Beta-adrenoceptor Density Research Articles

Exercise Training Stabilizes RyR2-Dependent Ca2+ Release in Post-infarction Heart Failure.

Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca2+ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca2+ release in rats with post-myocardial infarction HF.Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding.Results: ET increased VO2max in HF-ET rats to 127% of HF-SED (P < 0.05). This coincided with attenuated spontaneous SR Ca2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca2+ transient amplitude and slowed Ca2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca2+ homeostasis and major proteins involved in the regulation of SR Ca2+ release and reuptake could not explain the attenuated spontaneous SR Ca2+ release or reduced Ca2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta1-adrenoceptor density and beta1:beta2-adrenoceptor ratio in HF-ET.Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.

Brief Review: Atrial Fibrillation in Hyperthyroidism Increases Propensity to Stroke

Context: Deregulations of the bodily systems increase the predisposition to cerebrovascular diseases (CVDs). Thyroid hormone deregulations lead to an observed increase in predisposing such patients to stroke. Evidence Acquisition: Online literature search was conducted using PubMed, Google Scholar, and Cochrane as databases. Results: Increase in thyroid hormone level affects the cardiovascular system by increasing the density of beta-adrenergic receptors on cardiomyocytes. The highest post diagnosis risk in hyperthyroidism has been reported for atrial fibrillation and arterial embolism, which increases the risk of ischemic and nonischemic stroke. Atrial fibrillation has thromboembolic stroke as one of the feared outcomes. Conclusions: Preexisting literature has considerable evidence of increased risk of CVDs in patients with hyperthyroidism and atrial fibrillation together, compared with patients who have either of these diseases.

P1787Impact of cardiac beta-adrenergic receptor density evaluated by cardiac PET on chronotropic incompetence

P1787Impact of cardiac beta-adrenergic receptor density evaluated by cardiac PET on chronotropic incompetence

Hypertensive subjects with type-2 diabetes, the sympathetic nervous system, and treatment implications

Central obesity is closely linked to hypertension and type-2 diabetes (DM2) in young/middle-age. In the elderly, systolic hypertension is a reflection of aging/stiff arteries. Diastolic (±systolic) hypertension in young/middle-age is accompanied by increased sympathetic nerve activity, particularly in the presence of the metabolic syndrome or DM2. High beta-receptor density (Bmax) and cyclic AMP (cAMP) levels in human lymphoctes, independent of blood pressure, are associated with a high risk of myocardial infarction (not stroke-risk, which is dependent on blood pressure). This has treatment implications in the young/middle-aged hypertensive subject. Antihypertensive agents that increase sympathetic nerve activity e.g. dihydropyridine calcium blockers, angiotensin receptor blockers, and thiazide-type diuretics, do not reduce (and may increase) the risk of myocardial infarction. Beta-1 blockade, effective in reversing and stabilising coronary atheromataous plaque, and with possible anti-tumor properties, is superior to ACE-inhibition, and is the treatment of choice in young/middle-aged hypertension with DM2.

Hypoxia induced changes in lung fluid balance in humans is associated with beta-2 adrenergic receptor density on lymphocytes

BackgroundPrevious studies have demonstrated an important role for beta-2 adrenergic receptors (β2AR) in lung fluid clearance. The purpose of this investigation was to examine the relationship between β2AR density on lymphocytes and indices of lung water in healthy humans exposed to ∼17h of hypoxia (FIO2=12.5% in a hypoxia tent). MethodsThirteen adults (mean±SEM; age=31±3 years, BMI=24±1kg/m2, VO2 Peak=40±2 ml/kg/min) participated. Pulmonary function, CT derived lung tissue volume (Vtis-tissue, blood and water), lung diffusing capacity for carbon monoxide (DCO) and nitric oxide (DNO), alveolar-capillary conductance (DM), pulmonary capillary blood volume (Vc) and lung water (CT Vtis−Vc) were assessed before and after ∼17h normobaric hypoxia (FIO2=12.5%). β2AR density on lymphocytes was measured via radioligand binding. Arterial oxygen saturation (SaO2), cardiac output (Q), right ventricular systolic pressure (RVSP) and blood pressure (BP) were also assessed. ResultsAfter 17h hypoxia, SaO2 decreased from 97±1 (normoxia) to 82±4% and RVSP increased from 14±3 (normoxia) to 29±2mmHg (p<0.05) with little change in Q or BP. Vc and DM both increased with hypoxia with a small increase in DM/Vc ratio (p>0.05). CT Vtis decreased and lung water was estimated to decline 7±13%, respectively. β2AR density averaged 1497±187 receptors/lymphocyte and increased 21±34% with hypoxia (range −31 to +86%). The post-hypoxia increase in β2AR density was significantly related to the reduction in lung water (r=−0.64, p<0.05), with the subjects with the greatest increase in density demonstrating the largest decline in lung water. ConclusionsLung water decreases with 17h normobaric hypoxia are associated with changes in beta adrenergic receptor density on lymphocytes in healthy adults.

