elicited by noradrenaline and oxymetazoline. Oxymetazoline had an efficacy 5 times higher than that of noradrenaline and the 5-hydroxytryptamine receptor antagonist methysergide antagonized the contraction elicited by oxymetazoline. It is suggested that the contractile adrenoceptors in the human umbilical artery consist of both alpha 1 and alpha 2 subtypes. Furthermore, the contractile effect of oxymetazoline seems to be mediated via both alpha 2-adrenoceptors and 5-hydroxytryptamine receptors.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Norepinefrina/farmacologia , Oxigênio/sangue , Receptores Adrenérgicos/fisiologia , Vasoconstrição/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Cocaína/farmacologia , Feminino , Humanos , Técnicas In Vitro , Normetanefrina/farmacologia , Oximetazolina/farmacologia , Fenilefrina/farmacologia , Gravidez , Propranolol/farmacologia , Artérias Umbilicais , Vasoconstrição/efeitos dos fármacosRESUMO
Effects of nanomolar to submillimolar carteolol, a non-selective beta-antagonist, on the evoked release at 1 Hz and the spontaneous release in the absence and presence of uptake1 and uptake2 blockers were studied in pulmonary arteries, isolated from guinea pigs, and then preloaded with [3H]noradrenaline. dl-Carteolol at 10(-8), 10(-7) and 10(-6) M applied at the increasing concentrations inhibited the evoked [3H]-release in untreated arteries and in desipramine and corticosterone-treated arteries. The spontaneous [3H]-release slightly but significantly increased or tended to increase in untreated arteries. dl-Carteolol at 10(-5) and 10(-4) M clearly and concentration-dependently increased the spontaneous [3H]-release in untreated and cocaine-treated arteries. This increase was markedly inhibited by further pretreatment with normetanephrine. The evoked [3H]-release was not altered by dl-carteolol at 10(-5) M, but increased at 10(-4) M. This increase was not modified by cocaine and by cocaine and normetanephrine. d-Carteolol at 10(-5) and 10(-4) M produced effects similar to those of dl-carteolol. Nanomolar to micromolar dl-carteolol inhibits the evoked [3H]-release, which supports our previous conclusion that this inhibition is due to blockade of tonically functioning presynaptic beta 2-adrenoceptors. Carteolol at the higher concentrations seems to become a substrate for an uptake2 mechanism and to produce an unknown sympathomimetic activity in guinea pig pulmonary arteries.
Assuntos
Carteolol/farmacologia , Norepinefrina/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Animais , Carteolol/administração & dosagem , Carteolol/farmacocinética , Cocaína/farmacologia , Corticosterona/farmacologia , Desipramina/farmacologia , Interações Medicamentosas , Cobaias , Técnicas In Vitro , Masculino , Microeletrodos , Normetanefrina/farmacologia , Artéria Pulmonar/metabolismoRESUMO
The aim of the study was to determine whether the uptake process for catecholamines in rat lungs is Uptake1, Uptake2 or a distinct process with some properties of both Uptake1 and Uptake2. The initial rate of uptake of noradrenaline was measured in isolated lungs of rats perfused with 2 nmol/l 3H-(-)-noradrenaline for 2 min with monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) inhibited, in the absence or presence of drugs that are substrates or inhibitors of Uptake1 or Uptake2 or of alterations in the ionic composition of the Krebs solution. The rank order of the IC50 values for inhibition of uptake of noradrenaline in the lungs by drugs that are substrates or inhibitors of Uptake1 or Uptake2 is compatible with the conclusion that uptake of catecholamines in rat lungs occurs by Uptake1, and not by a process with the properties of Uptake2. Additional evidence was provided by the marked inhibition of uptake in the lungs when the Na+ concentration in the Krebs solution was decreased from 143 to 25 mmol/l and by the lack of inhibition when the K+ concentration was increased from 5.9 mmol/l to either 10.9 or 20.9 mmol/l. Further experiments were included in the study to obtain data additional to histological evidence (Hughes et al. 1969; Nicholas et al. 1974) regarding the site of Uptake1 in rat lungs. Pretreatment of rats with either 6-hydroxydopamine (to destroy noradrenergic neurones) or reserpine (to inhibit synaptic vesicle uptake) had no effect on the deamination or accumulation of noradrenaline in lungs perfused with 3H-noradrenaline (COMT inhibited).