RESUMEN
We examined the structure of the rat kinin B2 receptor gene (KB2r) and encoding messenger RNA (mRNA) processing. Differently from the closely related mouse and rabbit genes that have three exons and two introns, the rat gene purportedly consists of four exons and three introns. There are two purported gene products; one of them contains an upstream approximately 180-bp open reading frame region ("exon-X") potentially expressed as a result of alternative processing. To examine the processing of rat KB2r mRNA, cDNA amplicons were generated using primer pairs directed towards 5' or 3' exon or intron flanking regions. Analyses of intron/exon primary cDNA amplicons showed that introns 1 to 3 are removed sequentially and that "exon-X" removal follows that of intron-3. No evidence was found for "exon-X" expression in polyadenylated (mature) mRNA of adult Wistar, Wistar Kyoto, spontaneously hypertensive or Sprague-Dawley rat tissues. Nor was "exon-X" detected in tissues subject to inflammatory stimulus expressing B1 kinin receptor mRNA or in 1- to 21-day-old rat embryos or fetuses. The lack of evidence for the expression of "exon-X" in mature mRNA indicates that the structure of the rat gene is similar to that of the mouse, rabbit and human genes, all consisting of three exons and two introns. The "exon-X" fragment may result from interstitial gene duplication, be a fragment of the ancestral gene, or most likely heterologous transposon insertion of an exon-like fragment into intron-2 of the KB2r gene.
Asunto(s)
Envejecimiento/genética , Evolución Molecular , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica , Procesamiento Postranscripcional del ARN , Receptor de Bradiquinina B2/genética , Envejecimiento/efectos de los fármacos , Animales , Secuencia de Bases , Bases de Datos Genéticas , Embrión de Mamíferos/efectos de los fármacos , Embrión de Mamíferos/metabolismo , Exones/genética , Femenino , Feto/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Genoma/genética , Intrones/genética , Masculino , Datos de Secuencia Molecular , Pirógenos/farmacología , Procesamiento Postranscripcional del ARN/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptor de Bradiquinina B1/genética , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/metabolismoRESUMEN
Two enzymes with tonin-like activity, designated rSMT3 and rSMT4, were purified from rat submandibular glands and another, rPT1, was obtained from the prostate. The three enzyme fractions hydrolysed angiotensin I, angiotensinogen (AG) and synthetic AG(1-14) to form angiotensin II. With angiotensin I as substrate, pH optima were 6.5 for rSMT3, 6.8 for rSMT4 and 7.5 for rPT1. With AG(1-14), the three enzymes had optimal activity at pH 7.5. The three enzymes had negligible activity upon a kallikrein substrate, Ac-Phe-Arg-Nan. The enzymes were inhibited by aprotinin, soybean trypsin inhibitor and phenylmethanesulfonyl fluoride but not by two angiotensin converting enzyme inhibitors, ethylenediaminetetracetic acid or enalaprilat. N-tosyl-L-phenylalanine chloromethyl ketone (1 mM) inhibited rPT1 and rSMT4 but not rSMT3. Molecular weights (SDS-PAGE) were 31,700 for rSMT3, 29,800 for rSMT4 and 28,100 for rPT1. Total activity in the prostate is 150-times lower than in the submandibular gland, where 92% of the tonin activity is related to rSMT4. Physical and chemical properties suggest that rSMT4 is tonin, whereas rSMT3 and rPT1 are tonin-like enzymes which can generate angiotensin II from different substrates.
