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Vascular Pharmacology Oct 2022The mechanisms underlying the success of propranolol in the treatment of infantile hemangioma (IH) remain elusive and do not fully explain the rapid regression of...
UNLABELLED
The mechanisms underlying the success of propranolol in the treatment of infantile hemangioma (IH) remain elusive and do not fully explain the rapid regression of hemangiomatous lesions following drug administration. As autophagy is critically implicated in vascular homeostasis, we determined whether β-blockers trigger the autophagic flux on infantile hemangioma-derived endothelial cells (Hem-ECs) in vitro.
MATERIAL AND METHODS
Fresh tissue specimens, surgically removed for therapeutic purpose to seven children affected by proliferative IH, were subjected to enzymatic digestion. Cells were sorted with anti-human CD31 immunolabeled magnetic microbeads. Following phenotypic characterization, expanded Hem-ECs, at P2 to P6, were exposed to different concentrations (50 μM to 150 μM) of propranolol, atenolol or metoprolol alone and in combination with the autophagy inhibitor Bafilomycin A1. Rapamycin, a potent inducer of autophagy, was also used as control. Autophagy was assessed by Lysotracker Red staining, western blot analysis of LC3BII/LC3BI and p62, and morphologically by transmission electron microscopy.
RESULTS
Hem-ECs treated with either propranolol, atenolol or metoprolol displayed positive LysoTracker Red staining. Increased LC3BII/LC3BI ratio, as well as p62 modulation, were documented in β-blockers treated Hem-ECs. Abundant autophagic vacuoles and multilamellar bodies characterized the cytoplasmic ultrastructural features of autophagy in cultured Hem-ECs exposed in vitro to β-blocking agents. Importantly, similar biochemical and morphologic evidence of autophagy were observed following rapamycin while Bafilomycin A1 significantly prevented the autophagic flux promoted by β-blockers in Hem-ECs.
CONCLUSION
Our data suggest that autophagy may be ascribed among the mechanisms of action of β-blockers suggesting new mechanistic insights on the potential therapeutic application of this class of drugs in pathologic conditions involving uncontrolled angiogenesis.
Topics: Adrenergic beta-Antagonists; Amines; Atenolol; Autophagy; Cell Proliferation; Child; Endothelial Cells; Hemangioma; Humans; Macrolides; Metoprolol; Propranolol; Sirolimus
PubMed: 36103993
DOI: 10.1016/j.vph.2022.107110 -
Annals of Surgery Jun 1982For decades, the preparation of a hyperthyroid patient for surgery took several weeks or months utilizing thyroid blocking agents and iodine. In 1973, a preliminary...
For decades, the preparation of a hyperthyroid patient for surgery took several weeks or months utilizing thyroid blocking agents and iodine. In 1973, a preliminary report of 20 patients with hyperthyroidism treated with propranolol and thyroidectomy was presented. It was found that a thyrotoxic patient could be prepared for surgery, in an emergency, by intravenous propranolol in less than an hour, or electively by oral propranolol within 24 hours. Since then, 140 additional patients have been similarly treated. It continues to be true at this institution that propranolol, a beta-adrenergic blocking agent, effectively neutralizes the symptoms of autonomic hyperactivity, including sweating, tremor, fever, dilation of blood vessels, and increased pulse rate without significantly affecting thyroid function. An average dose of 160 mg/day was used, with a range of 40 to 320 mg/day. In none of these patients was iodine used; in fact, its use with propranolol is considered unnecessary. A subtotal, near total, or total thyroidectomy was done in all patients, resulting in a 55% incidence of hypothyroidism. There was no postoperative thyroid storm, nerve injury, or permanent hypoparathyroidism. It is believed that the administration of propranolol alone provides a rapid, safe, and effective preparation of the thyrotoxic patient for thyroidal or extrathyroidal surgical procedures during the perioperative period.
Topics: Adolescent; Adult; Aged; Cranial Nerve Diseases; Female; Humans; Hyperthyroidism; Hypothyroidism; Intraoperative Period; Iodine; Laryngeal Nerves; Male; Middle Aged; Parathyroid Glands; Postoperative Complications; Postoperative Period; Propranolol; Thyroidectomy
PubMed: 7082068
DOI: 10.1097/00000658-198206000-00013 -
Annals of Surgery Oct 2002To determine whether propranolol and growth hormone (GH) have additive effects to combat burn-induced catabolism. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
To determine whether propranolol and growth hormone (GH) have additive effects to combat burn-induced catabolism.