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Catecolaminas/metabolismo , Pulmão/metabolismo , Neurônios/metabolismo , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Animais , Inibidores de Catecol O-Metiltransferase , Corticosterona/farmacologia , Isoproterenol/análogos & derivados , Isoproterenol/farmacologia , Soluções Isotônicas , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Masculino , Metaraminol/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Neurônios/fisiologia , Norepinefrina/fisiologia , Normetanefrina/farmacologia , Concentração Osmolar , Oxidopamina/farmacologia , Perfusão , Potássio/farmacologia , Ratos , Ratos Endogâmicos , Reserpina/farmacologia , Sódio/farmacologia , TrítioRESUMO
Collateral arteries from canine hindlimb contain less norepinephrine (NE) than control (normal branch) arteries yet they release more NE per stimulation. This study examines basal neuronal function in developing collateral arteries to determine if the mechanism responsible for this impairment includes limitations on reuptake and/or release of NE. Uptake of NE, determined by accumulation of [14C]l-NE, was significantly less in collateral arteries compared to branch arteries. Cocaine (10(-5)M) decreased the rate of uptake of [14C]l-NE into branch arteries by 60% but had no effect on uptake into collateral arteries. Likewise, normetanephrine (10(-5)M) had no effect on uptake of [14C]l-NE into collateral arteries and only a slight effect on branch arteries. The rate of efflux of [14C]l-NE was greater from collateral arteries. Cocaine decreased the efflux of endogenous NE by 25-30% from collateral arteries while increasing the efflux of endogenous NE from branch arteries by 20-100%. Corticosterone (10(-4) M) and pargyline (10(-4) M) had little effect on endogenous NE efflux. These studies support the hypothesis that, compared with normal branch arteries, the decreased amount of neuro-transmitter in sympathetic neurons of collateral arteries is due to both decreased uptake and increased basal and stimulated efflux.
Assuntos
Artérias/metabolismo , Norepinefrina/metabolismo , Animais , Artérias/efeitos dos fármacos , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Cocaína/farmacologia , Cães , Masculino , Neurônios/efeitos dos fármacos , Normetanefrina/farmacologia , Pargilina/farmacologiaRESUMO
Glycerolformal (CAS 5464-28-8; a mixture of 1,3-dioxan-5-ol and 1,3-dioxolane-4-methanol) used as an organic solvent or vehicle for drugs has been shown to possess its own toxicopharmacological activities. The aim of the present investigation was to determine the effects of glycerolformal on sympathetic neurotransmission in the isolated rabbit heart. At concentrations between 0.05 and 1 mmol/l glycerolformal inhibits both the neuronal and extraneuronal uptake of noradrenaline and its metabolism degradation which could explain the initial positive inotropic action of glycerolformal on the heart by increasing noradrenaline concentration in the synaptic cleft. However, the preponderant effect of glycerolformal was an inhibition of noradrenaline release, resulting in a myocardial depression which may explain the hypotension observed in the anesthetized rat. Hence, it is important to take into account the interference effects of glycerolformal with other molecules, when used as solvent or vehicle for drugs.