Asunto(s)
Peptidil-Dipeptidasa A/metabolismo , Próstata/enzimología , Serina Endopeptidasas/aislamiento & purificación , Glándula Submandibular/enzimología , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Angiotensinógeno/metabolismo , Animales , Electroforesis en Gel de Poliacrilamida , Concentración de Iones de Hidrógeno , Calicreínas/metabolismo , Masculino , Ratas , Ratas Endogámicas , Serina Endopeptidasas/metabolismo , Inhibidores de Serina ProteinasaRESUMEN
The site of action for the pressor response to bradykinin administered into the lateral ventricle has been reported to be either in the septal area or in the ventral portion of the third ventricle. We obtained dose-response curves for the pressor effect of bradykinin injected into the lateral ventricle or the posterior region of the fourth ventricle of normotensive Wistar and spontaneously hypertensive rats (SHR). Responses to fourth ventricle injections had a shorter latency and larger maximal effect, and were 20 to 100 times greater than those to lateral ventricle injections, suggesting that the site of bradykinin's action is in the caudal region of the brain, probably close to the area postrema. Maximal effects were similar for lateral and fourth ventricle injections in both SHR and normotensive rats, but SHR were much more sensitive to bradykinin. The ED50 values for the lateral ventricle route in normotensive rats and SHR were 1.3 and 0.35 nmol, respectively, and, for the fourth ventricle route, 60 and 3.4 pmol, respectively. Responses to Lys-Lys-bradykinin, a kininase-resistant bradykinin analogue, showed that kininase activity is lower in SHR than in normotensive rats and that SHR are four times more sensitive to Lys-Lys-bradykinin than are normotensive rats. The responses of all rats were inhibited by a specific bradykinin receptor blocker [Thi5,8,DPhe7]bradykinin. Our results show that there is a site of bradykinin action that is far more caudal than those previously described. The shorter latency and higher sensitivity of the fourth ventricle injection suggest that bradykinin injected into the lateral ventricle diffuses to the fourth ventricle where it exerts its effects.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Bradiquinina/farmacología , Ventrículos Cerebrales/fisiología , Hipertensión/fisiopatología , Presorreceptores/efectos de los fármacos , Animales , Ventrículos Cerebrales/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Ratas , Ratas Endogámicas SHR , Ratas EndogámicasRESUMEN
Intravenous infusion of the converting-enzyme (CE) inhibitor, MK422 (1 mg X kg-1 X hr-1 for 30 minutes) in normotensive controls and two-kidney, one clip (2K1C) rats in the acute phase of renovascular hypertension had a significant hypotensive effect that persisted after 24 hours. In contrast to that prolonged effect, inhibition of the pressor responses to intraarterial or intravenous angiotensin I, and the potentiation of the depressor responses to intravenous bradykinin (BK), were evident during the hour following the infusion of MK422, but not 24 hours later. Potentiation of intraarterially administered BK, however, persisted for 24 hours after infusion of the CE inhibitor. It is concluded that at least the prolonged (24-hour) effect of the treatment with MK422 was due to inhibition of the CE activity in tissues other than the lung, and that increased levels of endogenous BK may be responsible for the inhibitor's hypotensive effect.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Bradiquinina/farmacología , Dipéptidos/farmacología , Hipertensión Renovascular/fisiopatología , Angiotensina I/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Bradiquinina/administración & dosificación , Relación Dosis-Respuesta a Droga , Enalaprilato , Hipertensión Renovascular/tratamiento farmacológico , Infusiones Parenterales , Ratas , Factores de TiempoRESUMEN
OBJECTIVE: To examine the metabolism of kinins and angiotensin I in the pulmonary circulation of spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR). METHODS: Bradykinin inactivation was estimated in vivo by comparison of the hypotensive effect of intra-arterial and intravenous injections, and in the in situ perfused lung by analysing the breakdown products using high-performance liquid chromatography. RESULTS: In vivo pulmonary degradation of bradykinin, but not that of higher homologues of this peptide, was shown to be significantly greater in SHR. Angiotensin I converting activity was found to be increased in lungs of SHR. The recovery of bradykinin and homologues from perfused SHR lung was decreased relative to NWR. Des-(Phe-Arg) fragments of all kinin analogues were identified in the pulmonary perfusates. When bradykinin and des-Arg9-bradykinin were injected in the perfused lungs, the respective fragments 4-9 and 4-8 were also identified in the perfusates. When kininase II was inhibited with enalaprilat, the recovery of bradykinin increased from 10 to 43% in SHR and from 23 to 58% in NWR, whereas about 90% of the higher bradykinin homologues were recovered in both SHR and NWR. Aminopeptidase P and dipeptidylaminopeptidase IV, as measured by the recovery of fragment 4-9 under kininase II inhibition, accounted for about 40% of the total pulmonary kininase activity in the SHR lungs and 25% of that of the NWR lungs. CONCLUSIONS: The results show that SHR have increased kininase and angiotensin converting activity compared with NWR, and that kinins as well as angiotensin may contribute to the pathogenesis of hypertension. Aminopeptidase P and dipeptidylaminopeptidase IV may contribute to the increased in vivo degradation of bradykinin observed in the SHR.