SUMMARY BACKGROUND DATA
Both GH and propranolol have been attributed anabolic properties after severe trauma and burn. It is conceivable that the two in combination would have additive effects.
METHODS
Fifty-six children with more than 40% TBSA burns were randomized to one of four anabolic regimens: untreated control, GH treatment, propranolol treatment, or combination GH plus propranolol therapy. Clinical treatment was identical for all groups. Resting energy expenditure was determined by indirect calorimetry and skeletal muscle protein kinetics were measured using stable amino acid isotope infusions before and after each anabolic regimen.
RESULTS
There were no differences in age, sex, or burn size between groups. Tachycardia and energy expenditure were decreased during propranolol treatment ( <.05). The net balance of muscle protein synthesis and breakdown was improved during propranolol and GH plus propranolol treatment ( <.05). There was no significant benefit of GH alone. No additive effect of combination therapy was seen.
CONCLUSIONS
Propranolol is a strongly anabolic drug during the early, hypercatabolic period after burn. No synergistic effect between propranolol and GH was identified.
Topics: Adrenergic beta-Antagonists; Burns; Child; Drug Therapy, Combination; Energy Metabolism; Female; Growth Hormone; Humans; Male; Metabolic Diseases; Muscle, Skeletal; Propranolol; Trauma Severity Indices
PubMed: 12368673
DOI: 10.1097/00000658-200210000-00007 -
Scandinavian Journal of Pain Jul 2018Background and aims The autonomic nervous system (ANS) is capable of modulating pain. Aberrations in heart rate variability (HRV), reflective of ANS activity, are... (Randomized Controlled Trial)
Randomized Controlled Trial
Background and aims The autonomic nervous system (ANS) is capable of modulating pain. Aberrations in heart rate variability (HRV), reflective of ANS activity, are associated with experimental pain sensitivity, chronic pain, and more recently, pain modulatory mechanisms but the underlying mechanisms are still unclear. HRV is lowered during experimental pain as well as in chronic pain conditions and HRV can be increased by propranolol, which is a non-selective β-blocker. Sensitization of central pain pathways have been observed in several chronic pain conditions and human mechanistic pain biomarkers for these central pain pathways include temporal summation of pain (TSP) and conditioned pain modulation (CPM). The current study aimed to investigate the effect of the β-blocker propranolol, and subsequently assessing the response to standardized, quantitative, mechanistic pain biomarkers. Methods In this placebo-controlled, double-blinded, randomized crossover study, 25 healthy male volunteers (mean age 25.6 years) were randomized to receive 40 mg propranolol and 40 mg placebo. Heart rate, blood pressure, and HRV were assessed before and during experimental pain tests. Cuff pressure pain stimulation was used for assessment of pain detection (cPDTs) and pain tolerance (cPTTs) thresholds, TSP, and CPM. Offset analgesia (OA) was assessed using heat stimulation. Results Propranolol significantly reduced heart rate (p<0.001), blood pressure (p<0.02) and increased HRV (p<0.01) compared with placebo. No significant differences were found comparing cPDT (p>0.70), cPTT (p>0.93), TSP (p>0.70), OA-effect (p>0.87) or CPM (p>0.65) between propranolol and placebo. Conclusions The current study demonstrated that propranolol increased HRV, but did not affect pressure pain sensitivity or any pain facilitatory or modulatory outcomes. Implications Analgesic effects of propranolol have been reported in clinical pain populations and the results from the current study could indicate that increased HRV from propranolol is not associated with peripheral and central pain pathways in healthy male subjects.
Topics: Adrenergic beta-Antagonists; Adult; Autonomic Nervous System; Blood Pressure; Cross-Over Studies; Heart Rate; Humans; Male; Pain Perception; Pain Threshold; Propranolol; Young Adult
PubMed: 29858911
DOI: 10.1515/sjpain-2018-0054 -
Translational Psychiatry Oct 2020Fear memories can be reactivated by a fear-associated conditioned stimulus (CS) or unconditioned stimulus (US) and then undergo reconsolidation. Propranolol...
