Non-selective Beta-blocker Propranolol Research Articles

Predatory Odor Exposure as a Potential Paradigm for Studying Emotional Modulation of Memory Consolidation-The Role of the Noradrenergic Transmission in the Basolateral Amygdala.

The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well-established. Specifically, multiple studies have demonstrated that the activation of the noradrenergic (NA) system within the BLA governs these modulatory effects. However, most current evidence has been obtained by direct infusion of synthetic NA or beta-adrenergic agonists. In the present study, we aimed to investigate the effect of endogenous NA release in the BLA, induced by a natural aversive stimulus (coyote urine), on memory consolidation for a low-arousing, hippocampal-dependent task. Our experiments combined a weak object location task (OLT) version with subsequent mild predator odor exposure (POE). To investigate the role of endogenous NA in the BLA in memory modulation, a subset of the animals (Wistar rats) was treated with the non-selective beta-blocker propranolol at the end of the behavioral procedures. Hippocampal tissue was collected 90 min after drug infusion or after the OLT test, which was performed 24 h later. We used the obtained samples to estimate the levels of phosphorylated CREB (pCREB) and activity-regulated cytoskeleton-associated protein (Arc)-two molecular markers of experience-dependent changes in neuronal activity. The result suggests that POE has the potential to become a valuable behavioral paradigm for studying the interaction between BLA and the hippocampus in memory prioritization and selectivity.

Propranolol, Promising Chemosensitizer and Candidate for the Combined Therapy through Disruption of Tumor Microenvironment Homeostasis by Decreasing the Level of Carbonic Anhydrase IX

Resistance to chemotherapy represents a persisting medical problem, ranking among main causes of chemotherapy failure and cancer mortality. There is a possibility to utilize and repurpose already existing therapeutics which were not primarily intended for oncological treatment. Overactivation of adrenergic receptors and signaling dysregulation promotes tumor progression, metastatic potential, immune system evasion, tumor angiogenesis and drug resistance. The non-selective beta-blocker propranolol, approved in infantile haemangioma treatment, has a high potential for use in cancer therapy. We analyzed the effects of propranolol and 5-fluorouracil combination on sensitive and resistant cells derived from colorectal carcinoma in monolayers, single-component and co-culture spheroids and in vivo mouse models. Our results revealed that propranolol is able to exert its effect not only in chemosensitive colorectal cells, but also in 5-fluorouracil resistant cells. Propranolol disrupts the hypoxic adaptation machinery by inhibiting HIF1α, carbonic anhydrase IX, and activates apoptosis, which may be important in the management of chemo-resistant patients. We showed that propranolol slows down the growth of xenografts formed from colorectal cancer cells, even from cells already adapted to the β-blocker. We provide clear evidence that blockade of β-adrenergic receptors affects essential signaling pathways modulating tumor microenvironment and thus the response to anticancer therapy. Our findings indicate that propranolol could be repurposed to serve as chemosensitizer in combined therapy aimed at disrupting homeostasis of tumor microenvironment.

Impairment of Hypoxia-Induced CA IX by Beta-Blocker Propranolol-Impact on Progression and Metastatic Potential of Colorectal Cancer Cells.

The coexistence of cancer and other concomitant diseases is very frequent and has substantial implications for treatment decisions and outcomes. Beta-blockers, agents that block the beta-adrenergic receptors, have been related also to cancers. In the model of multicellular spheroids formed by colorectal cancer cells we described a crosstalk between beta-blockade by propranolol and tumour microenvironment. Non-selective beta-blocker propranolol decreased ability of tumour cells to adapt to hypoxia by reducing levels of HIF1α and carbonic anhydrase IX in 3D spheroids. We indicated a double action of propranolol in the tumour microenvironment by inhibiting the stability of HIF1α, thus mediating decrease of CA IX expression and, at the same time, by its possible effect on CA IX activity by decreasing the activity of protein kinase A (PKA). Moreover, the inhibition of β-adrenoreceptors by propranolol enhanced apoptosis, decreased number of mitochondria and lowered the amount of proteins involved in oxidative phosphorylation (V-ATP5A, IV-COX2, III-UQCRC2, II-SDHB, I-NDUFB8). Propranolol reduced metastatic potential, viability and proliferation of colorectal cancer cells cultivated in multicellular spheroids. To choose the right treatment strategy, it is extremely important to know how the treatment of concomitant diseases affects the superior microenvironment that is directly related to the efficiency of anti-cancer therapy