Asunto(s)
Angiotensina I/metabolismo , Bradiquinina/metabolismo , Pulmón/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Circulación Pulmonar/fisiología , Ratas Endogámicas SHR/metabolismo , Ratas Wistar/metabolismo , Aminopeptidasas/metabolismo , Animales , Presión Sanguínea/fisiología , Bradiquinina/administración & dosificación , Bradiquinina/sangre , Dipeptidil Peptidasa 4 , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Pulmón/enzimología , Masculino , RatasRESUMEN
OBJECTIVE: The contribution made by different enzymes to the degradation of bradykinin in physiological conditions was estimated by examining bradykinin metabolism in rat serum, in the in situ perfused lung and in vivo. METHODS: Dose-response curves for the hypotensive effect of intra-arterially and intravenously injected bradykinin were obtained in unanaesthetized rats. High-performance liquid chromatography was used to analyse the products of bradykinin breakdown after incubation with rat serum and perfusion through in situ lung preparations. RESULTS: In rat serum, kininase I degraded 34% and kininase II 11% of bradykinin, no evidence for other activities being detected. In the awake rat, D,L-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid, an inhibitor of kininase I, did not reduce the percentage of bradykinin inactivation in the pulmonary circulation. In the in situ perfused lung 65% of bradykinin was metabolized and the main products were BK1-7, BK1-5 and BK4-9. Enalaprilat (an inhibitor of kininase II) blocked the formation of BK1-7 and BK1-5 and increased the recovery of BK4-9. beta-Mercapto-ethanol, which inhibits aminopeptidase P, and diprotin A, a specific inhibitor of dipeptidylaminopeptidase IV, both reduced the formation of BK4-9. Diprotin A also allowed the recovery of BK2-9. Bradykinin degradation and BK4-9 recovery were not affected by endopeptidase inhibitors. CONCLUSIONS: Our results show that the main degradation pathway of bradykinin in the lung is through the action of kininase II at the carboxyl terminus, and sequential cleavage by aminopeptidase P followed by dipeptidylaminopeptidase IV at the amino terminus. The amino-terminal degradation of bradykinin represents about 38% of the total lung kininase activity.
