RESUMO
Lesions of the subfornical organ (SFO) severely attenuated drinking induced by injections of angiotensin II into the lateral ventricles, but a few days (4 to 14) later a recovery of the drinking response is observed. A possible explanation for this is that other dipsogenic sites are involved which are beyond the interventricular foramen and that SFO lesions produce an obstruction by edema or debris at the foramen which blocks access of cerebrospinal fluid-borne angiotensin to those sites. This hypothesis is supported by tracer studies and by direct injection into the third ventricle of SFO-lesioned animals. Other studies reported implicate the anteroventral third ventricle as a likely site for angiotensin receptors.
Assuntos
Angiotensina II/farmacologia , Ventrículos Cerebrais/fisiologia , Comportamento de Ingestão de Líquido/fisiologia , Angiotensina II/administração & dosagem , Angiotensina II/metabolismo , Sítios de Ligação , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/metabolismo , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Injeções Intraventriculares , Receptores de Droga , Estimulação QuímicaRESUMO
BACKGROUND: The volatile anesthetic sevoflurane exhibits neuroprotective properties when assessed for motor function and histopathology after cerebral ischemia in rats. Damage of hippocampal neurons after ischemia relates to a number of cognitive deficits that are not revealed by testing animals for motor function. Therefore, the present study evaluates cognitive and behavioral function as well as hippocampal damage in rats subjected to cerebral ischemia under sevoflurane compared with fentanyl/nitrous oxide (N(2)O)/O(2) anesthesia. METHODS: Thirty-four rats were trained for 10 days using a hole-board test to detect changes in cognitive and behavioral function. Rats were randomly assigned to the following groups: (A) sham/fentanyl/N(2)O/O(2) (n=7); (B) ischemia/fentanyl/N(2)O/O(2) (n=10); (C) sham/2.0 vol% sevoflurane in O(2)/air (n=7); and (D) ischemia/2.0 vol% sevoflurane in O(2)/air (n=10). Cerebral ischemia was produced by unilateral common carotid artery occlusion combined with hemorrhagic hypotension (mean arterial blood pressure 40 mmHg for 45 min). Temperature, arterial blood gases, and pH were maintained constant. Cerebral blood flow was measured using laser-Doppler flowmetry. After surgery, cognitive and behavioral function was re-evaluated for 10 days. On day 11, the brains were removed for histopathologic evaluation (hematoxylin/eosin-staining). RESULTS: Cognitive testing revealed deficits in declarative and working memory in ischemic rats anesthetized with fentanyl/N(2)O. Rats anesthetized with sevoflurane during ischemia showed a significantly better outcome. Hippocampal damage was significantly worse with fentanyl/N(2)O. CONCLUSION: The present data add to previous investigations showing that sevoflurane prevents a deficit in cognitive function and histopathological damage induced by cerebral ischemia in rats.
Assuntos
Anestésicos/uso terapêutico , Isquemia Encefálica/complicações , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Éteres Metílicos/uso terapêutico , Desempenho Psicomotor/efeitos dos fármacos , Anestesia , Anestésicos Intravenosos/farmacologia , Animais , Gasometria , Encéfalo/patologia , Isquemia Encefálica/patologia , Transtornos Cognitivos/patologia , Interpretação Estatística de Dados , Fentanila/farmacologia , Imuno-Histoquímica , Masculino , Óxido Nitroso/farmacologia , Ratos , Ratos Sprague-Dawley , SevofluranoRESUMO
We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.
Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/fisiologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Inibidores de Fosfodiesterase/sangue , Inibidores de Fosfodiesterase/farmacocinética , Diester Fosfórico Hidrolases/genética , Ratos , Ratos Endogâmicos F344 , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologiaRESUMO
PURPOSE: Pediatric oral rehabilitation patients who receive presedation with oral Versed and general anesthesia (GA) occasionally experience prolonged sedation and delayed discharge. The Bispectral Index System (BIS) is an EEG monitor that measures the anesthesia level. The purpose of this study was to compare the effects of monitoring the BIS to not monitoring the BIS on time from discontinuation of GA to extubation and to discharge. METHODS: Twenty-nine children were enrolled. BIS was monitored from admission until discharge. Each child received 0.7 mg/kg of oral Versed. In the operating room, GA with sevoflurane (IH), rocuronium 1 mg/kg (IV), fentanyl 1 microg/kg (IV), and ondansetron 0.15 mg/kg (IV) was administered. Randomly, in half the patients, the anesthesiologist maintained the level of anesthesia and BIS by adjusting sevoflurane. In the rest, the anesthesiologist did not know BIS. The time from turning off sevoflurane to discharge was compared. RESULTS: Group 1 patients were extubated 5+/-2 minutes sooner than group 2 patients (P=.04). The post-anesthesia care unit stay for group 1 patients was 47+/-17 minutes compared to 63+/-17 minutes in group 2. (p=0.02). CONCLUSIONS: Monitoring anesthesia with BIS promotes earlier extubation and discharge for pediatric dental patients who receive oral Versed and sevoflurane GA.
