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Intravenous (i.v.) injections of adenosine exert marked effects on heart rate (HR) and arterial blood pressure (BP), but the role of an endogenous adenosine release by vagal stimulation has not been evaluated. In anaesthetized rats, we examined HR and BP changes induced by 1 min electrical vagal stimulation in the control condition, and then after i.v. injections of (i) atropine, (ii) propranolol, (iii) caffeine, (iv) 8 cyclopentyl-1,3-dipropylxanthine (DPCPX), or (v) dipyridamole to increase the plasma concentration of adenosine (APC). APC was measured by chromatography in the arterial blood before and at the end of vagal stimulation. The decrease in HR in the controls during vagal stimulation was markedly attenuated, but persisted after i.v. injections of atropine and propranolol. When first administered, DPCPX modestly but significantly reduced the HR response to vagal stimulation, but this disappeared after i.v. caffeine administration. Both the HR and BP responses were significantly accentuated after i.v. injection of dipyridamole. Vagal stimulation induced a significant increase in APC, proportional to the magnitude of HR decrease. Our data suggest that the inhibitory effects of electrical vagal stimulations on HR and BP were partly mediated through the activation of A1 and A2 receptors by an endogenous adenosine release. Our experimental data could help to understand the effects of ischemic preconditioning, which are partially mediated by adenosine.
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1. The aim of this study was first, to characterize alpha 2-adrenoceptor subtypes in human and rat pregnant myometrium and second, to investigate the possibility of a differential expression of the putative subtypes according to the stage of pregnancy. 2. In both species, specific [3H]-rauwolscine binding was inhibited by five different compounds with an order of affinity characteristic of the one described for alpha 2-adrenoceptors (yohimbine > or = clonidine > noradrenaline > phenylephrine > propranolol). Binding affinities (pKi) for the compounds tested were, in human and rat, respectively: 7.63 and 8.93 for yohimbine, 6.91 and 8.71 for clonidine, 6.23 and 6.09 for noradrenaline, 5.37 and 5.73 for phenylephrine, 4.64 and 4.72 for propranolol. 3. By use of non-linear iterative curve fitting procedures and by fitting the data to a two-site model, analysis of [3H]-rauwolscine inhibition binding curves performed in the presence of oxymetazoline (alpha 2A-selective), ARC239, prazosin or chlorpromazine (alpha 2B- and alpha 2C-selective) indicated that pregnant human and rat myometrium contain at least two pharmacologically distinct alpha 2-adrenoceptor subtypes (alpha 2A, alpha 2B and/or alpha 2C). RNA blot analysis with probes specific for each cloned human and rat alpha 2-adrenoceptor subtype demonstrated that alpha 2A- and alpha 2B-subtypes were present in both species but alpha 2C seems to be expressed only in human tissues. 4. In the pregnant rat myometrium, subtype selective compounds competition curves revealed a predominant expression of alpha 2A-adrenoceptors at mid-pregnancy whereas, at term, alpha 2A- and alpha 2B-subtypes density reached approximately the same level (alpha 2A:alpha 2B ratio = 73:27 at mid-pregnancy and = 43:57 at term). In addition, quantification of alpha 2A- and alpha 2B-transcripts by densitometry, following data normalization with an oligo(dT)12-18 probe, showed a pattern of expression comparable to the one characterized by pharmacological studies. 5. In conclusion, these data demonstrate heterogeneity of alpha 2-adrenoceptors in pregnant human and rat myometria and an alteration of the alpha 2A-/alpha 2B-subtypes expression pattern during rat pregnancy. Such observations lead us to suggest a multiple role for alpha 2-adrenoceptors in regulating specific functions of myometrium throughout the time course of pregnancy.
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When C57BL/6 mice were partially hepatectomized (PHx), severe lymphocytosis was induced in the liver in the early phase of hepatocyte regeneration (4 to 12 hours after PHx). A major lymphocyte subset expanding in this organ was estimated to be natural killer 1.1(+) (NK1.1(+)) intermediate CD3 (CD3(int)) cells (i.e., NKT cells). CD3(int) cells are extrathymic T cells generated in situ in the liver. These changes were suppressed when mice with PHx were pretreated with a beta-adrenergicD antagonist (i.e., beta-blocker), propranolol (PPL). This might have been caused by sympathetic nerve stimulation during hepatocyte regeneration. An alpha-blocker showed a similar effect, although the magnitude of suppression was lower than that of the beta-blocker. We previously showed that NK and NKT cells express surface beta-adrenergic receptors and are activated in number by sympathetic nerve stimulation. In the present study, NK cytotoxicity mediated by liver lymphocytes obtained from mice with PHx decreased, whereas NKT cytotoxicity against syngeneic thymocytes increased. Purified CD3(int) cells were also found to be able to mediate NKT cytotoxicity against regenerating hepatocytes. These results suggest that sympathetic nerve stimulation after PHx results in subsequent activation of NKT cells and that these NKT cells might be associated with immunologic surveillance during hepatocyte regeneration.