Diastolic dysfunction following HIV infection

The development of myocardial dysfunction in patients following HIV infection continues to be widely reported [1–6]. Compelling evidence of surprisingly frequent diastolic dysfunction followed by systolic dysfunction is observed in both the pediatric and adult populations [1–6]. Basic mechanisms proposed to explain these clinical observations include direct effects of HIV proteins, or indirect effects of cytokines, co-infection, autoimmunity and antiretroviral toxicity [1,7]. The advent of highly active antiretroviral therapies (HAART) has prolonged survival, but has been considered a potential source of cardiovascular complications of HIV infection [1]. Recent clinical studies in countries lacking universal access to HAART have provided some insights into the relative importance of HIV infection as opposed to its pharmacotherapy in HIV cardiomyopathy. These recent studies indicate that HIV cardiomyopathy is more prevalent among patients with HIV alone compared with those patients with HIV who also received HAART [1–6]. Thus, HIV infection appears to contribute more to HIV cardiomyopathy than does its treatment. Human autopsy data identifying gp120 in the hearts of HIV cardiomyopathy patients prior to HAART also support its potential pathogenic role in this condition [8]. The study by Kelly et al.[9] in this issue of AIDS provides an exciting and timely addition to the literature supporting a pathogenic role for HIV proteins in myocardial dysfunction following HIV infection. The authors use the most elegant and definitive hemodynamic and echocardiographic techniques to convincingly demonstrate the presence of diastolic dysfunction in their simian immunodeficiency virus (SIV) model. Their data are quite consistent with diastolic dysfunction in HIV patients that has been reported using echocardiographic methods. The authors found up-regulation of macrophage markers in the myocardium of SIV-infected animals that did not correlate with functional decline. On the contrary, SIV-induced diastolic dysfunction was strongly correlated with the extent of SIV replication in the myocardium. The authors concluded that their data support a pathogenic role for HIV virus or viral proteins in myocardial dysfunction. These clinical reports stimulated efforts to study the direct effects of recombinant HIV proteins in animal models to appreciate their potential pathogenic role in HIV cardiomyopathy [10–15]. The HIV coat protein, gp120, was reported to enhance IL-1beta-induced inducible nitric oxide synthase expression and nitric oxide production in neonatal rat cardiac myocytes in vitro[10]. A direct, negative inotropic effect of HIV gp120 on adult rat ventricular myocytes (ARVMs) was subsequently shown to be mediated through a novel CXCR4-iPLA2-p38 mitogen activated protein (MAP) kinase-troponin I signaling pathway [11–13]. Specifically relevant to Kelly et al. was a report that the injection of HIV gp120 resulted in a selective defect in the diastolic relaxation (lusitropic) response to adrenergic stimulation in vivo[14]. Defective adrenergic signaling is a common characteristic of both ischemic and nonischemic cardiomyopathies [16]. Previously described ‘classical’ mechanisms include decreased beta adrenergic receptor density, decreased adenylyl cyclase/protein kinase A activity, uncoupling the beta adrenergic receptor from stimulatory guanosine-5′-triphosphate (GTP)-binding protein, Gs, in conjunction with an increase in beta adrenergic receptor kinase (BARK) activity, as well as an increase in the content of the inhibitory GTP-binding protein, Gi [16]. Additional molecular insights into adrenergic signaling and diastolic function may provide an alternative mechanism for diastolic dysfunction in HIV [16]. Investigators using elegant experimental designs have provided compelling evidence for a role for p38 MAP kinase and troponin I as molecular components of signaling pathways participating in adrenergic-mediated enhancement of diastolic function. In particular, p38 MAP kinase has been reported to regulate pathways involved in the Ser 23/24 phosphorylation of troponin I [15,16]. Interestingly, a direct correlation was reported between the attenuation of the lusitropic effect of isoproterenol by the p38 MAP kinase inhibitor with blocking the phosphorylation of both p38 MAP kinase and troponin I [14]. These data are most consistent with a selective effect of HIV gp120 on p38 MAP kinase-troponin I signaling that results in attenuated adrenergic enhancement of diastolic relaxation. These clinical and experimental data are consistent with the hypothesis that HIV proteins may directly contribute to myocardial dysfunction. Kelly et al.[9] in this issue of AIDS now provide an excellent animal model with which to further explore potential molecular mechanisms contributing to myocardial dysfunction following HIV infection. Further studies into the signaling pathways stimulated by HIV proteins in the myocardium may provide novel insights and therapeutic targets relevant to HIV, as well, as other human cardiomyopathies. Acknowledgements The work was supported by NIH RO-1 #HL70565 and Department of Veterans Affairs MERIT Award. Conflicts of interest There are no conflicts of interest.

