Effect of selective beta-adrenoceptor blockade and surgical resection of the celiac-superior mesenteric ganglion complex on delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

There is evidence for participation of peripheral β-adrenoceptors in delayed liquid gastric emptying (GE) induced in rats by dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At). The present study aimed to determine whether β-adrenoceptors are involved in delayed GE induced by phenylpyrazole derivatives and the role of the prevertebral sympathetic nervous system in this condition. Male Wistar rats weighing 220-280 g were used in the study. In the first experiment rats were intravenously pretreated with vehicle (V), atenolol 30 mg/kg (ATE, β1-adrenergic antagonist), or butoxamine 25 mg/kg (BUT, β2-adrenergic antagonist). In the second experiment, rats were pretreated with V or SR59230A 2 mg/kg (SRA, β3-adrenergic antagonist). In the third experiment, rats were subjected to surgical resection of the celiac-superior mesenteric ganglion complex or to sham surgery. The groups were intravenously treated with saline (S), 240 µmol/kg Dp, AA, or At, 15 min after pretreatment with the antagonists or V and nine days after surgery. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. The %GR (means±SE, n=6) values indicated that BUT abolished the effect of Dp (BUT+Dp vs V+Dp: 35.0%±5.1% vs 56.4%±2.7%) and At (BUT+At vs V+At: 33.5%±4.7% vs 52.9%±2.6%) on GE, and significantly reduced (P<0.05) the effect of AA (BUT+AA vs V+AA: 48.0%±5.0% vs 65.2%±3.8%). ATE, SRA, and sympathectomy did not modify the effects of treatments. These results suggest that β2-adrenoceptor activation occurred in delayed liquid gastric emptying induced by the phenylpyrazole derivatives dipyrone, 4-aminoantipyrine, and antipyrine. Additionally, the released neurotransmitter did not originate in the celiac-superior mesenteric ganglion complex.

Stress-related hormone norepinephrine induces interleukin-6 expression in GES-1 cells

In the current literature, there is evidence that psychological factors can affect the incidence and progression of some cancers. Interleukin 6 (IL-6) is known to be elevated in individuals experiencing chronic stress and is also involved in oncogenesis and cancer progression. However, the precise mechanism of IL-6 induction by the stress-related hormone norepinephrine (NE) is not clear, and, furthermore, there are no reports about the effect of NE on IL-6 expression in gastric epithelial cells. In this study, we examined the effect of NE on IL-6 expression in immortalized human gastric epithelial cells (GES-1 cells). Using real-time PCR and enzyme-linked immunoassay, we demonstrated that NE can induce IL-6 mRNA and protein expression in GES-1 cells. The induction is through the β-adrenergic receptor-cAMP-protein kinase A pathway and mainly at the transcriptional level. Progressive 5′-deletions and site-directed mutagenesis of the parental construct show that, although activating-protein-1 (AP-1), cAMP-responsive element binding protein (CREB), CCAAT-enhancer binding protein-β (C/EBP-β), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) binding sites are all required in the basal transcription of IL-6, only AP-1 and CREB binding sites in the IL-6 promoter are required in NE-induced IL-6 expression. The results suggest that chronic stress may increase IL-6 secretion of human gastric epithelial cells, at least in part, by the stress-associated hormone norepinephrine, and provides basic data on stress and gastric cancer progression.

Evidence for the involvement of peripheral -adrenoceptors in delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

Dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At) delay liquid gastric emptying (GE) in rats. We evaluated adrenergic participation in this phenomenon in a study in male Wistar rats (250-300 g) pretreated subcutaneously with guanethidine (GUA), 100 mg·kg−1·day−1, or vehicle (V) for 2 days before experimental treatments. Other groups of animals were pretreated intravenously (iv) 15 min before treatment with V, prazosin (PRA; 1 mg/kg), yohimbine (YOH; 3 mg/kg), or propranolol (PRO; 4 mg/kg), or with intracerebroventricular (icv) administration of 25 µg PRO or V. The groups were treated iv with saline or with 240 µmol/kg Dp, AA, or At. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. %GR (mean±SE, n=8) indicated that GUA abolished the effect of Dp (GUA vs V=31.7±1.6 vs 47.1±2.3%) and of At (33.2±2.3 vs 54.7±3.6%) on GE and significantly reduced the effect of AA (48.1±3.2 vs 67.2±3.1%). PRA and YOH did not modify the effect of the drugs. %GR (mean±SE, n=8) indicated that iv, but not icv, PRO abolished the effect of Dp (PRO vs V=29.1±1.7 vs 46.9±2.7%) and At (30.5±1.7 vs 49±3.2%) and significantly reduced the effect of AA (48.4±2.6 vs 59.5±3.1%). These data suggest activation of peripheral β-adrenoceptors in the delayed GE induced by phenylpyrazolone derivatives.

Disfunção miocárdica e alterações no trânsito de cálcio intracelular em ratos obesos / Myocardial dysfunction and abnormalities in intracellular calcium handling in obese rats

FUNDAMENTO: Vários mecanismos têm sido propostos contribuir para a disfunção cardíaca em modelos de obesidade, tais como alterações nas proteínas do trânsito de cálcio (Ca+2) e nos receptores beta-adrenérgicos. Todavia, o papel desses fatores no desenvolvimento da disfunção miocárdica induzida pela obesidade ainda não está claro. OBJETIVO: Este estudo pretende investigar se a obesidade induzida por um ciclo de dieta hipercalóricas resulta em disfunção cardíaca. Além disso, foi avaliado se essa alteração funcional em ratos obesos está relacionada com o prejuízo do trânsito de Ca+2 e do sistema beta-adrenérgico. MÉTODOS: Ratos Wistar machos, 30 dias de idade, foram alimentados com ração padrão (C) e um ciclo de cinco dietas hipercalóricas (Ob) por 15 semanas. A obesidade foi definida pelo aumento da porcentagem de gordura corporal dos ratos. A função cardíaca foi avaliada mediante análise isolada do músculo papilar do ventrículo esquerdo em condições basais e após manobras inotrópicas e lusitrópicas. RESULTADOS: Em comparação com o grupo controle, os ratos obesos apresentaram aumento da gordura corporal e intolerância a glicose. Os músculos dos ratos obesos desenvolveram valores basais semelhantes; entretanto, as respostas miocárdicas ao potencial pós-pausa e aumento de Ca+2 extracelular foram comprometidas. Não houve alterações na função cardíaca entre os grupos após a estimulação beta-adrenérgica. CONCLUSÃO: A obesidade promove disfunção cardíaca relacionada com alterações no trânsito de Ca+2 intracelular. Esse prejuízo funcional é provavelmente ocasionado pela redução da atividade da bomba de Ca+2 do retículo sarcoplasmático (SERCA2a) via Ca+2 calmodulina-quinase.

BACKGROUND: Several mechanisms have been proposed to contribute to cardiac dysfunction in obesity models, such as alterations in calcium (Ca2+) handling proteins and β-adrenergic receptors. Nevertheless, the role of these factors in the development of myocardial dysfunction induced by obesity is still not clear. OBJECTIVE: The purpose of this study was to investigate whether obesity induced by hypercaloric diets results in cardiac dysfunction. Furthermore, it was evaluated whether this functional abnormality in obese rats is related to abnormal Ca2+ handling and the β-adrenoceptor system. METHODS: Male 30-day-old Wistar rats were fed with standard food (C) and a cycle of five hypercaloric diets (Ob) for 15 weeks. Obesity was defined as increases in body fat percentage in rats. Cardiac function was evaluated by isolated analysis of the left ventricle papillary muscle under basal conditions and after inotropic and lusitropic maneuvers. RESULTS: Compared with the control group, the obese rats had increased body fat and glucose intolerance. The muscles of obese rats developed similar baseline data, but the myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca2+ were compromised. There were no changes in cardiac function between groups after β-adrenergic stimulation. CONCLUSION: Obesity promotes cardiac dysfunction related to changes in intracellular Ca2+ handling. This functional damage is probably caused by reduced cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA2) activation via Ca2+ calmodulin kinase.