Assuntos
Período de Recuperação da Anestesia , Anestesia Dentária/métodos , Anestesia Geral/métodos , Monitorização Intraoperatória/instrumentação , Medicação Pré-Anestésica , Administração Oral , Procedimentos Cirúrgicos Ambulatórios , Anestesia Dentária/instrumentação , Anestesia Geral/instrumentação , Anestésicos Inalatórios/administração & dosagem , Pressão Sanguínea , Pré-Escolar , Dentística Operatória , Cuidado Periódico , Feminino , Frequência Cardíaca , Humanos , Hipnóticos e Sedativos/administração & dosagem , Masculino , Éteres Metílicos/administração & dosagem , Midazolam/administração & dosagem , Monitorização Intraoperatória/métodos , Estudos Prospectivos , Sevoflurano , Método Simples-Cego , TitulometriaRESUMO
We tested whether cerebral arteriovenous malformations (AVM) alter brain tissue oxygen pressure, PO2, carbon dioxide pressure PCO2, and pH before, during, and after hypercapnia. A craniotomy was performed and a sensor inserted into normal brain tissue (control) (n = 7) or into tissue adjacent to an AVM (n = 9). Under baseline conditions, tissue PO2 was 80% lower in AVM compared to control patients, but PCO2 and pH were normal. During a 10 mm Hg increase in PaCO2, tissue PO2 increased only in AVM patients, PCO2 increased in both groups, and pH decreased only in controls. When hypercapnia was reversed, tissue PCO2 decreased below baseline and pH increased in AVM patients. Results suggest that tissue CO2 washout and elevated pH result from increases in blood flow during hypercapnia. This response may be related to symptoms of hyperperfusion during AVM resection.
Assuntos
Encéfalo/metabolismo , Dióxido de Carbono/metabolismo , Artérias Cerebrais/anormalidades , Veias Cerebrais/anormalidades , Oxigênio/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Artérias Cerebrais/metabolismo , Veias Cerebrais/metabolismo , Circulação Cerebrovascular , Humanos , Concentração de Íons de HidrogênioRESUMO
Plasma and heart tissue catecholamines were measured in young (4-month) and aged (28-month) Sprague Dawley rats under unanesthetized conditions and following the induction of halothane anesthesia. Arterial blood pressure, blood gases, plasma and heart tissue norepinephrine, epinephrine and dopamine concentrations were measured in separate groups of unanesthetized and halothane anesthetized rats. Young and aged rats were tested under equal anesthetic levels and blood halothane concentrations were measured using gas chromatography. Aged rats required significantly less halothane to maintain anesthesia compared to young animals (7.25 +/- 1.43 vs. 14.91 +/- 0.93 mg/dL, p less than 0.05). Cardiovascular parameters were similar in young vs. aged rats under unanesthetized conditions, but blood pressure decreased significantly more in aged than in young rats during halothane anesthesia (43% vs. 17%, p less than 0.05). Heart tissue catecholamines were not different between young and aged and did not change during halothane anesthesia. Plasma norepinephrine concentrations were consistently elevated in aged vs. young rats under both unanesthetized and anesthetized test conditions, but there was no significant change in these levels from the unanesthetized to the anesthetized state. Results suggest that increased catecholamine levels in aged animals may be necessary to maintain a normal cardiovascular state under unanesthetized conditions and that catecholamines do not increase during the hypotensive state produced by halothane anesthesia in spite of marked hypotension.