Asunto(s)
Bradiquinina/metabolismo , Pulmón/metabolismo , Circulación Pulmonar/fisiología , Aminopeptidasas/metabolismo , Angiotensina I/metabolismo , Animales , Presión Sanguínea/fisiología , Bradiquinina/administración & dosificación , Bradiquinina/sangre , Dipeptidil Peptidasa 4 , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Pulmón/enzimología , Lisina Carboxipeptidasa/metabolismo , Masculino , Peptidil-Dipeptidasa A/metabolismo , Ratas , Ratas WistarRESUMEN
1. Previous work from our laboratory has shown that cannabis induces aggressive behaviour in rats that have been deprived of rapid eye movement (REM) sleep. It was suggested that this effect was related to brain catecholamines, with dopamine playing an agonist role and noradrenaline an inhibitory one. The present paper describes new experiments dealing with this subject. 2. Previous REM sleep-deprivation enhanced both delta9-tetrahydrocannabinol (THC)-induced hypothermia and nomifensine effects on aggressive behaviour. 3. A marihuana extract decreased brain dopamine turnover in REM sleep-deprived rats, an effect not observed in non-deprived rats. Noradrenaline metabolism was not altered. 4. Fighting behaviour was elicited in REM sleep-deprived rats treated with 4 different dopamine-beta-hydroxylase inhibitors. 5. Apomorphine, nomifensine and delta9-THC administered to non-deprived rats pretreated with bis(4-methyl-1-homopiperanzinyl-thiocarbonyl) disulphide (Fla-63), induced fighting behaviour. 6. Nomifensine and apomorphine induced fighting in non-deprived rats pretreated with delta9-THC. 7. Clonidine inhibited the fighting elicited in REM sleep-deprived rats by either delta9-THC or Fla-63 pretreatment. 8. The data are discussed in terms of the influence of REM sleep-deprivation (or the stress associated with deprivation) on the response to dopaminergic drugs and cannabis. Taken together they emphasize the participation of brain dopamine and noradrenaline systems in the aggressive behaviour studied.
Asunto(s)
Agresión/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Cannabis , Catecolaminas/análisis , Sueño REM/efectos de los fármacos , Animales , Apomorfina/farmacología , Temperatura Corporal/efectos de los fármacos , Catecolaminas/fisiología , Humanos , Masculino , Nomifensina/farmacología , Ratas , Factores de TiempoRESUMEN
1. Bradykinin (Bk) administered intracerebroventricularly to the rat causes an increase in arterial pressure. 2. Analogues of Bk with agonist and antagonist activity were injected, over a wide dose-range, into the posterior region of the fourth ventricle of unanaesthetized rats implanted with permanent ventricular canullae, and blood pressure was measured directly from the abdominal aorta. 3. The analogues Ile-Ser-Bk (T-kinin) and Lys-Lys-Bk, which interact with both B1 and B2 Bk receptors, produced pressor effects similar to those of Bk, although of greater duration, whereas des-Arg9-Bk, a B1-receptor agonist, had no effect. 4. The B1-antagonist des-Arg9-[Leu8]-Bk did not alter the Bk pressor response, but D-Arg-[Hyp3, Thi5,8,D-Phe7]-Bk, which interacts both with B1- and B2-receptors blocked the responses to Bk, T-kinin and Lys-Lys-Bk and caused parallel shifts to the right of the Bk dose-response curves. Neither antagonist, by itself, had any effect on blood pressure. 5. It is concluded that the central pressor response to Bk is mediated by receptors of the B2 subtype.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Bradiquinina/farmacología , Encéfalo/metabolismo , Receptores de Neurotransmisores/fisiología , Animales , Bradiquinina/análogos & derivados , Femenino , Ratas , Ratas Endogámicas , Receptores de BradiquininaRESUMEN
1. Kinin analogues bradykinin (BK), T-kinin, Met-Lys-BK, Lys-Lys-BK, Des-Arg9-BK with agonist activity and D-Arg0-Hyp3-Thi5,8-D-Phe7-BK (DAHTDBK) and Arg9-Leu8-BK with antagonist activity were injected into the posterior portion of the fourth cerebral ventricle of unanaesthetized rats implanted with permanent cannulae and arterial pressure was measured directly from the abdominal aorta. 2. The spontaneously hypertensive rats (SHR) were more sensitive than normotensive Wistar rats (NWR) to the pressor effect of BK and other kinin analogues. The SHR did not differ in sensitivity of the pressor response to centrally administered angiotensin II or endothelin-1. 3. Experiments with selective kinin agonists and antagonists revealed that in the SHR, as in the NWR, the receptors which mediated the central pressor response are of the BK2 subtype. 