Participation of hepatic α/β-adrenoceptors and AT1 receptors in glucose release and portal hypertensive response induced by adrenaline or angiotensin II

It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (∝1- and β-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ∝1-AR and β-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ∝1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of β-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between β-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.

Os polimorfismos dos receptores adrenérgicos na insuficiência cardíaca: o que a genética explica? / Adrenergic receptor polymorphisms in heart failure: what can genetics explain?

A insuficiência cardíaca (IC) é uma doença complexa, onde diversos mecanismos fisiopatológicos atuam e diferentes polimorfismos genéticos estão envolvidos. O sistema adrenérgico está diretamente relacionado a esta patologia participando da auto-regulação cardiovascular, tendo papel crucial na deteriorização da função cardíaca. Os beta-bloqueadores surgiram como um grande avanço da cardiologia no tratamento da IC, no entanto a resposta medicamentosa varia para cada paciente podendo estar relacionado a diversos fatores, entre eles o genético. A determinação pela genética do desenvolvimento da IC, da resposta medicamentosa e prognóstico são questões que serão abrangidas nesta revisão.

Heart failure (HF) is a complex disease, which involves several physiopathological mechanisms and different genetic polymorphisms. The adrenergic system is directly related to this pathology, as it participates in cardiovascular autoregulation and has a crucial role in the deterioration of cardiac function. The beta-blockers appeared as a great advance in cardiology for the treatment of HF; however, the drug response varies according to each patient, as several factors are associated, such as the genetic one. This review aims at assessing the genetic involvement in the development of HF, the drug response and the prognosis.

The role of adrenergic receptor polymorphisms in heart failure

The main function of the cardiac adrenergic system is to regulate cardiac work both in physiologic and pathologic states. A better understanding of this system has permitted the elucidation of its role in the development and progression of heart failure. Regardless of the initial insult, depressed cardiac output results in sympathetic activation. Adrenergic receptors provide a limiting step to this activation and their sustained recruitment in chronic heart failure has proven to be deleterious to the failing heart. This concept has been confirmed by examining the effect of ß-blockers on the progression of heart failure. Studies of adrenergic receptor polymorphisms have recently focused on their impact on the adrenergic system regarding its adaptive mechanisms, susceptibilities and pharmacological responses. In this article, we review the function of the adrenergic system and its maladaptive responses in heart failure. Next, we discuss major adrenergic receptor polymorphisms and their consequences for heart failure risk, progression and prognosis. Finally, we discuss possible therapeutic implications resulting from the understanding of polymorphisms and the identification of individual genetic characteristics.

Atenolol or butoxamine injection at the lateral septum doesn't inhibit male sexual behavior in rats.

To investigate the role of specific adrenoreceptors subtypes on sexual behavior, atenolol, butoxamine, a mixture of atenolol and butoxamine, and saline (vehicle) were injected into the lateral septum in four different groups of sexually active male rats. Application of a mixture of atenolol and butoxamine produced inhibition of copulatory activity. On the other hand, application of either atenolol or butoxamine alone did not inhibit copulatory activity. But it produced stimulation of some of the components of male sexual behavior. Inability of either atenolol or butoxamine to inhibit the male sexual behavior, and inhibition of the same by the mixture of atenolol and butoxamine, indicate that both beta-adrenoreceptors at the lateral septum are involved in the elaboration of male sexual behavior. Stimulation of some components of sexual behavior on application of atenolol or butoxamine could be attributed to an unbalanced activity of beta-adrenoreceptors.

Role of beta-adrenergic signal transduction pathway on myocardial ischemic preconditioning of rats / 华中科技大学学报（医学）（英德文版）

To study the changes in every part of the beta-adrenergic signal transduction pathway and their effects on ischemic preconditioning of rat myocardium in vivo. SD rats were divided into three groups: IP group, I/R group and CON group. The IP group was further divided into PC1-, 2-, 3-, and PC1+, 2+, 3+ groups according to preconditioning procedure. The rats received surgical procedure and underwent left coronary artery occlusion and reperfusion. We analyzed the infarct size by TTC staining, measured serum myocardial enzymes, studied the beta-AR Bmax and Kd by radioligand binding assay of receptors, checked the activity of AC and PKA by the method of biochemistry and examined the content of cAMP by radioimmunoassay. The infarct area was much smaller in the IP group than in the I/R group (P < 0.001), while the enzymes were significantly higher in I/R (P < 0.001). The Bmax of beta-AR in IP was much higher than that in I/R (P < 0. 001), but no difference in Kd could be seen between IP and I/R groups. In IP, the activity of AC and PKA and the content of cAMP were higher than those in I/R (P < 0.05, 0.002 and 0.001, respectively). In the procedure of preconditioning, the content of cAMP and the activity of PKA showed the characteristic of cyclic fluctuation. Ischemic preconditioning can protect the heart from necrosis and reduce endo-enzyme leakage. The system of beta-adrenergic signal transduction pathway probably takes part in the protection effect of the IP, which might be elicited by the PKA.