Assuntos
Envelhecimento , Anestesia Geral , Catecolaminas/metabolismo , Halotano , Miocárdio/metabolismo , Animais , Pressão Sanguínea , Catecolaminas/sangue , Frequência Cardíaca , Concentração Osmolar , Ratos , Ratos EndogâmicosRESUMO
Cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2) were measured in aged (24 month) spontaneously hypertensive rats (SHR) during sodium nitroprusside (SNP) and nitroglycerin induced hypotension. Both CBF and CMRO2 were decreased in SHR during hypotension induced with SNP. Significant decrements in CMRO2 were observed in aged SHR during even moderate hypotension (80-90 torr). Cerebral autoregulatory responses during nitroglycerin infusion in aged SHR were similar to SNP treated WKY and CMRO2 was maintained at control levels under all hypotensive test conditions. These results indicate that aged SHR are susceptible to cerebral ischemia during SNP induced hypotension, probably due to the combined effects of aging and hypertension on the cerebral vasculature. NTG moderated the decreases in CBF and CMRO2 seen during hypotensive challenges and may decrease the risk of stroke during hypotensive anesthesia.
Assuntos
Encéfalo/metabolismo , Circulação Cerebrovascular , Hipertensão/fisiopatologia , Hipotensão/fisiopatologia , Consumo de Oxigênio , Animais , Pressão Sanguínea , Hipertensão/genética , Hipotensão/induzido quimicamente , Nitroglicerina , Nitroprussiato , Ratos , Ratos MutantesRESUMO
Cerebrovascular and cerebral metabolic responses to changes in arterial PCO2 were tested in young (4 month) and aged (24 month) Sprague-Dawley rats. Rats were anesthetized with 70% nitrous oxide and 30% oxygen, paralyzed with tubocurare and artificially ventilated. Cerebral blood flow (CBF) was measured with radioactive microspheres and cerebral oxygen metabolism (CMRO2) was analyzed from arterial and sagittal sinus oxygen content differences. CBF increased in both young and aged rats with increasing arterial PCO2. Aged rats had significantly depressed cerebrovascular reactivity to changes in CO2 compared to young rats (p less than 0.05). CMRO2 was not significantly different between young and aged rats and did not significantly change with changes in arterial PCO2.
Assuntos
Encéfalo/crescimento & desenvolvimento , Dióxido de Carbono/sangue , Circulação Cerebrovascular , Envelhecimento , Animais , Encéfalo/metabolismo , Pressão Parcial , Ratos , Ratos Endogâmicos , Fluxo Sanguíneo RegionalRESUMO
It has been reported that pentobarbital facilities binding to benzodiazepine receptors binding at anesthetic concentrations and that this action may play a role in the anesthetic potency of this barbiturate. The interaction between pentobarbital and benzodiazepine receptors was tested with Ro 15-1788 which is reported to be a pure benzodiazepine antagonist and 3-hydroxymethyl-beta-carboline (3-HMC), an antagonist which has inverse activity alone. Cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2) were measured in rats after injections of pentobarbital with and without the antagonists. Pentobarbital produced dose-dependent decreases in cerebral blood flow and cerebral oxygen consumption at 15 and 30 mg/kg. The antagonist Ro 15-1788 (10 mg/kg) stimulated cerebral blood flow and cerebral oxygen consumption alone but did not alter the cerebral depression produced by pentobarbital. The cerebral metabolic stimulation produced by Ro 15-1788 was unexpected since the drug is reported to be a pure antagonist without agonistic activity, but the lack of effect on pentobarbital-induced cerebral depression is consistent with other reports. 3-Hydroxymethyl-beta-carboline at 10 mg/kg did not stimulate cerebral blood flow and cerebral oxygen consumption but significantly antagonized the decrease in cerebral oxygen consumption produced by 15 mg/kg pentobarbital. 3-Hydroxymethyl-beta-carboline had no significant effect on decreases in cerebral blood flow and cerebral oxygen consumption produced by phenobarbital, a barbiturate which is reported not to alter binding to benzodiazepine receptors. The ability of 3-HMC to antagonize the effects of pentobarbital would be consistent with an action of both drugs at the benzodiazepine receptor but not by altering binding to an endogenous receptor.