4. Measurements of the pressor activity of kinins with different degrees of susceptibility to degradation, as well as experiments with kininase inhibitors, enalaprilat and CPP-Ala-Ala-Phe-pAB, suggest that the kininase activity in the central nervous system of SHR is reduced in comparison to that of NWR. 5. The SHR also showed increased sensitivity to BK and Lys-Lys-BK, compared with the NWR, when the kinins were injected following the administration of a mixture of the kininase inhibitors, suggesting that mechanisms other than kininase activity may play a role in the increased sensitivity of the SHR to the central pressor action of kinins. 6. An in vivo characterization of the kinin receptors which mediate the central pressor response showed that the interaction with DAHTDBK was reversible and of competitive nature. The pA2 in vivo estimated for the kinin receptors of the SHR was 0.7 logarithm units larger than that obtained in the NWR. 7. The kinin receptors which mediate the central BK pressor effect in the SHR are of the BK2 subtype and are similar to receptors in the NWR. The increased sensitivity to kinins in the SHR may be explained, at least in part, by their decreased kininase activity. At present it is impossible to conclude whether the difference observed in the pA2 represents an increased affinity of the kinin receptors or can be attributed to differences amongst strains in the enzymatic degradation of the antagonist.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Bradiquinina/farmacología , Hipertensión/fisiopatología , Receptores de Neurotransmisores/efectos de los fármacos , Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Animales , Bradiquinina/administración & dosificación , Bradiquinina/análogos & derivados , Catéteres de Permanencia , Ventrículos Cerebrales/efectos de los fármacos , Ventrículos Cerebrales/fisiología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas , Receptores de BradiquininaRESUMEN
6-Hydroxydopamine (6OH-DA) pretreatment increased the aggressive behavior induced by marihuana in REM sleep-deprived rats. Brain catecholamine assays revealed that 6OH-DA depleted popamine (DA) and norepinephrine (NE) to a different extent, increasing the DA/NE ratio. Intraventricular injection of NE significantly decreased the aggressive behavior of these animals, whereas control solution or DA injections had no effect. The possible role played by DA and NE in the aggressive behavior induced by marihuana in REM sleep-deprived rats is discussed.
Asunto(s)
Agresión/efectos de los fármacos , Cannabis , Hidroxidopaminas/farmacología , Privación de Sueño , Sueño REM , Animales , Química Encefálica/efectos de los fármacos , Dopamina/análisis , Dopamina/farmacología , Sinergismo Farmacológico , Humanos , Masculino , Norepinefrina/farmacología , RatasRESUMEN
The paratrigerminal nucleus (Pa5), a constituent of the spinal interstitial system, was linked to the pressor effect caused by bradykinin injected in the dorsal lateral medulla of the rat. The nucleus receives primary afferent sensory fibers contained in branches of the trigeminal, glossopharyngeal and vagus nerves. In this investigation connections of the paratrigeminal nucleus to other medullary structures were studied with the use of retrograde and anterograde neuronal tracers. Fluorescent light microscopy analyses of medullary sections of rats injected with the retrograde transport tracer Fluoro-gold in the nucleus of the solitary tract (NTS) or in the pressor area of the rostral ventrolateral medulla (RVLM) revealed labeled neuronal cell bodies in the ipsi- and contralateral Pa5. FluoroGold microinjections in the caudal ventrolateral medulla (CVLM) did not produce fluorescent labeling of Pa5 neurons. Microinjection of the anterograde transport neuronal tracer biocytin in the Pa5 produced bilateral labeling of the solitary tract (sol). rostroventrolateral reticular nucleus (RVL), ambiguus nucleus (Amb), lateral reticular nucleus (LRt) and ipsilateral parabrachial nuclei, but not the contralateral Pa5. Confocal laser microscopy showed fluorescence labeling of fibers and presumptive terminal varicosities in the NTS, RVL, Amb and LRt. The present findings showing the paratrigeminal nucleus interposed between sensory afferent and stuctures associated to cardiovascular and respiratory functions, suggest that the structure may act as a medullary relay nucleus for sensory stimuli directly connecting primary afferents to structures mediating cardiovascular and respiratory reflexes.