Original Article Comprative Study between using Local Corticosteroid, Systemic Beta-Blockers and Combined Therapy in Manegment of Heamangioma in Pediatrics

Infantile hemangiomas (IHs), the most common tumor of childhood. For many years, the first-line medical treatment for complicated lesions was corticosteroids, including topical, intralesional, and systemic approaches. However, a major breakthrough occurred in 2008 observed that a group of children with IH who received therapy with the nonselective beta-blocker propranolol experienced marked improvement in their lesions. This examine meant will think about the middle of those impact of utilizing neighborhood corticosteroids (metamethasone) , systemic beta blocker (Propranolol) and both consolidated in the management about heamangiomas in pediatrics. This might have been a prospective consider that led during Benha college clinic What's more Benha Youngsters doctor's facility on tolerant with heamangioma. Patients for heamangioma who match consideration criteria were isolated haphazardly under three groups: aggregation a : 20 patients in this one assembly might have been undergone intralesional infusion for corticosteroid (betamethasone) during An measurements of 10 with 40 mg/ml On 5 differentiate sessions with a interim from claiming 3 weeks. Assembly B: 20 patients in this bunch were provided for oral b-blocker (propranolol) for 2-3mg/kg/day to 4 months. Bunch C: 20 tolerant in this one assembly were provided for both oral B-blocker (Propranlol) Furthermore intralesional infusion from claiming corticosteroid (Betamethasone) to 4 months. There might have been statistically huge between gathering An and aggregation b over bunch C, in regards repeat then afterward 6m. No repeat struck them Around gathering C, repeat happened for 20% Around bunch B, 10% in bunch An. Mean Contrast about aggregation a (18. 90), bunch b (12. 64) Also bunch c (19. 38), thereabouts assembly c's will be superior to assembly A, one assembly b. There were statistically huge certain unique hemangioma size (cm) Furthermore extent at 6 months around gathering C, However no statistically huge connection the middle of unique hemangioma size (cm) Also size at 6 months around aggregation An What's more bunch b. We discovered fundamentally preferred Conclusion in the joined medicine aggregation contrasted with monotherapy aggregations.

Effects of β-Adrenergic Antagonists on Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

Introduction: Locally advanced non-small cell lung cancer (NSCLC) is highly resistant to chemoradiotherapy, and many cancer patients experience chronic stress. Studies that suggest stimulation of β-adrenergic receptors (β-AR) promotes tumor invasion and therapy resistance. We investigated whether β-AR inhibition with beta-blockers acts as a chemotherapy and radiation sensitizer in vitro and in patients treated with chemoradiation for locally advanced NSCLC. Methods: We investigated the effects of the non-selective beta-blocker propranolol on two human lung adenocarcinoma cell lines (PC9, A549) treated with radiation or cisplatin. We retrospectively evaluated 77 patients with Stage IIIA NSCLC who received induction chemoradiation followed by surgery. Pathological and imaging response, metastatic rate, and survival were analyzed using SPSS v22.0 and PrismGraphpad6. Results: Propranolol combined with radiation or cisplatin decreased clonogenic survival of PC9 and A549 cells in vitro (p < 0.05). Furthermore, propranolol decreased expression of phospho-protein kinase A (p-PKA), a β-adrenergic pathway downstream activation target, in both cell lines compared to irradiation or cisplatin alone (p < 0.05). In patients treated for Stage IIIA NSCLC, 16 took beta-blockers, and 61 did not. Beta-blockade is associated with a trend to improved overall survival (OS) at 1 year (81.3% vs 57.4%, p = 0.08) and distant metastasis-free survival (DMFS) (2.6 years vs. 1.3 years, p = 0.16). Although beta-blocker use was associated with decreased distant metastases (risk ratio (RR) 0.19; p = 0.03), it did not affect primary tumor pathological response (p = 0.40) or imaging response (p = 0.36). Conclusions: β-AR blockade enhanced radiation and cisplatin sensitivity of human lung cancer cells in vitro. Use of beta-blockers is associated with decreased distant metastases and potentially improved OS and DMFS. Additional studies are warranted to evaluate the role of beta-blockers as a chemoradiation sensitizer in locally advanced NSCLC.

