Administration Of Propranolol Research Articles

Impact of Tumoral β2-Adrenergic Receptor Expression on Chemotherapeutic Response and Prognosis in Patients with Advanced Colorectal Cancer.

The β2-adrenergic receptor (β2-AR) is a therapeutic target for circulatory agonists and exhibits oncogenic activity in several cancers. However, its role in advanced colorectal cancer (CRC) treated using chemotherapy remains unclear. We investigated the potential of β2-AR as a novel chemosensitivity marker and therapeutic target in inoperable CRC. β2-AR expression was evaluated immunohistochemically in 80 advanced or recurrent CRC cases for which untreated resected specimens were available before systemic chemotherapy implementation. We assessed the relationship among β2-AR protein expression, clinicopathological factors, therapeutic response, and prognosis. Furthermore, we evaluated the significance of β2-AR as an in vitro and in vivo therapeutic target using CRC cell lines and a CRC xenograft model treated with the β-blocker, propranolol, and other anticancer agents. High tumoral β2-AR expression was associated with shorter progression-free survival and chemotherapeutic resistance in patients treated with oxaliplatin-based regimens and bevacizumab-based regimens. We found no synergistic effect between propranolol and oxaliplatin. However, combined administration of propranolol and bevacizumab induced significant tumor shrinkage in the CRC xenograft model. β2-AR is a possible biomarker for chemosensitivity and prognosis in advanced CRC. Repositioning existing β-blockers could be beneficial for treating CRC resistant to existing treatment regimens.

Systemic and cerebro-cardiac biomarkers following traumatic brain injury: an interim analysis of randomized controlled clinical trial of early administration of beta blockers

This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups (p = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 h post-injury (p = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI (p = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p = 0.001), GCS (r = − 0.125, p = 0.02), and serum S100B (r = 0.205, p = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI.Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28–30, 2024, in Estoril, Lisbon, Portugal.

Propranolol attenuates the establishment of conditioned context aversions: differential effects compared to MK-801 in an animal model of anticipatory nausea and vomiting.

Cancer patients often experience anticipatory nausea and vomiting (ANV) due to Pavlovian conditioning. Both N-methyl-D-aspartate and beta-adrenergic receptors are known to mediate memory formation, but their role in the development of ANV remains unclear. This study used a conditioned context aversion (CCA) paradigm, an animal model for ANV, to assess whether administration of the beta-adrenergic receptor antagonist propranolol or the N-methyl-D-aspartate receptor antagonist MK-801 immediately after CCA training has an effect on the later expression of CCA in CD1 male mice. In experiment 1, three groups were injected with lithium chloride (LiCl) to induce aversion in a novel context, resulting in CCA. A control group was injected with sodium chloride (NaCl). Following conditioning, two of the LiCl-treated groups received different doses of MK-801 (0.05 or 0.2 mg/kg), while the remaining LiCl-treated and NaCl-treated groups received a second NaCl injection. In experiment 2, two groups were injected with LiCl, and one group was injected with NaCl. After conditioning, one of the LiCl-treated groups received a propranolol injection (10 mg/kg). The remaining LiCl-treated and NaCl-treated groups received NaCl injections. Water consumption was measured in all groups 72 h later within the conditioning context. Postconditioning administration of propranolol, but not MK-801, attenuated CCA, as revealed by similar levels of water consumption in animals that received LiCl and propranolol relative to NaCl-treated animals. These findings suggest that beta-adrenergic receptor activation is crucial for the development of CCA. Therefore, propranolol may represent a novel therapeutic approach for cancer patients at high risk of ANV.

Systemic administration of propranolol reduces bone resorption and inflammation in apical periodontitis of chronically stressed rats.

To evaluate the effect of systemic administration of propranolol on the severity of apical periodontitis (AP) in chronically stressed rats. Twenty-four 70-day-old male Wistar rats (Rattus norvegicus, albinus) were distributed into three groups (n = 8): rats with AP without stressful conditions (AP-Control), rats with AP and submitted to a chronic unpredictable stress (CUS) protocol (AP + S) and rats with AP and submitted to a CUS protocol treated with propranolol (AP + S + PRO). Stress procedures were applied daily until the end of the experiment. After 3 weeks of CUS, AP was induced in all groups by exposing the pulpal tissue of mandibular and maxillary first molars to the oral environment. Propranolol treatment was administered orally once a day for the entire period of the experiment. Rats were sacrificed at 42 days, and the blood was collected for stress biomarkers serum dosage by multiplex assay. Mandibles were removed and submitted to microtomography and histopathological analyses. Periapical tissue surrounding the upper first molar was homogenized and subjected to RT-PCR analysis to evaluate the mRNA expression of RANKL, TRAP and OPG. Parametric data were assessed using one-way ANOVA followed by Tukey's test while the nonparametric data were analysed by the Kruskal-Wallis followed by Dunn's test. Significance level was set at 5% (p < .05) for all assessed parameters. Micro-CT revealed statistically significant differences in bone resorption which was greater in the AP + S group (p < .05), but no differences were observed between the Control and AP + S + PRO groups (p > .05). The AP + S + PRO group had a lower intensity and extent of inflammatory infiltrate compared to the AP + S group with smaller areas of bone loss (p < 0.05). The gene expression of RANKL and TRAP was significantly higher in the stressed group AP + S compared to the control group (p < .05), and a significantly higher OPG expression was observed in AP + S + PRO compared to the AP + S group (p < .05). Oral administration of propranolol had a significant effect on the AP severity in stressed rats, suggesting an anti-inflammatory effect and a protective role on bone resorption of AP in stressed animals. Further research is necessary to fully comprehend the underlying mechanisms.