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1. We have investigated the cardiovascular pharmacology of the crude venom extract (CVE) from the potentially lethal, very small carybdeid jellyfish Carukia barnesi, in rat, guinea-pig and human isolated tissues and anaesthetized piglets. 2. In rat and guinea-pig isolated right atria, CVE (0.1-10 microg/mL) caused tachycardia in the presence of atropine (1 micromol/L), a response almost completely abolished by pretreatment with tetrodotoxin (TTX; 0.1 micromol/L). In paced left atria from guinea-pig or rat, CVE (0.1-3 microg/mL) caused a positive inotropic response in the presence of atropine (1 micromol/L). 3. In rat mesenteric small arteries, CVE (0.1-30 microg/mL) caused concentration-dependent contractions that were unaffected by 0.1 micromol/L TTX, 0.3 micromol/L prazosin or 0.1 micromol/L omega-conotoxin GVIA. 4. Neither the rat right atria tachycardic response nor the contraction of rat mesenteric arteries to CVE were affected by the presence of box jellyfish (Chironex fleckeri) antivenom (92.6 units/mL). 5. In human isolated driven right atrial trabeculae muscle strips, CVE (10 microg/mL) tended to cause an initial fall, followed by a more sustained increase, in contractile force. In the presence of atropine (1 micromol/L), CVE only caused a positive inotropic response. In separate experiments in the presence of propranolol (0.2 micromol/L), the negative inotropic effect of CVE was enhanced, whereas the positive inotropic response was markedly decreased. 6. In anaesthetized piglets, CVE (67 microg/kg, i.v.) caused sustained tachycardia and systemic and pulmonary hypertension. Venous blood samples demonstrated a marked elevation in circulating levels of noradrenaline and adrenaline. 7. We conclude that C. barnesi venom may contain a neural sodium channel activator (blocked by TTX) that, in isolated atrial tissue (and in vivo), causes the release of transmitter (and circulating) catecholamines. The venom may also contain a 'direct' vasoconstrictor component. These observations explain, at least in part, the clinical features of the potentially deadly Irukandji syndrome.
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To test the hypothesis that a β-blocker might reduce the efficacy of ERT, because the action of β-blockers opposes those of β2-agonists.
The aim of the present study was to investigate the effects of propranolol and isoproterenol on the growth curve of infantile hemangioma endothelial cells (IHECs) in vitro and determine the functions of the β-adrenergic receptor in the pathogenesis of infantile hemangioma. IHECs were divided into three groups: The control group, the propranolol group (PG) and the isoproterenol group (IG). The PG and IG were administered with high, medium and low concentrations of the corresponding drugs. The cell growth in each group was determined using the MTT assay. A high propranolol concentration resulted in the inhibition of cell growth. By comparison, isoproterenol promoted cell growth. Within a specific time-frame (72-96 h), high drug concentrations (20 μg/ml) elicited strong effects on the cells. At certain concentrations, propranolol inhibited cell growth once the proliferation stage of IHECs had been affected for a specific length of time, whereas isoproterenol yielded opposite results. The β-adrenergic receptor elicits an important effect in the pathogenesis of infantile hemangioma.
The present results indicate that alpha(1) and alpha(2)-adrenoceptors mediate the cardiovascular responses to noradrenaline microinjected into the BST. In addition, they point to an inhibitory role played by the activation of local beta(1)-adrenoceptors in the cardiovascular response to noradrenaline microinjected into the BST.