EFFECT OF PROPRANOLOL ON AEROBIC-HEMODYNAMIC SUPPORT OF PHYSICAL ACTIVITY IN PATIENTS WITH EFFORT ANGINA, POSITIVE ANTIANGINAL ACTION AND THE ABSENCE OF CLINICAL EFFECT AFTER PROPRANOLOL-BASED TREATMENT

Aim. To analyze the changes in the aerobic-hemodynamic parameters during physical exercise in patients with effort angina administered with reference non-selective beta-blocker propranolol (Obsidan) with positive antianginal action and the absence of clinical effect after the drug intake.Material and Methods. A total of 58 patients (mean age of 54.2 [48.5; 59.5] years) with effort angina of functional class II–IV were examined with spiro-veloergometry tests before and after administration of propranolol (Obsidan: manufactured by Isis Pharma GmbH, Germany) at a dose of 40 mg. At threshold physical activity the following parameters were assessed: oxygen consumption (VO2 ), specific oxygen consumption, cardiac index (CI), rate pressure product (RPP); total peripheral vascular resistance (TPVR), arteriovenous oxygen difference (a-vDО2 ) and mechanical work of the heart (HW).Results. The efficacy of single-dose obsidian was observed in 58.6% of patients with angina (group 1); in this, tolerance to physical exercise increased from 50.0 [25.0; 75.0] W to 75.0 [50.0; 100.0] W. In the rest of patients (group 2), no antianginal effect was registered. At the first stage (at initial threshold physical activity level), administration of propranolol was characterized by saving pattern of heart function: statistically significant decrease in the heart rate, mean arterial pressure, CI and HW. This naturally resulted in reduction of myocardial oxygen demand (decrease in RPP from 163.0 [134.5; 218.5] U to 102.0 [90.0; 142.5] U; p&lt;0.001) and predetermined the drug anti-ischemic action. At the second stage (maximum physical effort), an increase in the physical activity, caused by increase in VO2 from 738.0 [604.5; 1148.0] mL/min to 972.0 [774.5; 1458.0] mL/min, occurred due to higher oxygen extraction from peripheral blood (a-vDО2 increase; p&lt;0.002). In group 2, despite the absence of an increase in tolerance to physical exercise, administration of propranolol was characterized by low RPP threshold i.e. the physical effort similar to the initial level was performed at a lower cardiac energy consumption.Conclusion. Therefore, anti-ischemic effect of Obsidan was due to a decrease in theenergy expenditure of the cardiac function along with a limitation in the hemodynamic productivity efficiently compensated by an increase in the oxygen extraction from circulating blood during physical activity.

EFFECT OF PROPRANOLOL ON AEROBIC-HEMODYNAMIC SUPPORT OF PHYSICAL ACTIVITY IN PATIENTS WITH EFFORT ANGINA, POSITIVE ANTIANGINAL ACTION AND THE ABSENCE OF CLINICAL EFFECT AFTER PROPRANOLOL-BASED TREATMENT