Fear memories can be reactivated by a fear-associated conditioned stimulus (CS) or unconditioned stimulus (US) and then undergo reconsolidation. Propranolol administration during CS retrieval-induced reconsolidation can impair fear memory that is specific to the reactivated CS. However, from a practical perspective, the US is often associated with multiple CSs, and each CS can induce a fear response. The present study sought to develop and test a US-based memory retrieval interference procedure with propranolol to disrupt the original fear memory and eliminate all CS-associated fear responses in humans. We recruited 127 young healthy volunteers and conducted three experiments. All of the subjects acquired fear conditioning, after which they received the β-adrenergic receptor antagonist propranolol (40 mg) or placebo (vitamin C) and were exposed to the US or CS to reactivate the original fear memory. Fear responses were measured. Oral propranolol administration 1 h before US retrieval significantly decreased subsequent fear responses and disrupted associations between all CSs and the US. However, propranolol administration before CS retrieval only inhibited the fear memory that was related to the reactivated CS. Moreover, the propranolol-induced inhibition of fear memory reconsolidation that was retrieved by the US had a relatively long-lasting effect (at least 2 weeks) and was also effective for remote fear memory. These findings indicate that the US-based memory retrieval interference procedure with propranolol can permanently decrease the fear response and prevent the return of fear for all CSs in humans. This procedure may open new avenues for treating fear-related disorders.
Topics: Adrenergic beta-Antagonists; Conditioning, Classical; Extinction, Psychological; Fear; Humans; Memory; Propranolol
PubMed: 33051441
DOI: 10.1038/s41398-020-01023-w -
British Journal of Clinical Pharmacology Sep 1986The potential interaction between ketanserin and propranolol has been investigated in eight healthy volunteers. Volunteers received single doses of placebo, propranolol... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The potential interaction between ketanserin and propranolol has been investigated in eight healthy volunteers. Volunteers received single doses of placebo, propranolol (80 mg), ketanserin (20 mg), and propranolol (80 mg) plus ketanserin (20 mg) following a randomised double-blind regimen. A single dose of ketanserin had little effect on resting heart rate and blood pressure and the effects of propranolol and ketanserin in combination were similar to those of propranolol alone. The inhibition of exercise induced tachycardia by propranolol was not affected by ketanserin. The pharmacokinetics of propranolol elimination were not influenced by the concurrent administration of ketanserin, nor the pharmacokinetics of ketanserin by propranolol.
Topics: Adult; Blood Pressure; Drug Administration Schedule; Female; Half-Life; Heart Rate; Humans; Ketanserin; Kinetics; Male; Middle Aged; Physical Exertion; Propranolol; Time Factors
PubMed: 3768242
DOI: 10.1111/j.1365-2125.1986.tb02891.x -
Journal of Cellular and Molecular... Jan 2024Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been...
Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been thoroughly elucidated. Autophagic cell death (ACD) of activated hepatic stellate cells (HSCs) is important in the alleviation of liver fibrosis. Our study aims to assess the mechanisms of propranolol regulating HSC ACD and liver fibrosis. ACD of HSCs was investigated using lentivirus transfection. The molecular mechanism was determined using a PCR profiler array. The role of autophagy-related protein 9b (ATG9b) in HSC ACD was detected using co-immunoprecipitation and co-localization of immunofluorescence. Changes in the signalling pathway were detected by the Phospho Explorer antibody microarray. Propranolol induces ACD and apoptosis in HSCs. ATG9b upregulation was detected in propranolol-treated HSCs. ATG9b upregulation promoted ACD of HSCs and alleviated liver fibrosis in vivo. ATG9b enhanced the P62 recruitment to ATG5-ATG12-LC3 compartments and increased the co-localization of P62 with ubiquitinated proteins. The PI3K/AKT/mTOR pathway is responsible for ATG9b-induced ACD in activated HSCs, whereas the p38/JNK pathway is involved in apoptosis. This study provides evidence for ATG9b as a new target gene and propranolol as an agent to alleviate liver fibrosis by regulating ACD of activated HSCs.
Topics: Humans; Hepatic Stellate Cells; Propranolol; Autophagic Cell Death; Up-Regulation; Phosphatidylinositol 3-Kinases; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Liver Cirrhosis; Liver; Autophagy
PubMed: 37970991
DOI: 10.1111/jcmm.18047 -
ELife Aug 2023Rodent premotor cortex (M2) integrates information from sensory and cognitive networks for action planning during goal-directed decision-making. M2 function is regulated...