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Organisms in the environment are exposed to a number of pollutants from different compound groups. In addition to the classic pollutants like the polychlorinated biphenyls, polyaromatic hydrocarbons (PAHs), alkylphenols, biocides, etc. other compound groups of concern are constantly emerging. Pharmaceuticals and personal care products (PPCPs) can be expected to co-occur with other organic contaminants like biocides, PAHs and alkylphenols in areas affected by wastewater, industrial effluents and intensive recreational activity. In this study, representatives from these four different compound groups were tested individually and in mixtures in a growth inhibition assay with the marine algae Skeletonema pseudocostatum (formerly Skeletonema costatum) to determine whether the combined effects could be predicted by models for additive effects; the concentration addition (CA) and independent action (IA) prediction model. The eleven tested compounds reduced the growth of S. pseudocostatum in the microplate test in a concentration-dependent manner. The order of toxicity of these chemicals were irgarol>fluoxetine>diuron>benzo(a)pyrene>thioguanine>triclosan>propranolol>benzophenone 3>cetrimonium bromide>4-tert-octylphenol>endosulfan. Several binary mixtures and a mixture of eight compounds from the four different compound groups were tested. All tested mixtures were additive as model deviation ratios, the deviation between experimental and predicted effect concentrations, were within a factor of 2 from one or both prediction models (e.g. CA and IA). Interestingly, a concentration dependent shift from IA to CA, potentially due to activation of similar toxicity pathways at higher concentrations, was observed for the mixture of eight compounds. The combined effects of the multi-compound mixture were clearly additive and it should therefore be expected that PPCPs, biocides, PAHs and alkylphenols will collectively contribute to the risk in areas contaminated by such complex mixtures.
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Sodium taurocholate (5 mM, apical side) and bovine serum albumin (4.5% w/v, basal side) increased the permeated amount of poorly water-soluble drugs. Both additives were considered to be effective at mimicking in vivo conditions of intestinal drug absorption. From the correlation between the permeated amount of 13 drugs (% dose/2 h) in the D/P system and their percentage dose absorbed in humans in vivo, this system was found to be useful in evaluating oral absorption of poorly water-soluble drugs.
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En nuestra serie el propranolol fue eficaz sin evidenciar complicaciones en el período neonatal. Si los beneficios del propranolol sobrepasan los riesgos, se recomienda administrar la menor dosis eficaz, de forma hospitalaria y precoz para obtener mejores resultados.
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Lymphatic malformation (LM), which was previously termed lymphangioma, is a rare congenital malformation of the lymphatic system and its treatment is still challenging. Propranolol (beta blocker) has been recently developed as a first-line treatment of infantile hemangioma. Our study aimed to assess the effect of propranolol on pediatric LM and the relationship between its effectiveness and vascular endothelial growth factor (VEGF) family members (VEGF-A, C and D). Six Japanese patients with LM (age range: 10 months-19 years old; 2 macrocystic, 2 microcystic and 2 combined type) were enrolled. Oral propranolol was administered at 2 mg/kg/day. The efficacy of propranolol for LM was evaluated by the rate of volume change as calculated from MRI imaging and by symptomatic improvement. In all patients, there were no significant side effects. Patients 3 and 5 were classified as objective responders with tumor volume reduction of 30.6% and 22.9%, respectively, at 24 weeks. Patient 1 showed 8% tumor volume reduction and patient 6 showed symptomatic improvement, hence, both were classified as minimal responders. The other two patients were classified as non-responders. Plasma VEGF-A, C, and D levels were significantly higher in the LM group than in the controls (all P < 0.01 by Mann-Whitney test). VEGF-A and D levels at 24 weeks were significantly lower than those at pre-treatment (P = 0.031, 0.047 by Wilcoxon matched pairs test). Though further trials with this treatment must be carried out, we propose that propranolol may be an alternative therapy option for intractable LM.
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Obtaining a better understanding of mechanisms involved in bacterial infections is of paramount importance for the development of novel agents to control disease caused by (antibiotic resistant) pathogens in aquaculture. In this study, we investigated the impact of catecholamine stress hormones on growth and virulence factor production of pathogenic vibrios (i.e. two Vibrio campbellii strains and two Vibrio anguillarum strains). Both norepinephrine and dopamine (at 100 μM) significantly induced growth in media containing serum. The compounds also increased swimming motility of the tested strains, whereas they had no effect on caseinase, chitinase, and hemolysin activities. Further, antagonists for eukaryotic catecholamine receptors were able to neutralize some of the effects of the catecholamines. Indeed, the dopaminergic receptor antagonist chlorpromazine neutralized the effect of dopamine, and the α-adrenergic receptor antagonists phentolamine and phenoxybenzamine neutralized the effect of norepinephrine, whereas the β-adrenergic receptor antagonist propranolol had limited to no effect. Finally, pretreatment of pathogenic V. campbellii with catecholamines significantly increased its virulence toward giant freshwater prawn larvae. However, the impact of catecholamine receptor antagonists on in vivo virulence was less clear-cut when compared to the in vitro experiments. In summary, our results show that—similar to enteric pathogens—catecholamines also increase the virulence of vibrios that are pathogenic to aquatic organisms by increasing motility and growth in media containing serum.
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In this LQT3 model, an increase in adrenergic activity by epinephrine had dose-dependent, opposite effects on ventricular electrical stability. Since beta-adrenergic blockade suppressed epinephrine-induced PVC and polymorphic VA, it might be considered for supplemental therapy to suppress VA in patients presenting with LQT3.