Aim. To analyze the changes in the aerobic-hemodynamic parameters during physical exercise in patients with effort angina administered with reference non-selective beta-blocker propranolol (Obsidan) with positive antianginal action and the absence of clinical effect after the drug intake.Material and Methods. A total of 58 patients (mean age of 54.2 [48.5; 59.5] years) with effort angina of functional class II–IV were examined with spiro-veloergometry tests before and after administration of propranolol (Obsidan: manufactured by Isis Pharma GmbH, Germany) at a dose of 40 mg. At threshold physical activity the following parameters were assessed: oxygen consumption (VO2 ), specific oxygen consumption, cardiac index (CI), rate pressure product (RPP); total peripheral vascular resistance (TPVR), arteriovenous oxygen difference (a-vDО2 ) and mechanical work of the heart (HW).Results. The efficacy of single-dose obsidian was observed in 58.6% of patients with angina (group 1); in this, tolerance to physical exercise increased from 50.0 [25.0; 75.0] W to 75.0 [50.0; 100.0] W. In the rest of patients (group 2), no antianginal effect was registered. At the first stage (at initial threshold physical activity level), administration of propranolol was characterized by saving pattern of heart function: statistically significant decrease in the heart rate, mean arterial pressure, CI and HW. This naturally resulted in reduction of myocardial oxygen demand (decrease in RPP from 163.0 [134.5; 218.5] U to 102.0 [90.0; 142.5] U; p&lt;0.001) and predetermined the drug anti-ischemic action. At the second stage (maximum physical effort), an increase in the physical activity, caused by increase in VO2 from 738.0 [604.5; 1148.0] mL/min to 972.0 [774.5; 1458.0] mL/min, occurred due to higher oxygen extraction from peripheral blood (a-vDО2 increase; p&lt;0.002). In group 2, despite the absence of an increase in tolerance to physical exercise, administration of propranolol was characterized by low RPP threshold i.e. the physical effort similar to the initial level was performed at a lower cardiac energy consumption.Conclusion. Therefore, anti-ischemic effect of Obsidan was due to a decrease in theenergy expenditure of the cardiac function along with a limitation in the hemodynamic productivity efficiently compensated by an increase in the oxygen extraction from circulating blood during physical activity.

Modern Approach and Successful Experience of Conservative Treatment of Infantile Hemangiomas with Non-Selective Beta-Blocker Propranolol

The article deals with the actual problem of modern treatment of infant hemangiomas. The accumulated 10-year experience of using propranolol in 512 patients has shown its effectiveness and safety. The team of authors developed a protocol for managing patients with infantile hemangiomas of various localization at all stages of treatment. Special attention was paid to the cardiological aspect of patient monitoring using modern methods of instrumental diagnostics. Due to the clear application of the created protocol with the use of ultrasound control, in most cases, it was possible to achieve complete cure of this pathology, minimize incidence of undesirable effects and avoid the formation of relapses (rebound effect). The effectiveness of the developed algorithm of diagnosis and treatment is confirmed by both clinical results and the results of instrumental examinations.

Amelioration of Aggression and Echolalia With Propranolol in Autism Spectrum Disorder

Amelioration of Aggression and Echolalia With Propranolol in Autism Spectrum Disorder

Električna oluja kod pacijenta nakon akutnog infarkta miokarda - prikaz slučaja

Background: Electrical storm is a life-threatening syndrome with dramatic clinical presentation. It presents with 3 or more episodes of sustained ventricular tachycardia or ventricular fibrillation during 24 hours with hemodynamic instability requiring termination with DC shocks. In general the prognosis of this syndrome is unfavorable. Case report: We present a patient with electrical storm 12 days after the acute myocardial infarction terminated with non-selective beta blocker Propranolol. The patient was stabilized with 80mg of Propranolol qd and the storm was eliminated. Conclusion: The efficient treatment of electrical storm implies understanding of arrhythmia mechanisms, and different treatment modalities (from implantable cardioverter defibrillator placement to radio frequent catheter ablation).

ВІСЦЕРАЛЬНІ ГЕМАНГІОМИ У ДІТЕЙ: ОСОБЛИВОСТІ КЛІНІЧНИХ ПРОЯВІВ, УСКЛАДНЕННЯ, ЛІКУВАННЯ.