Assuntos
Dioxolanos/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Desipramina/farmacologia , Iodeto de Dimetilfenilpiperazina/farmacologia , Feminino , Técnicas In Vitro , Masculino , Miocárdio/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Norepinefrina/metabolismo , Normetanefrina/farmacologia , Coelhos , Tiramina/farmacologiaRESUMO
In evaluating positron-emitting analogs of dopamine (DA) as imaging agents for visualizing tissue sympathetic innervation and function, we assessed the metabolic fate of systemically injected [3H]-6-fluorodopamine [( 3H]-6F-DA) in plasma, in sympathetically innervated tissues (left ventricle, spleen and salivary glands) and in excretory organs (liver and kidney) of rats. By 5 min after intravenous bolus injection of a physiologically inactive amount (450 ng, 10 microCi) of [3H]-6F-DA, 3H was concentrated in all the organs compared with that in blood or plasma. In the sympathetically innervated organs, most of the radioactivity was in [3H]-6F-DA and [3H]-6-fluoronorepinephrine [( 3H]-6F-NE), whereas in the blood, plasma and excretory organs most of the radioactivity was in noncatechol compounds such as O-methylated and conjugated metabolites. In sympathetically innervated organs, tissue/blood ratios exceeded 1.0 at all time points between 5 and 120 min after injection of [3H]-6F-DA and increased progressively (from 8 to 60 in myocardium), whereas the tissue/blood ratios in the kidney and liver increased by less than 2-fold during this interval. In all the studied tissues, the proportion of total tissue 3H that was due to [3H]F-NE increased progressively while that due to [3H]F-DA declined, consistent with conversion of [3H]F-DA to [3H]F-NE in vesicles in sympathetic nerve endings.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Dopamina/análogos & derivados , Sistema Nervoso Simpático/fisiologia , Animais , Desipramina/farmacologia , Dopamina/farmacocinética , Exocitose , Masculino , Nitroprussiato/farmacologia , Normetanefrina/farmacologia , Ratos , Reserpina/farmacologia , Distribuição Tecidual , Tomografia Computadorizada de Emissão , Trítio , Ioimbina/farmacologiaRESUMO
Using hepatocytes isolated by collagenase perfusion, we studied the accumulation of 3H-noradrenaline. Cells incubated during 15 min in the presence of 0.4 mumol/l 3H-noradrenaline (without inhibition of noradrenaline metabolism) accumulated 8.32 +/- 1.77 pmol/10(6) cells (n = 3). The accumulation of 3H-noradrenaline in isolated parenchymal liver cells was sensitive to 10 mumol/l cocaine (inhibition 36.6 +/- 7.9%, n = 3) and 1 mumol/l desipramine (inhibition 27.2 +/- 6.9, n = 3). Accumulation of 3H-noradrenaline was temperature and sodium dependent (inhibition 33.2 +/- 9.4%, n = 9, when Na+ was replaced by Tris+) and was influenced by the inhibition of the membrane Na(+)-K(+)-adenosine triphosphatase (Na(+)-K(+)-ATPase) by 150 mumol/l ouabain (34.7 +/- 6.9% inhibition, n = 3). Accumulation of 3H-noradrenaline in the hepatocytes was not affected by the presence of uptake2 inhibitors, normetanephrine (30 mumol/l) and corticosterone (30 mumol/l), but was reduced by 30 mumol/l isoprenaline (76.3 +/- 5.0% inhibition, n = 6). Thus, the system that takes up and accumulates noradrenaline in the isolated rat liver cells possesses some characteristics of both, uptake1 and uptake2 systems and appears to be different from other extraneuronal cocaine-sensitive systems, such as the one reported for pulmonary endothelial cells.