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Kasabach-Merritt syndrome (KMS) is a rare but life-threatening illness. The purpose of this study is to report our single-center experience with KMS.
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Essential tremor (ET) is the most common movement disorder. In most patients the course of ET is mild and pharmacological therapy controls postural and kinetic components of tremor. The first-line treatment of ET is pharmacotherapy with propranolol, primidone and gabapentin. In patients with marked head and voice tremor, local botulinum toxin injections have been found to be very effective. Despite optimal drug therapies it is estimated that approximately 50% of patients with ET have medication-resistant tremor. ET can cause more functional impairment than parkinsonian resting tremor because most prominent components of ET are postural and kinetic ones. For patients with drug-resistant debilitating tremor, surgical therapy (thalamotomy) and more recently deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus (VIM) is a viable treatment modality. Several long-term studies have confirmed the high effectiveness rate of ablative surgery and thalamic DBS in the treatment of ET. The most striking advantage of thalamic DBS is the possibility of performing bilateral surgery in one operative session with a significantly lower rate of side effects. Nowadays the bilateral staged thalamotomy is performed rarely because of unacceptable side effects. Moreover, many authors have observed that in bilaterally stimulated patients the head and voice tremor have diminished in postoperative course. Thalamic DBS is a very efficacious and safe procedure in the treatment of ET.
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Previously, nonselective beta-blockade (BB) with propranolol demonstrated protection of the bone marrow (BM) after trauma and hemorrhagic shock (HS). Because selective beta-1 blockers are used commonly for their cardiac protection, the aim of this study was to more clearly define the role of specific beta adrenergic receptors in BM protection after trauma and HS.
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The most appropriate treatment for acute gastric variceal bleeding (GVB) is currently endoscopic gastric variceal obturation (GVO) using Histoacryl®. However, the secondary prophylactic efficacy of beta-blocker (BB) after GVO for the first acute episode of GVB has not yet been established. The secondary prophylactic efficacy of BB after GVO for the first acute episode of GVB was evaluated in this study.
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To prospectively assess the efficacy and safety or propranolol as a first-line treatment for problematic infantile haemangioma in China.
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Propranolol induced a significant dose dependent cytotoxic effect at ≥ 0.2 mM concentration on all three human cell lines (Molt-4, Jurkat and U937) used in this study, after 12 hours incubation onwards, compared to untreated control cells.
Excessive levels of catecholamines have long been known to be cardiotoxic, but less well known are their toxic effects on skeletal muscle. By using an antimyosin monoclonal antibody and quantitative methods to measure the extent of myocyte necrosis, and by employing modulators of adrenoceptors (ARs), including clenbuterol, bupranolol, propranolol, bisoprolol, atenolol, ICI-118551, phenoxybenzamine, prazosin, and yohimbine, the involvement of ARs in isoproterenol-induced myotoxicity was characterized. In the myocardium, the toxic effects were predominantly mediated via the beta(1)-ARs. In the soleus muscle, it was almost solely via the beta(2)-ARs. Myotoxicity was also observed in the myocardium when challenged with the beta(2)-AR agonist clenbuterol. This was found to be mediated via sympathetic presynaptic beta(2)-ARs, leading to enhanced release of norepinephrine. This effect was abolished by prior treatment with reserpine. The skeletal muscle was found to be more sensitive to the myotoxic effects than cardiac muscle at lower doses of beta-AR agonists. These experiments introduce a new way of assaying beta-AR antagonists by classifying them according to their ability to prevent catecholamine-induced myotoxicity. Further research along these lines may deepen understanding of which beta-blockers work best in heart failure therapy.
To compare intralesional corticosteroid (IC) injections with oral propranolol in children with periorbital infantile hemangioma (IH).
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Two different column-switching HPLC systems (CSWs), employing restricted access material for initial pretreatment of biological samples, were developed for the determination of propranolol enantiomers in microdialysate. CSW 1 was a single-pump set-up based on an initial sample clean-up step with a RP-18 ADS precolumn coupled with an ovomucoid analytical column for direct drug enantioseparation. For the two-pump column set-up (CSW 2), a teicoplanin analytical column was applied for the enantioselective assay after initial sample pretreatment using a RP-8 ADS precolumn. The inter-day precision of the CSW 1 ranged from 0.5 to 5.1% for (R)-propranolol and from 5.1 to 10.5% for (S)-propranolol. The limit of detection (LOD) was set at 10 ng/ml and 15 ng/ml for (R)- and (S)-propranolol, respectively. Inter-day relative standard deviation values of the CSW 2 ranged from 1.1 to 9.9% for (R)-propranolol and from 1.3 to 9.6% for (S)-propranolol. The LOD of the method was 3.0 ng/ml for (R)-propranolol and 2.5 ng/ml for (S)-propranolol. Both approaches were successfully applied for stereoselective monitoring of unbound propranolol levels in rat microdialysates.