Гемангіоми дихальних шляхів (ГДШ) і гемангіоми печінки (ГП) можуть мати тяжкі клінічні прояви і супроводжуватися ускладненнями, небезпечними для життя. Метою роботи було визначити клінічні прояви, фактори ризику, ускладнення та можливості лікування гемангіом дихальних шляхів і печінки. У дослідження включено 16 дітей віком від 1 до 12 місяців за період 2011–2015 роки. ГДШ діагностовано у 7 пацієнтів, ГП – у 8 дітей. Діагноз ГДШ встановлювали за результатами трахеобронхоскопії, КТ з контрастуванням та МРТ. Для діагностики ГП використовували УЗД, КТ з контрастуванням, МРТ. Виділяли три види ГП: вогнищеві, багатовогнищеві та дифузні. 14 пацієнтів отримували пропранолол у дозі 2 мг кг/добу. В дитини з вогнищевою гемангіомою печінки лікування не проводилося, лише спостереження. ГДШ поєднувалися із сегментарними гемангіомами обличчя у 42,3 %, усі мультифокальні емангіоми печінки поєднувалися з численними інфантильними гемангіомами (ІГ) шкіри. Клінічні прояви ГДШ відзначали у віці від 2 до 5 місяців (у середньому 4,2 місяця). Мультифокальні гемангіоми печінки діагностовано у 62,5 %, дифузні – у 25,0 % та вогнищеві – в 12,5 %. Дифузні гемангіоми печінки клінічно проявлялися відразу після народження ознаками печінкової недостатності та гіпотиреоїдизмом. Лікування ІГ дихальних шляхів розпочинали відразу після встановлення діагнозу, термін початку лікування складав 2,5–4,5 місяця, за винятком однієї дитини, в якої лікування розпочато в 1 рік у зв’язку з пізно встановленим діагнозом. Тривалість лікування складала в середньому 16,1 місяця. У дітей з мультифокальними ІГ печінки лікування розпочинали у віці 2–5 місяців. У дітей з дифузними гемангіомами печінки пропранолол призначали у 14 і 20 днів. Тривалість лікування гемангіом печінки складала в середньому 10,1 місяця. На фоні лікування пропранололом інволюція пухлини настала у всіх пацієнтів. Ускладнень не було. ІГ дихальних шляхів поєднуються із сегментарними гемангіомами обличчя, мультифокальні гемангіоми печінки – з множинними ІГ шкіри. Дифузні гемангіоми печінки ускладнюються печінковою недостатністю і гіпотиреоїдизмом. Неселективний бета-блокатор пропранолол є ефективним у лікуванні ІГ дихальних шляхів і печінки.

A STUDY OF EFFICACY OF TREATMENT FOR ESSENTIAL TREMOR USING TREMOROGRAPHY

Background: Essential tremor is one of the most prevalent extrapyramidal disorders, while treatment efficacy in such patients remains low. Clinical polymorphism of essential tremor requires a differentiated treatment approach, that should be implemented with consideration of objective tremor parameters. Aim: To study efficacy of treatment of essential tremor based on tremorography. Materials and methods: We followed up 85 patients with essential tremor (mean age, 69.05±1.2 years) who were treated with anticonvulsants as monotherapy (primidone or topiramate), or with combination treatment with non-selective beta-blockers (propranolol), anxiolytics (hydroxizine, etifoxine) and aminophenylbutyric acid. During the treatment, we assessed changes in functional status by Fahn-Tolosa-Marin Tremor Severity Scale and by tremorography. Results: Under treatment with primidone, there was a decrease in global tremor assessment of postural tremor (p=0.036) and of action tremor (p=0.001). During treatment with topiramate, there was a decrease in global tremor assessment in all tests performed (p<0.0002). Non-specific treatment (anxiolytics) exerted a positive effect on the functional state of patients with essential tremor. Conclusion: Tremor amplitude and duration are the objective parameters that define its severity. The treatment guidelines for essential tremor in the elderly patients have been developed.

Alpha2-adrenergic blockade emulates the enhancing effect of chronic stress on breast cancer progression

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of beta-adrenergic receptors. Catecholamines also signal alpha-adrenergic receptors, and greater alpha-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of alpha-adrenergic receptors can result in elevated catecholamine levels, which may increase alpha-adrenergic signaling, because pre-synaptic alpha2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of alpha-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective alpha-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective beta-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective alpha2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective alpha1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that alpha2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of beta-adrenergic signaling on tumor progression-relevant biology.