Asunto(s)
Tronco Encefálico/citología , Neuronas Aferentes/citología , Centro Respiratorio/citología , Estilbamidinas , Animales , Barorreflejo/fisiología , Presión Sanguínea/fisiología , Colorantes Fluorescentes , Lisina/análogos & derivados , Masculino , Microinyecciones , Ratas , Ratas Wistar , Formación Reticular/citología , Núcleo Solitario/citología , Núcleo Espinal del Trigémino/citologíaRESUMEN
The paratrigeminal nucleus, which receives sensory input from trigeminal, glossopharyngeal and vagus nerves, has efferent projections to bulbar, pontine and possibly to thalamic structures associated with nociception, thermoregulation and cardiovascular control. Anterograde neuronal tracers were used to study paratrigeminal efferent connections. Labeled terminal fibers, evidencing bilateral efferent paratrigeminal projections were observed in the medial and caudal solitary tract (sol), lateral reticular nucleus (LRt), ambiguus nucleus (Amb), rostroventrolateral reticular nucleus (RVL), while ipsilateral projections were found in the parabrachial (PB) nuclei and ventral portion of the ventral posteromedial thalamic nucleus (VPM). This extends other findings that describe paratrigeminal projections. Retrograde neuronal transport tracers, microinjected in the defined projection areas were used to map distribution of the paratrigeminal neurons originating different efferent connections. Microinjection of latex microspheres containing fluorescein or rhodamine and Fluoro-gold in the ventral VPM, PB, RVL, Amb, LRt and NTS revealed sets of labeled paratrigeminal nucleus neurons respectively organised in a rostral-caudal sequence. The largest extent of the paratrigeminal nucleus (medial portion) contained neurons projecting to the RVL/Amb, structures associated with cardiovascular regulation. The data show a segmented topographical organization of the nucleus, with different sets of neurons within delimited segments, projecting to neuronal structures associated with different functions. This points to a complex and extensive role for the paratrigeminal nucleus in the integration of somatosensory reflexes related to cardiovascular, respiratory and pain mechanisms. The nucleus may act as a medullary relay interposed between sensory afferents and different structures related to homoeostatic functions.
Asunto(s)
Fenómenos Fisiológicos Cardiovasculares , Interneuronas/fisiología , Vías Nerviosas/anatomía & histología , Vías Nerviosas/fisiología , Puente/anatomía & histología , Puente/fisiología , Fenómenos Fisiológicos Respiratorios , Sensación/fisiología , Médula Espinal/anatomía & histología , Médula Espinal/fisiología , Núcleos Talámicos/anatomía & histología , Núcleos Talámicos/fisiología , Núcleos del Trigémino/anatomía & histología , Núcleos del Trigémino/fisiología , Animales , Procesamiento de Imagen Asistido por Computador , Masculino , Vías Nerviosas/citología , Puente/citología , Ratas , Ratas Wistar , Médula Espinal/citología , Técnicas Estereotáxicas , Terminología como Asunto , Núcleos Talámicos/citología , Núcleos del Trigémino/citologíaRESUMEN
A quantitative evaluation of the types of afferent synaptic contacts in the pars oralis, using transganglionic degeneration and a comparison of previous data obtained from the pars interpolaris (Lapa & Bauer, 1992), of the rat was performed. Following left inferior alveolar nerve transection or partial pulpectomy of the first and second left lower molar teeth well-defined degenerating terminals appeared bilaterally. In both experiments, the majority of these afferent synapses formed single asymmetric contacts with intermediate and distal dendritic segments in the pars oralis. Fewer contacts were observed with dendritic spines, proximal dendritic segments, perikarya, and other terminals. Double and multiple synaptic contacts, preferentially with small dendritic profiles, were also found. Pars oralis showed higher density of degenerating terminals and higher proportion of the contralateral contacts than pars interpolaris suggesting that it is a prime input area and that it may play a role in the bilateral management of sensory information. Pars oralis showed a higher density of contacts with intermediate and distal dendritic segment and a lower density of double contacts in comparison to the pars interpolaris. Partial pulpectomy revealed a distribution in synaptic types similar to that following IAN transection suggesting that sensory fibers conveying pain-related stimuli are not distinguished from fibers of other sensory modalities as to preference of synaptic contacts. The overall pattern demonstrates a structural organization of the sensory inputs to the spinal trigeminal nucleus regarding the bilateral handling of sensory information.