Assuntos
Barbitúricos/farmacologia , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Animais , Benzodiazepinonas/farmacologia , Carbolinas/farmacologia , Flumazenil , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Pentobarbital/farmacologia , Fenobarbital/antagonistas & inibidores , Fenobarbital/farmacologia , Ratos , Ratos EndogâmicosRESUMO
The present report summarizes experiments with monoclonal antibodies to the TSH receptor. The data provide further insight into the TSH receptor structure and into the basis of autoimmune antibodies implicated in the pathogenesis of Graves' disease. They resolve many clinical questions and provide new approaches to enhance our understanding of autoimmune disease. In one new approach, it has been noted that the 11E8 TBIAb can precipitate the phosphorylated beta subunit of the insulin and IGF1 receptor. This cross-reactivity or recognition of determinants adjacent to the TSH receptor may not be random. Insulin, IGF1, alpha 1 adrenergic, and TSH receptors have been linked to a synergistic cascade response system of the thyroid involving growth, thyroglobulin biosynthesis, iodination of thyroglobulin, and thyroid hormone formation. Future studies with the monoclonals may help unravel this cascade system and its regulatory relationships, along with the relationships between autoimmune thyroid disease and autoimmune diseases of other organs.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Doença de Graves/imunologia , Receptores da Tireotropina/imunologia , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Divisão Celular , Tecido Conjuntivo/imunologia , Exoftalmia/imunologia , Gangliosídeos/imunologia , Glicoproteínas/imunologia , Humanos , Idiótipos de Imunoglobulinas/imunologia , Proteínas de Membrana/imunologia , Mixedema/imunologiaRESUMO
Angiotensin II injected in small doses into the cerebral ventricles produces an increase in blood pressure and drinking behavior. The site of action for both of these effects was studied in 3 main experiments. (1) The response to several doses of angiotensin delivered to each ventricle was investigated with multiple ventricular cannulation. This revealed that the rostral ventricular system was involved in angiotensin II mediated responses. (2) CSF flow was limited by plugging specific anterior and posterior ventricular regions and then testing for angiotensin II induced drinking and pressor responses. This technique showed that the ventral anterior third ventricle must be reached by the peptide in order to produce either blood pressure or drinking effects. (3) In order to separate pressor components due to vasopressin release and sympathetic activation, hypophysectomized rats were also tested. The experiment showed that the pressor response to intraventricular angiotensin II is due to both sympathetic and pituitary hormonal components and both are dependent on sites sensitive to angiotensin in the anterior third ventricule. The ventral anterior third ventricle or periventricular tissue surrounding it seems to be essential for both blood pressure and drinking responses to intraventricular angiotensin II.
Assuntos
Angiotensina II/farmacologia , Ventrículos Cerebrais/efeitos dos fármacos , Receptores de Droga , Angiotensina II/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Aqueduto do Mesencéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Masculino , Hipófise/efeitos dos fármacos , Ratos , Tempo de Reação , Fatores de TempoRESUMO
The role of the subfornical organ (SFO) as the unique receptor site for the drinking behavior induced by intracranial injections of angiotensin II (AII) was investigated. It was found that: (1) drinking in response to intraventricular (IVT) injections of AII was reduced in 6 rats but was unchanged after 80-100% damage of the SFO in 4 cases; (2) reduction of drinking to lateral ventricular application of AII was seen with no apparent SFO damage in 4 rats; (3) recovery of the AII induced drinking deficit was consistently observed within a short time interval (14 days), even in those animals with complete SFO lesions: (4) the presence of ventricular debris was correlated with deficits in water intake to IVT angiotensin injections. In a second experiment artificial blockade of the ventricular space was produced by a plugging technique. Plugging the anterior third ventricle simulated the effects of SFO lesioning. It was concluded that the SFO is not a unique receptor area since the ventral anterior third ventricle is also sensitive for AII (IVT) induced drinking. If the SFO is a receptor site for AII circulating in the CSF it is probably not the only periventricular receptor site. Access of AII to the anterior ventral third ventricle appears to be essential for inducement of drinking.