Propranolol efficiency in prevention of sustained ventricular tachycardia in patients with implanted cardioverter-defibrillator: a case series

Propranolol efficiency in prevention of sustained ventricular tachycardia in patients with implanted cardioverter-defibrillator: a case series

Inferior frontal gyrus preserves working memory and emotional learning under conditions of impaired noradrenergic signaling

Compensation has been widely applied to explain neuroimaging findings in neuropsychiatric patients. Functional compensation is often invoked when patients display equal performance and increased neural activity in comparison to healthy controls. According to the compensatory hypothesis increased activity allows the brain to maintain cognitive performance despite underlying neuropathological changes. Due to methodological and pathology-related issues, however, the functional relevance of the increased activity and the specific brain regions involved in the compensatory response remain unclear. An experimental approach that allows a transient induction of compensatory responses in the healthy brain could help to overcome these issues. To this end we used the non-selective beta-blocker propranolol to pharmacologically induce sub-optimal noradrenergic signaling in healthy participants. In two independent functional MRI (fMRI) experiments participants received either placebo or propranolol before they underwent a cognitive challenge (Experiment 1: working memory; Experiment 2: emotional learning: Pavlovian fear conditioning). In Experiment 1 propranolol had no effects on working memory performance, but evoked stronger activity in the left inferior frontal gyrus (IFG). In Experiment 2 propranolol produced no effects on emotional memory formation, but evoked stronger activity in the right IFG. The present finding that sub-optimal beta-adrenergic signaling did not disrupt performance and concomitantly increased IFG activity is consistent with, and extends, current perspectives on functional compensation. Together, our findings suggest that under conditions of impaired noradrenergic signaling, heightened activity in brain regions located within the cognitive control network, particularly the IFG, may reflect compensatory operations subserving the maintenance of behavioral performance.

Cerebral oxygenation decreases during exercise in humans with beta‐adrenergic blockade

Beta-blockers reduce exercise capacity by attenuated increase in cardiac output, but it remains unknown whether performance also relates to attenuated cerebral oxygenation. Acting as their own controls, eight healthy subjects performed a continuous incremental cycle test to exhaustion with or without administration of the non-selective beta-blocker propranolol. Changes in cerebral blood flow velocity were measured with transcranial Doppler ultrasound and those in cerebral oxygenation were evaluated using near-infrared spectroscopy and the calculated cerebral mitochondrial oxygen tension derived from arterial to internal jugular venous concentration differences. Arterial lactate and cardiac output increased to 15.3 +/- 4.2 mM and 20.8 +/- 1.5 L min(-1) respectively (mean +/- SD). Frontal lobe oxygenation remained unaffected but the calculated cerebral mitochondrial oxygen tension decreased by 29 +/- 7 mmHg (P < 0.05). Propranolol reduced resting heart rate (58 +/- 6 vs. 69 +/- 8 beats min(-1)) and at exercise exhaustion, cardiac output (16.6 +/- 3.6 L min(-1)) and arterial lactate (9.4 +/- 3.7 mM) were attenuated with a reduction in exercise capacity from 239 +/- 42 to 209 +/- 31 W (all P < 0.05). Propranolol also attenuated the increase in cerebral blood flow velocity and frontal lobe oxygenation (P < 0.05) whereas the cerebral mitochondrial oxygen tension decreased to a similar degree as during control exercise (delta 28 +/- 10 mmHg; P < 0.05). Propranolol attenuated the increase in cardiac output of consequence for cerebral perfusion and oxygenation. We suggest that a decrease in cerebral oxygenation limits exercise capacity.

Investigation of the relaxant effects of pancuronium, rocuronium, vecuronium and mivacurium on rat thoracic aorta