Asunto(s)
Degeneración Nerviosa/fisiología , Fibras Nerviosas/ultraestructura , Sinapsis/ultraestructura , Núcleo Espinal del Trigémino/ultraestructura , Vías Aferentes/ultraestructura , Animales , Ratas , Ratas Wistar , Núcleo Espinal del Trigémino/fisiologíaRESUMEN
1. delta 9-Tetrahydrocannabinol (THC) induced aggressive behavior in rats previously deprived of REM sleep. This aggressiveness was significantly potentiated by tryptophan and fluoxetine, drugs which increase brain serotonin availability. 2. Conversely, drugs which decrease serotonergic function such as D,L-p-chlorophenylalanine, cinanserin and cyproheptadine strongly blocked the aggressive behavior. 3. On the basis of previous data indicating an involvement of dopaminergic mechanisms in this type of aggressiveness and the present results showing a role for serotonin, it is concluded that REM deprivation-THC aggression is under the control of at least these two neurotransmitters.
Asunto(s)
Agresión/efectos de los fármacos , Dronabinol/farmacología , Serotonina/fisiología , Privación de Sueño , Animales , Cinanserina/farmacología , Ciproheptadina/farmacología , Interacciones Farmacológicas , Fenclonina/farmacología , Fluoxetina/farmacología , Humanos , Masculino , Ratas , Sueño REM , Triptófano/farmacologíaRESUMEN
The aim of the present study was to compare the toxic effects of fluoxetine (F) (8 and 16 mg/kg) and venlafaxine (V) (40 and 80 mg/kg) administered during the third week of pregnancy on early development of rats. Both antidepressants were administered by gavage on pregnancy days 15 to 20 to groups of 10 to 12 animals each. Duration of gestation, food and water consumtion, number of live pups and birth weight were recorded. Litters were culled to six pups at birth (day 1) and followed for growth until weaning (day 25). On day 60, a male and a female from each litter were injected with the 5-HT1 agonist, 5-methoxy-N,N-dimethyltryptamine (6 mg/kg, i.p.) and the serotonergic syndrome was graded. Fluoxetine but not venlafaxine reduced the duration of pregnancy when compared to the control (C) group (F = 21.1 days and C = 21.6 days, mean, P < 0.02: maximum = 22 days and minimum = 21 days in both groups). The highest doses of both fluoxetine, 16 mg/kg (F16), and venlafaxine, 80 mg/kg (V80), reduced the food intake of pregnant rats, resulting in different rates of body weight gain during treatment (from pregnancy day 15 to day 20): F16 = 29.0 g, V80 = 28.7 g vs C = 39.5 g (median). Birth weight was influenced by treatment and sex (P < 0.05; two-way ANOVA). Both doses of fluoxetine or venlafaxine reduced the body weight of litters; however, the body weight of litters from treated dams was equal to the weight of control litters by the time of weaning. At weaning there was no significant difference in weight between sexes. There was no difference among groups in number of live pups at birth, stillbirths, mortality during the lactation period or in the manifestation of serotonergic syndrome in adult rats. The occurrence of low birth weight among pups born to dams which did not show reduced food ingestion or reduction of body weight gain during treatment with lower doses of fluoxetine or venlafaxine suggests that these drugs may have a deleterious effect on prenatal development when administered during pregnancy. In addition, fluoxetine slightly but significantly affected the duration of pregnancy (about half a day), an effect not observed in the venlafaxine treated groups.