Assuntos
Fígado/metabolismo , Norepinefrina/metabolismo , Animais , Técnicas In Vitro , Isoproterenol/farmacologia , Fígado/citologia , Masculino , Normetanefrina/farmacologia , Ouabaína/farmacologia , Ratos , Ratos Endogâmicos , Sódio/fisiologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Temperatura , Fatores de TempoRESUMO
Sites of uptake, storage, and metabolism of [18F]fluorodopamine and excretion of [18F]fluorodopamine and its metabolites were visualized using positron emission tomographic (PET) scanning after intravenous injection of the tracer into anesthetized dogs. Radioactivity was concentrated in the renal pelvis, heart, liver, spleen, salivary glands, and gall bladder. Uptake of 18F by the heart resulted in striking delineation of the left ventricular myocardium. Pretreatment with desipramine markedly decreased cardiac positron emission, consistent with dependence of the heart on neuronal uptake (uptake-1) for removal of circulating catecholamines. In reserpinized animals, cardiac positron emission was absent within 30 minutes after injection of [18F]-6-fluorodopamine, demonstrating that the emission in untreated animals was from radioactive labeling of the sympathetic storage vesicles. Decreased positron emission from denervated salivary glands confirmed that the tracer was concentrated in sympathetic neurons. Radioactivity in the gall bladder and urinary system depicted the hepatic and renal excretion of the tracer and its metabolites. Administration of tyramine or nitroprusside increased and ganglionic blockade with trimethaphan decreased the rate of loss of myocardial radioactivity. The results show that PET scanning after administration of [18F]fluorodopamine can be used to visualize sites of sympathetic innervation, follow the metabolism and renal and hepatic excretion of catecholamines, and examine cardiac sympathetic function.
Assuntos
Coração/inervação , Sistema Nervoso Simpático/anatomia & histologia , Tomografia Computadorizada de Emissão , Animais , Desipramina/farmacologia , Cães , Dopamina/análogos & derivados , Radioisótopos de Flúor , Gânglios Simpáticos/fisiologia , Ganglionectomia , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Nitroprussiato/farmacologia , Normetanefrina/farmacologia , Reserpina/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Trimetafano/farmacologia , Tiramina/farmacologiaRESUMO
The effects of a single administration (48 hours) and of chronic (14 days) treatment with tricyclic (desipramine, nortryptiline) and nontricyclic (mianserin, nomifensine) antidepressant drugs on responses of the isolated anococcygeus muscle to the alpha 2-adrenoceptor agonist xylazine (inhibition of contraction to field stimulation at 1 Hz) and to the alpha 1-adrenoceptor agonist phenylephrine (contraction of the muscle) have been studied. Of the drugs used only desipramine and nortryptiline administered chronically reduced the responsiveness of the anococcygeus muscle to phenylephrine suggesting a desensitization of postsynaptic alpha 1-adrenoceptors. Long-term but not acute administration of antidepressants resulted in significant decrease in sensitivity of presynaptic alpha 2-adrenoceptors to xylazine. These results show that the adaptative changes of alpha-adrenoceptors in the rat anococcygeus muscle following long-term administration may depend on the efficiency to inhibit the neuronal uptake and the ability to antagonize alpha 1-adrenoceptors.
Assuntos
Antidepressivos/farmacologia , Músculos/efeitos dos fármacos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Cocaína/farmacologia , Desipramina/farmacologia , Estimulação Elétrica , Masculino , Mianserina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculos/metabolismo , Nomifensina/farmacologia , Normetanefrina/farmacologia , Nortriptilina/farmacologia , Fenilefrina/farmacologia , Propranolol/farmacologia , Ratos , Ratos Endogâmicos , Xilazina/farmacologiaRESUMO
1. A comparison between the effect of equal dose regimens of Tourette's medications on mouse motor activity and regional brain monoamines suggests differential responses which may underlie drug-induced side-effects. 2. Haloperidol was more potent than pimozide in altering striatal dopamine concentration which may account for the greater incidence of haloperidol-induced extrapyramidal disorders compared to pimozide. 3. Pimozide, but not the haloperidol treatment, altered brain serotonin concentrations to suggest a decrease in turnover rate which may underlie pimozide-caused sedation in Tourette's syndrome. 4. Pimozide was more potent than haloperidol in duration of behavioral depression which suggests differential dopamine receptor subtypes blockade. 5. Pimozide was more potent than haloperidol in altering 3 of the 6 brain regions content of norepinephrine-derived normetanephrine which may be responsible for the increase in blood pressure reported during pimozide treatment.