P203 Effets comparés de l’hémodialyse et de la dialyse péritonéale sur l’état nutritionnel et le statut redox chez l’insuffisant rénal chronique

Aging alters motor performance. Changes in adrenergic systems also occur and may be involved in altered motor function. Since beta-adrenergic input is prominently involved in cerebellar control, the current study investigated the relationship between cerebellar beta-adrenergic status and motor function in old (27 month) and mature (10 month) C57BL mice. Plank balance, photocell box activity and novelty-induced locomotion were all greater in mature compared to old mice (P < 0.01) as was beta-adrenergic receptor density. Beta-adrenergic receptor density, but not receptor affinity for antagonist, was highly correlated to these measures of motor function when results from both groups of animals were analyzed: Plank balance (R = 0.80, P < 0.01); locomotion in an open field (R = 0.60, P < 0.01) and in a photocell box (R = 0.59, P < 0.02). Aging alters cerebellar motor function and part of this dysfunction is correlated with beta-adrenergic receptor density.

Characterization of bovine neutrophil β2‐adrenergic receptor function

This study compares bovine leukocyte beta-adrenergic receptor densities to that of the rat, demonstrates for the first time a functional beta(2)-adrenergic receptor signaling pathway in steer neutrophils, and investigates the effect of an inflammatory stimulus on that signaling pathway. The beta(1)-/beta(2)-adrenergic antagonist ([3H])CGP-12177 demonstrated that rat lymphocyte specific binding-site density was highest, followed by steer and dairy cow lymphocytes, and lastly steer and dairy cow neutrophils. The beta(2)-adrenergic agonist terbutaline stimulated steer neutrophil adenosine 3,5-cyclic monophosphate (cAMP) production, an effect increased by inclusion of > or = 1 x 10(-8) M phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C. Both terbutaline and the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) independently decreased steer neutrophil superoxide anion production in a concentration-dependent manner, with 1 x 10(-4) M IBMX enhancing both the potency and efficacy of the terbutaline effect (up to 74% reduction in superoxide anion production). Superoxide anion production was also reduced by the synthetic cAMP analog 8-bromo-cAMP, which increased the potency of the IBMX effect on superoxide anion production. Taken together, these data demonstrate the presence of a beta(2)-adrenergic receptor signaling pathway in bovine neutrophils much like that described in other animal species, as well as the potential for an inflammatory stimulus to alter its function.