Asunto(s)
Antidepresivos de Segunda Generación/toxicidad , Ciclohexanoles/toxicidad , Fluoxetina/toxicidad , Crecimiento/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Aumento de Peso/efectos de los fármacos , Animales , Animales Recién Nacidos , Peso al Nacer/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Femenino , Masculino , Embarazo , Ratas , Ratas Wistar , Clorhidrato de VenlafaxinaRESUMEN
Based on observations that vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) have altered resting potentials as well as abnormal cell proliferation rates, neointima formation after controlled balloon injury was compared in arteries from SHR and Wistar Kyoto rats (WKY). SHR aortic VSMC showed hyperpolarized resting membrane potentials (-93+/-8 mV) when compared to those from WKY (-61+/-6 mV). Histomorphometric analysis of cross sections from aortic segments submitted to balloon injury showed reduced neointima formation in SHR (neointima/media ratio: 0.04+/-0.03) as compared to WKY (0.2+/-0.1). On the other hand, in injured carotid arteries, neointima formation was more extensive in SHR (neointima/media ratio 5.0+/-0.9) than in WKY (0.8+/-0.7), leading in most cases to luminal occlusion. Measurements of VSMC resting potential showed that carotid artery cells from SHR were depolarized with respect to those from WKY (-46+/-4 vs. -69+/-5 mV, respectively). The results demonstrate an inverse relationship between VSMC membrane polarization and neointima formation in SHR arteries, suggesting that genetic modifications in SHR determine a dysfunctional cellular physiology that may influence cell proliferation subsequent to injury.
RESUMEN
We have previously shown that the hypotensive action of angiotensin I (ANG I) converting enzyme (ACE) inhibitors is temporally related to a long-lasting inhibition of kininase activity in the arterial wall. More recently, we showed that conversion of ANG I in the perfused mesenteric vascular bed was not inhibited by enalaprilat at concentrations above those which maximally inhibited kininase activity. The present study extends these observations to two other ACE inhibitors and to another vascular bed, the rat hindlimb preparation. Like enalaprilat, captopril (0.06-1.5 mumol/l) or teprotide (0.4-10 mumol/l) did not inhibit the conversion of ANG I in the perfused mesenteric bed, although the response to bradykinin was substantially potentiated, indicating that the ACE inhibitor decreased kininase activity. In the perfused hindlimb preparations, enalaprilat reduced kininase activity without altering the conversion of ANG I. Enalaprilat or captopril administered to rats caused a decrease in mean arterial blood pressure that lasted for over 24 h. In mesenteric preparations taken from animals 24 h after treatment with ACE inhibitors, kininase activity was inhibited whereas converting activity was unchanged. Therefore, the long-lasting hypotensive effect of ACE inhibition is apparently related to a prolonged inhibition of kininase activity in the arterial wall, which is believed to be the target for ACE inhibitor activity.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Arterias Mesentéricas/efectos de los fármacos , Angiotensina I/farmacología , Animales , Bradiquinina/farmacología , Captopril/farmacología , Enalapril/análogos & derivados , Enalapril/farmacología , Enalaprilato , Masculino , Ratas , Ratas Endogámicas , Teprotido/farmacologíaRESUMEN
Ten types of bovine papillomavirus (BPV) have been described and there are reports of viral transmission via blood. The presence of viral DNA in lymphocytes was described to be associated with chromosome instability in these cells. This study presents an evaluation of chromosome instability in short-term peripheral lymphocyte cultures from cows presenting skin papillomatosis, compared with asymptomatic infected animals and non-infected healthy bovines. In a total of 2203 cells, 918 (42%) showed at least one chromosome aberration: 42.7 (± 7.8) in animals with papillomatosis (BPV + W), 40.2 (± 11) in asymptomatic animals (BPV-W) and 4 (± 2) in control animals. Significant differences were found between the infected group (with or without symptoms) and the control group (P < 0.0001). The increased frequencies of chromosome aberrations suggest an interaction between the virus and host cell chromatin.