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In 12 dogs, anesthetized with sodium pentobarbital, a right thoracotomy was performed. We stabilized a basket electrode catheter within the left pulmonary artery (LPA) through a purse string suture in the right ventricle. Electrode catheters were sutured to multiple atrial sites including the four pulmonary veins and the right and left atrial appendages, along Bachman's bundle and the coronary sinus.
To explain the distinctive pharmacological profiles observed for adrenergic stimulation of cell proliferation (beta1) and cell differentiation (beta3), the adrenergic control of cAMP accumulation was investigated during brown adipocyte development. In preadipocytes, norepinephrine (NE) increased cAMP levels but the beta3-agonists BRL-37344 and CGP-12177 did not; in contrast, when the cells had differentiated into mature brown adipocytes, a large cAMP response to the beta3-agonists had emerged and was now double that to NE (although the affinity of NE had increased 10-fold). Beta1-messenger RNA (mRNA) levels were high in both pre- and mature brown adipocytes; beta3-mRNA did not appear until maturation but then abruptly. Although beta1-receptors remained detectable by [3H]CGP-12177 binding in the mature brown adipocytes, the cAMP response to NE (based on propranolol inhibitory potency) switched from beta1 to beta3. Even the established beta1-agonist dobutamine acted through beta3-receptors in the mature brown adipocytes. The increases in cAMP levels could adequately explain the increased cell proliferation in NE-stimulated preadipocytes and the NE-induced UCP1 gene expression in mature brown adipocytes. The distinctive adrenergic profiles for stimulation of proliferation and of differentiation were thus not due to the existence of additional pathways but to a switch in the type of beta-receptor mediating the NE response, coordinated with an alteration in the nuclear response to increased cAMP levels. The study implies that full recruitment of brown adipose tissue cannot be induced by exclusive beta3-stimulation.
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To assess the clinical response to and predictors of propranolol use in the treatment of IH.
The average percent magnitude changes from baseline tremor measurements were +15%, +31%, and -22% for placebo, caffeine, and propranolol groups, respectively. Analysis of variance techniques accounting for effects of individuals, drugs, and day order demonstrated that only drug effects on percent magnitude change of tremor were statistically significant (P = .01, F test). Detailed comparisons of the 2 drug groups with the placebo group revealed that, after adjusting for individual and order effects, only the mean decrease in tremor due to ingestion of propranolol was a statistically significant trend (P = .03, F test). Although caffeine caused a larger mean increase in percent magnitude change in tremor than placebo, this trend was not statistically significant (P = .34, F test). The evaluation of systemic physiologic measurements showed that there were statistically significant drug effects on percent change in systolic (P < .001, F test) and diastolic (P = .002, F test) blood pressure and pulse rate (P = .002, F test). Individual and day order effects were not significant. No adverse side effects were observed or reported in our test subjects.
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An influence of hydroxylation phenotype on the concentration of propranolol [corrected] was examined in 52 subjects with hyperlipidemia divided into 4 groups: 1--control, normolipemic, 2--hypercholesterolemic, 3--hypertriglyceridemic, and 4--mixed-form hyperlipidemic. Each study group included extensive metabolizers and one subject characterized by a poor hydroxylation phenotype. Propranolol was given intragastrically at a single dose of 80 mg [corrected]. Blood was sampled within 24 hours following the drug administration. HPLC method was used for determining blood serum concentrations of propranolol. In each study group mean blood serum concentrations of propranolol in poor metabolizers were at maximum in subject with hypertriglyceridemia, at minimum in the normolipemic one, and intermediate in hypercholesterolemic (upper) and mixed-form hyperlipidemic ones. Lipid metabolic disturbances also affected blood serum concentrations. They were the highest in hypertriglyceridemic patients, whereas in hypercholesterolemic were, in early stage of observation, even lower then in normolipemic subjects. Blood serum concentrations of propranolol [corrected] attained minimal values in patients with mixed form of hyperlipidemia. In the light of the present study we can state that hyperlipidemia modifies the blood serum concentrations of propranolol [corrected]. Although, the type of hyperlipidemia and lipophilic propranolol are not the only determinants affecting blood serum concentrations of propranolol, but also a genetic factor, i.e. hydroxylation phenotype may play an important role.