Myocardial -adrenoceptor down-regulation early after infarction is associated with long-term incidence of congestive heart failure

Adverse left ventricular (LV) remodelling after myocardial infarction (MI) frequently leads to congestive heart failure (CHF). We have previously shown that myocardial beta-adrenoceptor density (beta-ARD) is reduced soon after acute MI and correlates with LV dilatation in the short term. The aim of the present study was to determine whether myocardial beta-ARD measured early after MI was associated with progression to CHF in the long term. We prospectively included 61 consecutive patients (mean age, 52 +/- 11 years, 10 female) in whom MI was the first manifestation of coronary artery disease. Two to 4 weeks after MI, patients underwent positron emission tomography with S-[(11)C]CGP 12177 to measure beta-ARD and (15)O-labelled water to measure myocardial blood flow and coronary flow reserve. Patients were followed-up for a median of 12.7 years (interquartile range, 6.5-13.7 years) and incidence of CHF was recorded. Eleven patients (18%) developed CHF during follow-up. They had lower beta-ARD compared with those who did not (5.35 vs. 6.49 pmol/g, P < 0.001). In patients with myocardial beta-ARD < or =5.57 pmol/g, 10-year CHF incidence rates were higher than in patients with beta-ARD >5.57 pmol/g (57% vs. 9%, P < 0.001). In a Cox regression model, only whole-heart beta-ARD [hazard ratio (HR) 0.29; 95% confidence interval (CI), 0.15-0.58, P < 0.001] and beta-ARD in remote myocardium (HR 0.32; 95% CI, 0.16-0.61, P = 0.001) were significantly associated with the incidence of CHF at follow-up. Reduced myocardial beta-ARD early after MI is associated with the incidence of CHF on long-term follow-up.

The Role of Lipophilic Bile Acids in the Development of Cirrhotic Cardiomyopathy

Marked hemodynamic changes occur in humans and experimental animals with cirrhotic liver disease. In the heart, basal contractility, responsiveness to beta-adrenoceptor activation, and excitation-contraction coupling (ECC) are negatively affected in models of cirrhosis and portal hypertension with portosystemic shunting (PVS), and comprise what has been called cirrhotic cardiomyopathy. These effects are accompanied by elevated circulating levels of bile acids. We investigated whether elevated bile acids act as a myocardial toxicant by exposing cardiac muscle in vitro to bile acids and compared these results with two models of cirrhotic cardiomyopathy with elevated bile acids: CCl4-induced cirrhosis and PVS. Cholic acid, a lipophilic bile acid, produced a decrease in basal cardiac contractility and responsiveness to beta-adrenoceptor activation, both of which appeared to result from altered ECC. beta-Adrenoceptor density and signaling were unaffected. Acutely, ursodeoxycholic acid, a more hydrophilic bile acid, had no effect. Cirrhosis produced a decrease in basal force, depressed beta-adrenoceptor responsiveness, and altered ECC similar to cholic acid. However, cirrhosis also altered beta-adrenoceptor signaling including decreases in cyclic AMP formation, expression of the stimulatory G protein, GS, and beta-adrenoceptor density. Displacement of lipophilic bile acids by chronic administration of ursodeoxycholic acid to rats during the development of cirrhotic cardiomyopathy produced by PVS produced attenuation of the effect on ECC. These results suggest a possible role for lipophilic bile acids in some, but not all of the myocardial consequences of chronic portal vein stenosis and CCl4-induced cirrhosis.

The p75 neurotrophin receptor, semaphorins, and sympathetic traffic in the heart

the sympathetic and parasympathetic branches of the autonomic nervous system control cardiac function through the coordinated activity generated by neurons within the intracardiac autonomic ganglia and central nervous system (3). Activation of the sympathetic efferent projections to the heart increases heart rate, modifies the pattern and conduction velocity of the impulse through the heart, and augments both atrial and ventricular contractility while hastening myocardial relaxation. In the vasculature, the sympathetic nervous system (SNS) reduces venous capacitance and constricts resistance vessels, increasing blood pressure. Conversely, the parasympathetic nervous system (PSNS) decreases heart rate and cardiac impulse conduction. More recent evidence has suggested that the PSNS may also affect ventricular function, indirectly by countering β-adrenergic action or directly via inhibition of L-type Ca2+ channels (34). A transient imbalance between these two branches can lead to increased heart rate and blood pressure when cardiac output is increased. When subnormal cardiac PSNS activity concomitant with sympathetic hyperactivation persists, such as after myocardial infarction, this disequilibrium may increase the risk for cardiac adverse events, including arrhythmias, hypertension, cardiac hypertrophy, and, ultimately, heart failure. This condition is called “autonomic neural remodeling” and can greatly contribute to the induction of ventricular fibrillation, thus increasing the patient's susceptibility to sudden cardiac death (41, 47). It is plausible that neurotrophic factors, target organ-secreted proteins essential for the development and differentiation of neurons, are involved in the remarkable neuroplasticity exhibited by the SNS in the adult life, including autonomic remodeling after infarction and/or in the onset and progression of congestive heart failure (17, 30, 32).

Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3

AimsClinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). β-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease.Methods and resultsWe studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (ΔKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. β-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. β-Adrenoceptor density was reduced in LQT3 hearts. Acute β-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05).ConclusionCholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. β-Adrenoceptor density is reduced, and β-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and β-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.

Paroxetine pretreatment does not change the effects induced in the rat cortical β-adrenergic receptor system by repetitive transcranial magnetic stimulation and electroconvulsive shock

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a clinically effective antidepressant treatment, but meta-analysis suggests that its efficacy is marginal. We investigated whether the administration of rTMS together with paroxetine would enhance its effects on the beta-adrenergic system of the rat. We compared our results with the effects of electroconvulsive shock therapy (ECS). The experiment was performed for 12 d on male Wistar rats that received a physical treatment of either rTMS (B=1.4 T, f=10 Hz, 300 s) or ECS (I=130 mA, f=50 Hz, t=500 ms), preceded by sterile water or paroxetine (10 mg/kg i.p. 30 min earlier). All rats were decapitated 24 h after the final treatment. Cyclic AMP (cAMP) was measured in cortical slices prelabelled with [3H]adenine and stimulated with noradrenaline. beta-adrenoceptor parameters (Bmax and KD) were assessed in the P2 fraction of cortical homogenates using [3H]CGP 12177 as a ligand. ECS resulted in down-regulation of both the cAMP response and beta-adrenoceptor density, while rTMS depressed only the responsiveness of the cAMP-generating system. Paroxetine, which was only effective in dampening the cAMP response, did not change the effects of either physical treatment. The data suggest that any possible interaction between paroxetine and rTMS or ECS does not involve the beta-adrenergic mechanisms.

Involvement of the β-adrenergic system in the cardiac chronic form of experimental Trypanosoma cruzi infection

Changes in the cardiac beta-adrenergic system in early stages of Trypanosoma cruzi infection have been described. Here, we studied an early (135 days post-infection-p.i.) and a late stage (365 days p.i.) of the cardiac chronic form of the experimental infection (Tulahuen or SGO-Z12 strains), determining plasma epinephrine and norepinephrine levels, beta-receptor density, affinity and function, cardiac cAMP concentration and phosphodiesterase activity, cardiac contractility, and the presence of beta-receptor autoantibodies. Tulahuen-infected mice presented lower epinephrine and norepinephrine levels; lower beta-receptor affinity and density; a diminished norepinephrine response and higher cAMP levels in the early stage, and a basal contractility similar to non-infected controls in the early and augmented in the late stage. The Tulahuen strain induced autoantibodies with weak beta-receptor interaction. SGO-Z12-infected mice presented lower norepinephrine levels and epinephrine levels that diminished with the evolution of the infection; lower beta-receptor affinity and an increased density; unchanged epinephrine and norepinephrine response in the early and a diminished response in the late stage; higher cAMP levels and unchanged basal contractility. The SGO-Z12 isolate induced beta-receptor autoantibodies with strong interaction with the beta-receptors. None of the antibodies, however, acted a as beta-receptor agonist. The present results demonstrate that this system is seriously compromised in the cardiac chronic stage of T. cruzi infection.

High beta-adrenoceptor density on peripheral blood mononuclear cells in progressive multiple sclerosis: a manifestation of autonomic dysfunction?