Histological evidences of reparative and regenerative effects of beta-adrenoceptor agonists, clenbuterol and isoproterenol, in denervated rat skeletal muscle.

The aim of this study was to determine the contribution of beta-adrenoceptor activation in the reconstruction of the structural and functional organization of denervated skeletal muscle. beta-agonists, clenbuterol (1.2 mg/kg body weight) and isoproterenol (2 mg/kg body weight), administration (daily oral administration; maximum 7 days) to normal innervated rats as well as denervated animals caused muscle hypertrophy. An increase in mean fiber diameter confirmed this stimulated growth both in normal innervated and denervated rat gastrocnemius muscle. Examination of muscle nuclei from treated but normal innervated rat gastrocnemius exhibited features like large size, active nucleoplasm and an increase in their number per fiber cross section and per mm mean fiber length indicating towards an elevated biosynthetic activity in tissue in the presence of beta adrenoceptor agonists. Administration of drugs to normal innervated animals resulted in an emergence of central muscle nuclei. The hyperactive and enlarged muscle nuclei ultimately organized themselves into unusually elongated nuclear streaks. beta agonist treatment to denervated rats resulted in amelioration of atrophic state of tissue characterized by hypertrophy of muscle fibers thus lending to a restoration of structural organization of tissue. Bizarre shapes of nuclei in denervated muscle tend to recover to that characteristic to normal innervated muscle in presence of clenbuterol and isoproterenol hydrochloride. All observations were confirmed by administering butoxamine, a beta-adrenoceptor antagonist along with beta-agonists. The results suggests that both clenbuterol and isoproterenol hydrochloride are capable of mimicking normal innervation functions in skeletal muscle and thus play important role in the structural and functional reorganization of tissue. Amelioration of denervation atrophy in rat gastrocnemius in the presence of beta-agonists supports this.

Overview of molecular mechanisms in chagasic cardioneuromyopathy and achalasia

Evidence accumulated by our investigations over the years give adequate proof for the existence of circulating antibodies in Chagas disease which bind to beta adrenergic and muscarinc cholinergic receptor of myocardium. The interaction of agonist-like antibodies with neurotransmitter receptors, triggers in the cells intracellular signal transductions that alter the physiological behaviour of the target organs. These events convert the normal cells into pathologically active cells. The interaction of antibodies with heart beta adrenergic and cholinergic receptors triggers physiologic, morphologic, enzymatic and molecular alterations, leading to tissue damage. The analysis of the prevalence and distribution of these antibodies reveals a strong association with cardiac and esophageal autonomic dysfunction in seropositive patients in comparison with those without alteration of the heart and esophagus autonomic disorders: therefore, the presence of these antibodies may partially explain the cardiomyoneurophathy and achalasia of Chagas disease, in which the sympathetic and parasympathetic systems are affected. The deposit of autoantibodies behaving like an agonist on neurotransmitter receptors, induceds desensitization and/or down regulation of the receptors. This is turn, could lead to a progressive blockade of neurotransmitter receptors, with sympathetic and parasympathetic dennervation, a phenomenon that has been described during the course of Chagas cardioneuropathy and achalasia. The clinical relevance of these findings is the demonstration, using biomolecules, of a strong association between the existence of circulating autoantibodies against peptides corresponding to the second extracellular loop of the human heart beta, adrenoceptor and M2 cholinoceptor in chagasic patients, and the presence of dysautonomic symptoms, making these autoantibodies a proper early marker of heart and digestive autonomic dysfunction.