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.

Sistema nervioso autónomo y estres gástrico, en ratas / Autonomic nervous system and gastric stress in rats

En grupos diferentes de ratas Wistar (n=10), se estudió el efecto fisiopatológico del sistema nervioso autónomo en el estrés gástrico, en el modelo experimental de estrés, por inmovilización e inmersión en agua a 15 grados Celsius durante 6 hs., en el que se tabuló el por ciento lesional macroscópica de la mucosa gástrica y en sangre se midió el cortisol, malatonina, nor-adrenalina, adrenalina, dopamina y serotonina. En estrés testigo se encontró un área necrótica gástrica de un 80 por ciento en sangre solo se halló aumento de nor-adrenalina y adrenalina. Se estudiaron fármacos en dosis dependientes, agonistas y antagonistas de los receptores Beta adrenérgicos, antagonistas alpha adrenérgicos postinápticos; colinérgicos y anticolinérgicos, de los receptores endorfínicos y de los GABA. Se encontró que Isoproterenal, Prazosim, Doxazosina, Tramadol y Vgabatrin dieron marcada protección de la mucosa gástrica en el estrés, con un área necrótica cercana al 0 por ciento (P<0.001); en contraste, Propanolol, Acetilcolina, Atropina, Naloxona y Flumazenil no se diferenciaron del estrés testigo (P>0.5). Todos los fármacos estudiados dieron similares aminas vasoactivas que el estrés testigo. Se concluyó que el sistema nervioso autónomo en su vinculado a sus receptores con incremento de la microcirculación esplácnica.

Angiogenesis: characterization of a cellular model

Endothelial cell proliferation and differentiation into blood capillaries (i.e., angiogenesis) are essential for growth and development, wound healing, osetogenesis, etc. But abnormal angiogenesis during tumor progression could lead to serious consequences. Angiogenesis is a complex biochemical process, and is often difficult to study the molecular mechanism in vivo due to interference by multitude of factors. Here, I present a non-transformed capillary endothelial cell line as a model which has been extensively characterized morphologically and biochemically to study the fundamentals of the angiogenic process. Studies completed in our laboratory also evidenced that expression of Glc3Man9GlcNAc2-PP-Dol is intricately connected with the balance between the cellular proliferation and apoptosis during angiogenesis.

Correlación entra la proliferación celular y la expresión de receptores beta adrenérgicos en linfocitos T activados / Relation between cell proliferation and beta adrenergic receptors expression in activated T lymphocytes

Se caracterizó la presencia de receptores (R)ß adrenérgicos em linfocitos murinos normales estimulados com Concanavalina A (Con A) y en una línea celular hiperproliferativa (BW5147) mediante la unión específica del radioligando 125Iodo-cianopindolol (125I/CYP)) a las células. La funcionalidad de los R se midió a través de cambios en la produccón de AMPc en presencia del agonista ß adrenérgico isoproterenol (ISO). Ambos tipos celulares mostraron un número disminuido de R ß adrenérgicos por unión específica al 125I-CYP. Se midieron los niveles intracelulares de AMPc en presencia de un agonista ß adrenérgico, las células BW5147 no mostraron un incremento significativo en los niveles de AMPc mientras que las células con Con A mostraron un incremento aunque menor al que presentan linfocitos normales, sin embargo, ambos tipos celulares respondieron a la prostaglandina E1(PGE1) produciendo un incremento en la produción de AMPc. Podemos concluir que la línea celular hiperproliferativa BW5147 no posee R funcionales, en este trabajo se analiza la posible implicancia de un camino intracelular alternativo y su control neuroendocrino

Experimental autoimmune myocarditis: a suitable model to study neuroimmune crosstalk

This review regards the main functional characteristics of hearts subjected to an autoimmune response focusinf especially on the role of T lymphocytes and autoantibodies in the development of cardiac dysfunction. Evidence of a strong association in the onset and time-course of immune response and cardiac dysfunction is presented and the results are viewed comparatively with myocarditis models induced by heart, parasite or virus inoculation. Cardiac damage is evaluated regarding various aspects, namely histologic, immunologic, biochemical, pharmacologic, physiologic. Finally, the model, for its characteristics of resulting from an autoimmune response against the heart with functional consequences, has proved its usefulness to study neuroimmune interaction, mainly the immune to nervous direction, as autoantibodies and T cell-derived factors have a role in cardiac failure.