In multiple sclerosis (MS) up-regulation of beta-adrenoceptors on peripheral blood mononuclear cells (PBMCs) has been attributed to either autonomic dysfunction, inflammation or a combination of the two. We have compared secondary progressive MS patients with normal subjects (NS) and two models of autonomic dysfunction; pure autonomic failure (PAF) and multiple system atrophy (MSA, Shy-Drager syndrome). There was up-regulation of beta-adrenoceptors on PBMCs in MS and PAF patients but not in MSA patients. Only in PAF patients beta-adrenoceptor up-regulation was correlated with low plasma levels of noradrenaline (NA) and adrenaline (Ad). In addition to studies in the basal state, measurements also were made after the centrally acting sympatholytic agent clonidine. These were combined with haemodynamic and neurohormonal measurements. After clonidine, there was a fall in blood pressure in NS and MSA patients but not in MS and PAF patients; a rise in growth hormone (GH) in NS and PAF patients but not in MS and MSA patients; and an up-regulation in PBMCs beta-adrenoceptors in NS but not in MS, MSA and PAF patients. Up-regulation of beta-adrenoceptors on PBMCs in MS could be attributed to autonomic dysfunction but the disparity between MS and PAF patients when considering their plasma levels of NA and Ad argue against. Although the neurohormonal responses to clonidine and the physiological assessment of autonomic function in progressive MS patients, demonstrate central autonomic dysfunction resembling that of the MSA patients, the normal basal beta-adrenoceptor densities in the latter, suggests that the up-regulation of these receptors is independent of the central autonomic dysfunction in MS.

Diagnostic and prognostic imaging of the cardiac sympathetic nervous system

Individuals with systolic dysfunction congestive heart failure may have decreased neuronal density, decreased neuronal function (reuptake or retention of norepinephrine), or a combination of these, plus reduction in postsynaptic beta-receptor density. Cardiac neuronal distribution and function can be imaged with standard gamma cameras and PET using radiolabeled analogs of norepinephrine. Postsynaptic beta-adrenergic receptor distribution and density can be determined using PET. Multiple imaging studies of the presynaptic component have reported that those individuals with the lowest retention or fastest washout of the radiolabeled analogs have a much greater annual mortality than do those with greater retention or slower washout rate. The results of some studies have suggested that the image abnormalities are better predictors of death than are more common predictors of outcome such as ejection fraction, heart rate variability, and microvolt T-wave alternans. The variability between these studies makes it unclear which measure of presynaptic dysfunction is the most predictive. beta-Receptor imaging has not been evaluated as extensively as a prognostic tool as has presynaptic imaging. Preliminary data suggest that regional mismatch between beta-receptors and presynaptic norepinephrine transporter function may serve as a marker for adverse outcome.

Receptor-independent sensitization of the adenylyl cylase after chronic treatment with cyclosporine A

Chronic treatment with cyclosporine A (CyA) is often complicated by severe hypertension. If activation of the beta-adrenergic-receptor-linked adenylyl cyclase (AC) system contributes to hypertension is unresolved. Rats were treated with CyA (20 mg kg(-1) day(-1)) for 7 days. beta-adrenergic, muscarinic, and alpha-adrenergic receptors, G-proteins, and the activity of AC were determined in cardiac and pulmonary plasma membranes. The density of cardiac beta-adrenergic receptors, muscarinic receptors, alpha-adrenergic receptors, G(alphas) and, G(alphai) remained unchanged after treatment with CyA. However, CyA increased the responsiveness of AC to different stimulators. The responsiveness of AC was even more pronounced after solubilization and partial purification, suggesting a direct modulation of the enzyme. These data suggest that CyA modulates the activity of the sympathoadrenergic system by a direct, receptor-independent sensitization of AC, suggesting that this pathway contributes to hypertension in patients treated with CyA.