Assuntos
Angiotensina II/farmacologia , Ventrículos Cerebrais/efeitos dos fármacos , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Animais , Mapeamento Encefálico , Ventrículos Cerebrais/fisiologia , Comportamento de Ingestão de Líquido/fisiologia , Injeções Intraventriculares , Masculino , Ratos , Receptores de Droga , Estimulação QuímicaRESUMO
Injections of angiotensin II into the cerebral ventricles of the rat produces both a drinking and a pressor response. We have measured both responses simultaneously in conscious animals. The effect of saralasin acetate (P113), a specific angiotensin II competitive antagonist, has been studied on these angiotensin II induced responses. The results show that: (1) P113 given intravenously (i.v.) in doses of 500 ng/min or 1800 ng/min has no observable effect on 50 ng angiotensin given intraventricularly (IVT). At 72 mug/min, however, there was a 55% reduction in the drinking and pressor responses to 50 ng angiotensin II (IVT); (2) 500 ng of P113 given IVT abolished the effects of 50 ng angiotensin II also given IVT and (3) P113 given i.v. at all doses antagonized the pressor effects of angiotensin II (i.v.) responses. The data indicate that both the drinking and pressor responses to angiotensin II (IVT) injections are centrally mediated and show that when a high enough dose of P113 is given peripherally the central effects of angiotensin II can be reduced. This suggests that a fraction of the P113 injected i.v. may pass across the blood-CSF barrier. Since P113 has a similar structure to angiotensin II the results have implications for studies in which high peripheral doses of angiotensin II are used.
Assuntos
Angiotensina II/análogos & derivados , Angiotensina II/antagonistas & inibidores , Barreira Hematoencefálica , Saralasina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Injeções Intravenosas , Injeções Intraventriculares , Ratos , Saralasina/líquido cefalorraquidiano , Estimulação QuímicaRESUMO
Angiotensin II and carbachol when injected in the brain ventricles of the rat produce similar responses of an increase in blood pressure and drinking behavior. The question of whether these effects are produced by independent receptors or via a cholinergic circuit is debatable for the drinking behavior and evidence is lacking for the blood pressure effect. We have used a chronic rat preparation for recording blood pressure and drinking at the same time during intraventricular injections (i.v.t.) of both angiotensin and carbachol and i.v.t. or intravenous infusions of appropriate antagonists. The results show that drinking and blood pressure response to angiotensin II can be blocked by P113 (500 ng 1.v.t.) an angiotensin antagonist; they are not blocked by atropine (10 mug i.v.t.) a cholinergic antagonist; carbachol effects, however, are not blocked by P113, but are totally blocked by atropine (10 mug i.v.t.), At high doses of atropine there is inhibition of both agents but this probably represents a general inhibition. The hormone and cholinomimetic administered together interact and both are inhibited by adrenergic stimulation. We conclude from these experiments that angiotensin and carbachol act upon independent receptors in the brain to produce blood pressure and drinking responses but at some point they share common, central effector pathways.
Assuntos
Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Carbacol/farmacologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Receptores de Angiotensina/efeitos dos fármacos , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Droga/efeitos dos fármacos , Animais , Atropina/farmacologia , Ventrículos Cerebrais/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Fentolamina/farmacologia , Ratos , Tempo de Reação , Saralasina/farmacologiaRESUMO
Cerebral autoregulation was tested here in 3- and 18-month-old spontaneously hypertensive rats (SHR) and Wistar Kyoto controls (WKY). Cerebral blood flow (CBF) was measured in each rat using radioactive micropheres under unanesthetized control conditions and after hypotension induced by ganglionic blockade. Under control conditions there was no significant difference in CBF between SHR and WKY. During drug induced hypotension CBF decreased significantly in all except 3 month WKY. CBF was decreased significantly more in 18 month SHR after ganglionic blockade compared to other test groups. These results indicate an influence of both age and hypertension in altering the ability of the cerebrovasculature to autoregulate.
Assuntos
Envelhecimento , Pressão Sanguínea , Circulação Cerebrovascular , Animais , Pressão Sanguínea/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Compostos de Hexametônio/farmacologia , Homeostase/efeitos dos fármacos , Masculino , RatosRESUMO
The mechanisms by which intracerebroventricular (i.v.t.) prostaglandin E2 (PGE2) produce hyperthermia in the rat were investigated. I.v.t. PGE2 produced dose-related increases in blood pressure, heart rate and rectal temperature which were significant with a dose of 0.5 ng. Oxygen consumption also increased and remained above baseline over an hour with 50 and 500 ng PGE2 doses. Ganglionic blockade with hexamethonium (20 mg/kg) attenuated the blood pressure and heart rate response to PGE2 but metabolic rate and rectal temperature increases were unchanged. Propranolol (2 mg/kg i.v.) decreased the heart rate response to PGE2 but had no significant effect on blood pressure, metabolic rate and rectal temperature responses. These results suggest a similar sensitivity of central receptors for mediating cardiovascular and metabolic rate/temperature increases but suggest that the mechanisms mediating these effects are separate.