Influence of Antedorsal Thalamic nuclei on the hypophyseal-adrenal axis and cardiac beta receptors in tars submitted to vatriable chronic stress

The limbic structures play an important role in the control of the neuroendocrine and sympathical adrenal function in basal and stress conditions. This work was undertaken to evaluate plasma ACTH, adrenocortical activity, cardiac adrenoceptors density and affnity response to variable chronic stress (VCS) in anterodorsal thalamic nuclei (ADTN) lesioned rats. Thirty days after lesion, shamlesioned stressed animals increased plasma ACTH and corticosterone as compared to sham-lesioned unstressed animals (p<0.05); lesioned rats increased ACTH levels after VCS (p<0.05) as compared unstressed-lesioned rats. Whereas in sham-lesion plasma corticosterone (C) increased after stress. in lesioned animals (C) remained unchanged as compared to unstressed-lesioned animals. In the stressed groups, adrenal C contents were below those found in unstressed rats. Beta-receptors affinity, in all the experimental groups, was similar, but VCS sham-lesioned animals underwent a significant increase in cardiac D-adrenergic receptors density when compared with basal and lesioned groups (P<0.001). Our findings would demonstrate that the increment in cardiac Beta adrenoceptors density appears as a consequence of the increase in ACTH, plasma corticosterone and sympathetic response provoked by stress situations. ADTN lesion attenuated this hipophisoadrenal system response to chronic stress as well as the above mentioned cardiac beta adrenoceptors density increment.

Cardiac beta receptors' density or affinity modified by different Trypanosoma cruzi amount

Chagas'disease presents complex physiopathogenic mechanism, many of them poorly understood, that in our country generally produce cardiac lesions. The acute phase related with the presence of the parasite is usually asymptomatic. This report studies if the amount of T. cruzi that induced acute infection could modify the myocardiopathy evolution. Previous works have shown that Albino Swiss mice inoculated with 45 tripomastigotes (AcL) presented alterations in the cardiac pharmacological response to adrenergic agonist and anatogonist studied at 30 days post-infection (p.i.). Mice inoculated with 7 x 10(4) parasites/animal showed similar behaviour at 7 days p.i. We studied the involvement of the affinity and density of cardiac beta receptors in both acute groups by binding with (3)H/DHA. The AcH group presented less cardiac beta receptors number (p<0.001), but their affinity was conserved. The AcL model presented significantly less affinity (p<0.01) but desinty, was not different from non infected animals. Beta receptors'affinity of both infected groups were similar, but AcH density was significantly diminished when compared with AcL. These studies demonstrates that the amount of T. cruzi received by the host determines and acelerates the evolution of the chagasic myocardiopathy.

Participation of the ß-adrenoceptors of the medial septal area on urine flow rate, sodium and potassium excretion

Investigou-se a participaçäo dos ß-adrenoceptores da área septal (AS) na excreçäo urinária de sódio, potássio e fluxo urinário. As alteraçöes na pressäo arterial e algumas funçöes renais foram também investigadas. A injeçäo de 2.10-8 à 16.10-8 M de isoproterenol, através de cânulas de demora implantadas permanentemente na AS, produziu uma diminuiçäo significante dose-dependente na excreçäo urinária de sódio, potássio e fluxo urinário. Pré-tratamento com 16.10-8 M de butoxamina antagonizou o efeito de 4.10-8 M de isoproterenol mas o pré-tratamento com 16.10-8 M de practolol näo aboliu o efeito do isoproterenol. Os ß2 agonistas, terbutalina e salbutamol (4.10-8 M) quando injetados intraseptalmente produziram também um decréscimo no fluxo urinário e na excreçäo de sódio e potássio. Após injeçäo de isoproterenol ou salbutamol (4.10-8 M) na AS, a pressäo arterial, taxa de filtraçäo glomerular (TFG) e a filtraçäo de sódio foram reduzidas, enquanto que a fraçäo de reabsorçäo de sódio foi aumentada. Os resultados indicam que os ß2 adrenoceptores da AS tem influência na diminuiçäo de sódio, potássio e fluxo urinário e este efeito pode ser devido a queda na TFG e no sódio filtrado e pelo aumento na reabsorçäo tubular de sódio

Changes in cardiac lactate dehydrogenase isoenzymes following experimental necrosis in rats.