Chemotherapy of chronic indeterminate Chagas disease: a novel approach to treatment

Treatment of Chagas disease is a controversial issue because the available drugs are highly toxic. Clomipramine is a tricyclic antidepressant drug that inhibits Trypanosoma cruzi's trypanothione reductase, provoking the death of the parasite and preventing the cardiac damage when used for the treatment of acutely infected mice. Here, we studied the effectiveness of clomipramine (5 mg/kg/day for one month) as chemotherapy for T. cruzi-infected mice in the chronic indeterminate stage of the infection. The animals were analyzed in the cardiac chronic phase. Survival of treated animals was 84% while for the untreated ones was 40%; most of the animals presented electrocardiographic abnormalities. Affinity and density of cardiac beta receptors from infected and treated mice were similar to those in the indeterminate phase, showing that clomipramine treatment stopped the increment of functional alterations provoked by the infection, while untreated mice presented affinity and density significantly diminished. Hearts from infected and untreated mice in the chronic stage presented mononuclear cells, necrosis and fiber dissolution while hearts from treated animals showed only isolated inflammatory infiltrates. Present results demonstrate that clomipramine used in the chronic indeterminate phase of the T. cruzi infection modified the natural evolution of the chagasic cardiopathy.

Lack of persistent effects of ketamine in rodent models of depression

We investigated the immediate and enduring effects of ketamine in behavioral and neurochemical assays predictive of antidepressant activity. One week after a single administration of ketamine (50-160 mg/kg), otherwise experimentally naive rats and mice were tested either in the forced swim test (FST) or the tail suspension test (TST). Other mice were also tested twice in the FST: immediately and 2 weeks after a single dose (1.25-50 mg/kg) of ketamine. In the next series of experiments, rats treated for 2 weeks twice daily with ketamine (50 or 160 mg/kg) or desipramine (10 mg/kg) were challenged with apomorphine and scored for locomotor activity and assayed for the density of cortical beta-adrenoceptors. The latter test was also carried out in rats that had received a single dose of ketamine (50 mg/kg) 1 week before the assay. The antidepressant-like (FST) and locomotor effects of ketamine (50 mg/kg) and desipramine (10 mg/kg) were assessed after their chronic (2 weeks, twice daily) administration as well. We report the lack of enduring antidepressant-like effect of ketamine in both rats and mice. A 2-week treatment with ketamine neither changed apomorphine-evoked locomotor hyperactivity nor did it decrease the density of cortical beta-adrenoceptors. However, some tolerance to the antidepressant-like effect of ketamine was noted in the FST, but it was accompanied by sensitization to its locomotor stimulatory effects. These data indicate that ketamine neither produces enduring antidepressant-like effects in rodents nor does it display antidepressant-like behavioral or neurochemical effects after chronic treatment.

Acute β-blockade prevents myocardial β-adrenergic receptor desensitization and preserves early ventricular function after brain death

Beta-adrenergic receptor desensitization through activation of the G protein-coupled receptor kinase 2 is an important mechanism of early cardiac dysfunction after brain death. We hypothesized that acute beta-blockade can prevent myocardial beta-adrenergic receptor desensitization after brain death through attenuation of G protein-coupled receptor kinase 2 activity, resulting in improved cardiac function. Adult pigs underwent either sham operation, induction of brain death, or treatment with esmolol (beta-blockade) for 30 minutes before and 45 minutes after brain death (n = 8 per group). Cardiac function was assessed at baseline and for 6 hours after the operation. Myocardial beta-adrenergic receptor signaling was assessed 6 hours after operation by measuring sarcolemmal membrane adenylate cyclase activity, beta-adrenergic receptor density, and G protein-coupled receptor kinase 2 expression and activity. Baseline left ventricular preload recruitable stroke work was similar among sham, brain death, and beta-blockade groups. Preload recruitable stroke work was significantly decreased 6 hours after brain death versus sham, and beta-blockade resulted in maintenance of baseline preload recruitable stroke work relative to brain death and not different from sham. Basal and isoproterenol-stimulated adenylate cyclase activities were preserved in the beta-blockade group relative to the brain death group and were not different from the sham group. Left ventricular G protein-coupled receptor kinase 2 expression and activity in the beta-blockade group were markedly decreased relative to the brain death group and similar to the sham group. Beta-adrenergic receptor density was not different among groups. Acute beta-blockade before brain death attenuates beta-adrenergic receptor desensitization mediated by G protein-coupled receptor kinase 2 and preserves early cardiac function after brain death. These data support the hypothesis that acute beta-adrenergic receptor desensitization is an important mechanism in early ventricular dysfunction after brain death. Future studies with beta-blocker therapy immediately after brain death appear warranted.