Assuntos
Temperatura Corporal/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Prostaglandinas E/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Dinoprostona , Frequência Cardíaca/efeitos dos fármacos , Hexametônio , Compostos de Hexametônio/farmacologia , Injeções Intraventriculares , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Propranolol/farmacologia , Ratos , Ratos EndogâmicosRESUMO
Neurons synthesize NO, which may act as a retrograde messenger, involved in either potentiating or depressing neuronal excitability. NO may also play a role in the cerebral vasodilatory response to increased neuronal activity (i.e., seizures). In this study, two questions were asked: (1) is NO an endogenous anticonvulsant or proconvulsant substance? and (2) is the cerebral blood flow (CBF) increase accompanying bicuculline (BC)-induced seizures mediated by NO? The experiments were performed in 300-400-g Wistar rats anesthetized with 0.6% halothane and 70% N2O/30% O2. CBF was measured using the intracarotid 133Xe clearance method or laser-Doppler flowmetry. EEG activity was recorded. Chronic treatment (4 days) with nitro-L-arginine (L-NA), a potent NO synthase (NOS) inhibitor (400 mg/kg total), suppressed brain NOS by > 97% and prolonged seizure duration from 6 +/- 1 (saline-treated controls) to 12 +/- 2 min. In the L-NA-treated group, the CBF increase was sustained as long as seizure activity remained, indicating that CBF was still tightly coupled to seizure activity. Interestingly, the supposed inactive enantiomer of L-NA, D-NA, also showed an inhibition of brain NOS activity, ranging from 87 to 100%. The duration of seizures in this group (average 8 +/- 2 min) corresponded directly to the magnitude of reduction in NOS activity (r = 0.83, P < 0.05). Specifically, the D-NA results indicated that NOS inhibition had to exceed 95% before any effect on seizure duration could be seen.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Aminoácido Oxirredutases/antagonistas & inibidores , Anticonvulsivantes/metabolismo , Arginina/análogos & derivados , Circulação Cerebrovascular/efeitos dos fármacos , Óxido Nítrico/fisiologia , Convulsões/fisiopatologia , Animais , Arginina/farmacologia , Bicuculina , Masculino , Óxido Nítrico Sintase , Nitroarginina , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , EstereoisomerismoRESUMO
There is a need in clinical practice for an antagonist which can reverse the sedative action of benzodiazepines. Recently, 3-hydroxymethyl-beta-carboline (3-HMC) has been reported to inhibit the sleep inducing effects of flurazepam. The effects of flurazepam (0.5, 5 and 50 mg/kg) on cerebral blood flow (CBF) and cerebral O2 consumption (CMRO2) were evaluated in rats and the ability of 3-HMC to reverse these changes was determined. Regional CBF was measured with radioactive microspheres and cortical CMRO2 was calculated from sagittal sinus-arterial O2 content differences and cortical CBF. Flurazepam produced dose dependent decreases in CBF and CMRO2 which were significant at 5 and 50 mg/kg. 3-HMC (5 mg/kg) inhibited flurazepam induced changes at the 5 mg/kg dose but had little effect on the CBF and CMRO2 depression produced by 50 mg/kg flurazepam. At a dose of 25 mg/kg, 3-HMC inhibited the effects of both 5 and 50 mg/kg flurazepam. Blood pressure and heart rate were also decreased by flurazepam but these variables were not reversed as effectively by 3-HMC treatment. The results indicate that 3-HMC is an active antagonist of the cerebrovascular and cerebral metabolic depression produced by flurazepam and can stimulate CBF and CMRO2 at high doses when given alone.
Assuntos
Benzodiazepinas/antagonistas & inibidores , Encéfalo/efeitos dos fármacos , Carbolinas/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Flurazepam/farmacologia , Indóis/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Masculino , Metoxamina/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos EndogâmicosRESUMO
Twenty-four nephrectomized rats were infused intracranially with angiotensin II (AII), synthetic tetradecapeptide substrate and purified rat and dog plasma substrates. Significant drinking responses were observed with all four substances. Drinking to the renin substrate infusions was inhibited by intracranial infusions of either angiotensin I-converting enzyme inhibitor (SQ 20881) or a specific AII antagonist, saralasin, indicating that conversion of the substrates to AII was a necessary step in order to produce the drinking responses. These results indicate that brain iso-renin can operate under physiological conditions to produce angiotensin from both synthetic and naturally occurring substrates.