Pancuronium, vecuronium, mivacurium and rocuronium are nondepolarizing neuromuscular blocking agents, which are competitive antagonists against acetylcholine at nicotinic receptors, and considered to have no direct actions on vascular smooth muscle. We aimed to investigate the relaxant effects and possible underlying mechanisms of these agents on isolated rat thoracic aorta. The preparations were precontracted with prostaglandin F2alpha (10(-7) mol l(-1)) and pancuronium (10(-7)-10(-4) mol l(-1)), rocuronium (10(-7)-10(-4) mol l(-1)), vecuronium (10(-7)-10(-4) mol l(-1)) and mivacurium (10(-7)-10(-4) mol l(-1)) added at cumulative concentrations in the presence or absence of a prostaglandin synthesis inhibitor, indomethacin (10(-6) M), and a nitric oxide synthesis inhibitor, N(omega)-nitro-L-arginine methylester (3 x 10(-5)). The same protocol was applied to both endothelia (+) and endothelia (-) aortic rings. The preparations precontracted with prostaglandin F2alpha (10(-7) mol l(-1)) were stimulated with electrical field stimulation at a frequency of 10 Hz as square-wave pulses of 50 V (0.2 ms) in the presence of a noradrenaline reuptake inhibitor desipramine (10(-7) mol l(-1)) and a nonselective beta-blocker propranolol (10(-6) mol l(-1)). Drugs were added at ineffective concentration of 10(-7) mol l(-1). Tetrodotoxin (10(-7) mol l(-1)) was added to test whether the changes were dependent on the neuronal response. Pancuronium and rocuronium relaxed aortic rings precontracted by prostaglandin F2alpha in a dose-dependent manner, but vecuronium and mivacurium did not. The relaxation effect of pancuronium and rocuronium was endothelium independent because there was not a significant response difference from the endothelium-denuded group. In conclusion, their relaxation effect may be due to an increase in prostaglandin synthesis. The increased relaxation effect of these agents at electrical field stimulation may be by the decreasing effect of noradrenaline reuptake from nerve endings because a noradrenaline reuptake inhibitor desipramine did not change this effect. Also, these neuromuscular agents may affect beta-receptors, because a nonselective beta-blocker agent, propranolol, decreased their electrical field stimulation-induced relaxations.

Metoprolol and propranolol in migraine prophylaxis: a double-blind multicentre study

In a double-blind, cross-over multicentre trial, the prophylactic antimigraine effect of the beta 1-selective beta-blocker metoprolol was evaluated and compared with that of the non-selective beta-blocker propranolol. Metoprolol was used in a dosage of 50 mg b.i.d. and propranolol in 40 mg b.i.d. 56 patients with classical or common migraine were included in the double-blind part of the investigation. 3 patients withdrew, but none because of side-effects. The data suggest that metoprolol is clinically equivalent in effectiveness to propranolol in migraine prophylaxis regarding parameters such as attack frequency, improvement in sum of severity score and subjective evaluation. Both drugs were generally well tolerated and the number of reported side-effects was similar to those reported during the run-in period (placebo).

Primary prophylaxis of esophageal variceal bleeding in cirrhosis

Variceal bleeding is a common and severe complication of liver cirrhosis. The risk of bleeding increases with the size of varices, red wheal marks and disease severity. Noninvasive tests are not accurate enough for the diagnosis of varices, so all patients with cirrhosis should be screened by endoscopy. Nonselective beta-blockers (propranolol, nadolol) are indicated for primary prophylaxis in patients with medium/large varices, and for those with small varices and red signs or advanced liver failure (Child C). In such patients, beta-blockers have been shown to reduce the risk of bleeding from 25 to 15%. There is no evidence to support using beta-blockers with nitrates or spironolactone. In patients with contraindication or intolerance to beta-blockers, endoscopic band ligations are indicated.

The role of α1-and β-adrenoceptors in initiation and development of thermoregulatory reactions during fast and slow cooling

Ionophoretic application of alpha1- and beta-adrenoceptor blockers into the skin produces no effect on the parameters of thermal homeostasis under thermoneutral conditions. alpha1-Adrenoblocker verapamil inhibits cold shivering during fast and slow cold exposure; it elevates the temperature threshold and moderates the vasoconstrictor response during rapid cooling. These changes are accompanied by a compensatory decrease in the threshold and stimulation of non-shivering thermogenesis. Application of non-selective beta-blocker propranolol had no effect on the temperature thresholds of the thermoregulatory reactions, but augmented the maximum amplitude of shivering during both cooling protocols, thereby compensating the decrease in non-shivering thermogenesis. In the whole organism, block of one type adrenoceptors during cold exposure is accompanied by activation of the compensatory mechanisms mediated by adrenoceptors of the other type.