Rodent premotor cortex (M2) integrates information from sensory and cognitive networks for action planning during goal-directed decision-making. M2 function is regulated by cortical inputs and ascending neuromodulators, including norepinephrine (NE) released from the locus coeruleus (LC). LC-NE has been shown to modulate the signal-to-noise ratio of neural representations in target cortical regions, increasing the salience of relevant stimuli. Using rats performing a two-alternative forced choice task after administration of a β-noradrenergic antagonist (propranolol), we show that β-noradrenergic signaling is necessary for effective action plan signals in anterior M2. Loss of β-noradrenergic signaling results in failure to suppress irrelevant action plans in anterior M2 disrupting decoding of cue-related information, delaying decision times, and increasing trial omissions, particularly in females. Furthermore, we identify a potential mechanism for the sex bias in behavioral and neural changes after propranolol administration via differential expression of β2 noradrenergic receptor RNA across sexes in anterior M2, particularly on local inhibitory neurons. Overall, we show a critical role for β-noradrenergic signaling in anterior M2 during decision-making by suppressing irrelevant information to enable efficient action planning and decision-making.
Topics: Female; Animals; Rats; Motor Cortex; Propranolol; Locus Coeruleus; Neurons; Norepinephrine
PubMed: 37606362
DOI: 10.7554/eLife.85590 -
Blood Advances Feb 2020Preclinical research shows that stress-induced activation of the sympathetic nervous system can promote hematopoietic malignancies via β-adrenoreceptor-mediated... (Randomized Controlled Trial)
Randomized Controlled Trial
Preclinical research shows that stress-induced activation of the sympathetic nervous system can promote hematopoietic malignancies via β-adrenoreceptor-mediated molecular pathways. Hematopoietic cell transplant (HCT) recipients exposed to conditions of chronic stress show activation of a conserved transcriptional response to adversity (CTRA) gene expression profile, which in turn is associated with increased relapse and decreased disease-free survival. We conducted a randomized controlled phase 2 biomarker trial testing the impact of the nonselective β-antagonist propranolol on CTRA-related gene expression of 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected at baseline, day -2, and day +28. Intention-to-treat analyses controlling for demographic characteristics, high-risk disease (International Myeloma Working Group risk score), and tumor stage tested effects on a 53-gene CTRA indicator profile and measures of CTRA-related cellular processes in peripheral blood mononuclear cells. Twelve participants were randomized to the intervention and 13 to the control. Relative to the control group, propranolol-treated patients showed greater decreases from baseline to HCT day -2 and day +28 for both CTRA gene expression (P = .017) and bioinformatic measures of CD16- classical monocyte activation (P = .005). Propranolol-treated patients also showed relative upregulation of CD34+ cell-associated gene transcripts (P = .011) and relative downregulation of myeloid progenitor-containing CD33+ cell-associated gene transcripts (P = .001). Ancillary analyses identified nonsignificant trends toward accelerated engraftment and reduced posttransplant infections in propranolol-treated patients. Peri-HCT propranolol inhibits cellular and molecular pathways associated with adverse outcomes. Changes in these pathways make propranolol a potential candidate for adjunctive therapy in cancer-related HCT.
Topics: Biomarkers; Hematopoietic Stem Cell Transplantation; Humans; Leukocytes, Mononuclear; Neoplasm Recurrence, Local; Propranolol
PubMed: 32027744
DOI: 10.1182/bloodadvances.2019000765 -
Journal of the National Medical... Oct 1987The cost effectiveness of labetalol and propranolol in the treatment of black adults with mild to moderate hypertension was assessed using published reports from US... (Clinical Trial)
Clinical Trial Comparative Study Review
The cost effectiveness of labetalol and propranolol in the treatment of black adults with mild to moderate hypertension was assessed using published reports from US clinical trials of these agents among such patients. Data from these studies suggest that labetalol and propranolol lower diastolic blood pressure among black hypertensive adults by 11.2 mmHg and 8.4 mmHg, respectively. Results indicate that, for a hypothetical cohort of 1,000 patients on monotherapy, patients treated with labetalol would experience two to seven fewer strokes over a ten-year period, depending upon age and sex, and annual drug costs would be reduced by $190. For stepped care, annual costs would be $205 and $212 lower for those treated initially with labetalol. Labetalol therefore may be more cost effective than propranolol among black adults with mild to moderate hypertension.
Topics: Aged; Black People; Clinical Trials as Topic; Cost-Benefit Analysis; Female; Humans; Hypertension; Labetalol; Male; Middle Aged; Propranolol
PubMed: 3119865
DOI: No ID Found