Participation of autonomic nervous system in the pathogenesis of Chagas disease

Evidences accumulated over the last decade give adequate proof for the existence of circulating antibodies in Chagas disease which binds to ß adrenergic and muscarinic cholinergic receptor of lymphocytes and myocardium. The interaction of the antibodies with lymphocytes and cardiac neurotransmitter receptors behaving as an agonist, triggers in the cells intracellular signal transductions that alter the physiological behaviour of this cells. These events converted the cells in pathologically active cells. Thus, antibodies activating ß adrenergic receptors of T helper (Th) lymphocytes increase cAMP and releases PGE2 by T suppressor/cytotoxic (Ts/c) cell, inducing in this way, immunosuppression by simultaneous inhibition of Th and stimulation of Ts/c cell function. All these antibodies actions were mimetized by parasite's membranes. On the other hand, the interaction of antibodies against heart ß adrenergic and cholinergic receptors trigger physiologic, morphologic, enzymatic and molecular alterations, that leading to cardiac damage. The analysis of the prevalence and distribution of these antibodies shows a strong association with seropositive asymptomatic patients with autonomic dysfunction in comparison with those asymptomatic without alteration of the heart autonomic disorders: pointing to that the presence of these antibodies may partially explain the cardiomyoneuropathy of Chagas disease, in which the sympathetic and parasympathetic systems are affected. The deoposit of autoantibodies on the myocardial neurotransmitter receptors, behaving like an agonist, could induced desensitization and/or down regulation of the receptors. This in turn, could led to a progressive blockade of myocardium neurotransmitter receptors, with sympathetic and parasympathetic dennervation, a phenomenon that has been described in the course of Chagas cardioneuropathy

Midbrain adrenergic mechanism modulating predatory attack behaviour induced by hypothalamic stimulation.

The present study was carried out in ten cats which did not attack the rats spontaneously. Predatory attack on a rat was produced by lateral hypothalamic stimulation using mean current strength of 340-690uA. This attack was accompanied by minimal affective display and culminated in neck biting. It was found that norepinephrine (NE) when microinjected into dorsal periaqueductal gray (dPAG) region in doses of 2, 4 and 10ug significantly lowered the mean current strength required for the elicitation of predatory attack by hypothalamic stimulation. Microinjection of propranolol (Prop), a beta-blocker, within the same region in similar doses significantly blocked the response as indicated by the increase in current strength required to produce the response. Control injections of normal saline and propylene glycol failed to produce any change. These findings indicate that hypothalamically induced aggressive responses involves beta adrenoceptive mechanisms located in the dPAG.

Sistema adrenérgico en los residentes de grandes alturas / Adrenergic system at high altitude population

Heart rate (FC) response to perfusion with isoprenaline is decreased in sealevel natives on expuser to high altitude hypoxia. Since noredraline concentration in plasma is elevated under these condition as phenomenon of downregulation of the betareceptors (BAR) cuold be evoked. For the fisrt time, this aspect was explored in a population native from and residing at 3600 m consisting of normocythemics (HAN) and polycythemics (HAP). the results were compared to those obtained from a sealevel population, exmined in normoxia (SLN) at 4800 m (J. Appl. Physiol. 65:1975-61, 1988). The dose necessary to increase FC by 25 beats per min (125) was identical for HAN and HAP as well as SLN. This iondicates that the chronotropic responses is igual in the two populations when they are studied in their habitual environment; to the contrary, this response is diminished in SLH, thus correlating to the phenomenon of downregulation.

Functional ß2-adrenoceptors in right atria isolated from footshock-stressed rats

The participation of ß2-adrenoceptors in the chronotropic response was evaluated in righ atria isolated from rats submitted to daily footshock stress for three days. Footshock increased both the sensitivity to salbutamol and the pA2 of butoxamine. These results provide additional support for the proposal that repeated footshock stress increases the functional of rat atrial postjunctional ß2-adrenoceptors