Following a subcutaneous injection of isoproterenol (ISO) into adult rats (30 mg/100 g, B.W.), the cardiac total lactate dehydrogenase (LDH) activity was decreased by about 53.81% in less than 24 H. Restoration of myocardial LDH activity was seen at 24 H and 48 H. LDH-I activity exceeded LDH-V in the control heart, while LDH-I, LDH-II and LDH-III decreased at 48 H following ISO injection. These changes were associated with concomitant elevation in LDH-V activity. Percentage M-LDH was less than H-LDH till 12 H in the necrotic heart muscle but exceeded the latter at 24H and 48 H. Similar changes were marked in absolute H-LDH and M-LDH activities when compared with the total LDH activity. Histopathological studies revealed and confirmed the occurrence of infarcts. The results indicate the potential of myocardial tissue for efficient shifting of H-LDH synthesis to M-LDH synthesis in the necrotic heart.

Los marcadores biológicos de la esquizofrenia y otras psicosis / Biological markers of schizophrenia and other psychoses

La investigación psiquiátrica biológica ha evolucionado en forma muy importante desde Kraepelin, a fines del siglo pasado, hasta el momento actual, en que se están buscando los llamados marcadores biológicos de las psicosis funcionales. La búsqueda de marcadores biológicos tuvo en un principio el fin de depurar los diagnósticos psiquiátricos y, fundamentalmente, encontrar una teoría respecto a estas enfermedades. En un principio se buscaban marcadores especíicos de enfermedad, parámetros que permiten determinar los diferentes tipos de depresión o que facilitaran el diagnóstico de la esquizofrenia. Se esperaba que por este medio se pudiera establecer la etiología o, cuando menos, contar con un elemento relacionado con la patogénesis. Dado el estado actual de la investigación, parece probable que sólo se encuentran marcadores que puedan señalar la predisposición y que podrían no estar relacionados con la etiopatogénesis. En este momento se han establecido los conceptos de marcador de rasgo, que se refiere a los hallazgos invariables que pueden observarse en los pacientes con trastornos mentales endógenos en la fase aguda, y aún en su remisión; y el de marcador de estado, que indica que sólo va a manifestarse en grado variable mientra esté presente la sintomatología de la enfermedad. Uno de los marcadores de estado que ha sido ampliamente estudiado es la prueba de supresión con dexametasona, que se encuentra alterada en la depressión y que no es específica para este trastorno psiquiátrico, pues se ve alterada por las modificaciones en el peso y en la anorexia nervosa. Esta prueba ha sido utilizada como un predictor bastante atinado de respuesta al tratamiento, así como de la recaída. Hay otras pruebas, como la propuesta por Matussek, con clonidina, que investiga la sensibilidad de los receptores adrenérgicos centrales por medio de la respuesta de la hormona de crecimiento en la depresión, y que se comporta como un marcador de estado, pues no sólo es anormal...

Efecto de las variaciones del pH sobre la union de agonistas y antagonistas al receptor beta adrenergico / Effect of pH changes on agonists and antagonists binding to the adrenergic beta receptor

Se examinó en el sarcolema de corazones caninos el efecto del cambio de pH sobre la fijación específica de DHA-3H- y su desplazamiento por ligandos radiactivos. A valores bajos de pH (6.69) la afinidad de los receptores por los agonistas es menor que a pH 7.65, tanto para la noradrenalina como para el isoproterenol, produciendo un aumento de 1.5 veces en la constante de inhibición. El cambio en la afinidad fue atenuado agregando GTP 300 uM en el medio de incubación. Similares cambios de pH no afectan ni la afinidad de antagonistas (dihidroalprenolol, alprenolol, propranolol) por el receptor ß adrenérgico, ni el número de sitios de fijación determinado por la fijación de DHA-3H-. El efecto del pH sugiere que los iones H+ inducen en los receptores ß la formación de un estado de baja afinidad para los agonistas. Este mecanismo dependiente de la concentración de iones H+ podría ser capaz de regular el proceso por el cual los agonistas estimulan la adenil ciclasa