Propranolol can correct prolonged QT intervals in patients with cirrhosis.

Prolonged QT intervals are extremely common in patients with cirrhosis and affect their treatment outcomes. Propranolol is often used to prevent gastroesophageal variceal hemorrhage in patients with cirrhosis; however, it is uncertain whether propranolol exerts a corrective effect on QT interval prolongation in patients with cirrhosis. The study aimed to investigate the therapeutic effects of propranolol on patients with cirrhosis and prolonged QT intervals. A retrospective cohort study approach was adopted. Patients with cirrhosis complicated by moderate-to-severe gastroesophageal varices, who were hospitalized at the Affiliated Hospital of Guangdong Medical University between 1 December 2020 and 31 November 2022, were included in the study. The patients were divided into the propranolol and control groups based on whether they had received propranolol. Upon admission, the patients underwent tests on liver and kidney functions, electrolytes, and coagulation function, as well as abdominal ultrasonography and electrocardiography. In addition to conventional treatment, the patients were followed up after the use or non-use of propranolol for treatment and subsequently underwent reexamination of the aforementioned tests. The propranolol group (26 patients) had an average baseline corrected QT (QTc) interval of 450.23 ± 37.18ms, of which 14 patients (53.8%) exhibited QTc interval prolongation. Follow-up was continued for a median duration of 7.00 days after the administration of propranolol and conventional treatment. Electrocardiographic reexamination revealed a decrease in the QTc interval to 431.04 ± 34.64ms (p = 0.014), and the number of patients with QTc interval prolongation decreased to five (19.2%; p < 0.001). After treatment with propranolol and multimodal therapy, QTc interval normalization occurred in nine patients with QTc interval prolongation, leading to a normalization rate of 64.3% (9/14). The control group (n = 58) had an average baseline QTc interval of 453.74 ± 30.03ms, of which 33 patients (56.9%) exhibited QTc interval prolongation. After follow-up for a median duration of 7.50 days, the QTc interval was 451.79 ± 34.56ms (p = 0.482), and the number of patients with QTc interval prolongation decreased to 30 (51.7%; p = 0.457). The QTc interval normalization rate of patients in the control group with QTc interval prolongation was merely 10.0% (3/33), which was significantly lower than that in the propranolol group (p < 0.001). In patients with cirrhosis complicated by QT interval prolongation, the short-term use of propranolol aids in correction of a long QT interval and provides positive therapeutic value for cirrhotic cardiomyopathy.

Parotid hypersalivation after inferior salivatory nucleus glutamate/NMDA receptor excitation in the rat

Although salivation is essential during eating behavior, little is known about the brainstem centers that directly control the salivary glands. With regard to the inferior salivatory nucleus (ISN), the site of origin of the parasympathetic preganglionic cell bodies that innervate the parotid glands, previous anatomical studies have located it within the rostrodorsal medullary reticular formation. However, to date there is no functional data that shows the secretory nature of the somas grouped in this region. To activate only the somas and rule out the activation of the efferent fibers from and the afferent fibers to the ISN, in exp. 1, NMDA neurotoxin was administered to the rostrodorsal medullary region and the secretion of saliva was recorded during the following hour. Results showed an increased secretion of parotid saliva but a total absence of submandibular-sublingual secretion. In exp. 2, results showed that the hypersecretion of parotid saliva after NMDA microinjection was completely blocked by the administration of atropine (a cholinergic blocker) but not after administration of dihydroergotamine plus propranolol (α and β-adrenergic blockers, respectively). These findings suggest that the somata of the rostrodorsal medulla are secretory in nature, controlling parotid secretion via a cholinergic pathway. The data thus functionally supports the idea that these cells constitute the ISN.

Abstract 3391: Effects of repeated psychological stress on NNK-induced lung cancer development in young female mice

Abstract Lung cancer is the second most common cancer in both men and women in the US and the leading cause of cancer death. Among younger US women, lung cancer incidence rates have in recent years become higher than rates seen in men, despite comparable histories of tobacco use. The possible contribution of stress to higher lung cancer risk in young women has received little research attention despite preclinical evidence that exposure to stress-related neuroendocrine responses can cause DNA damage. The present study used a well-established lung cancer model in young female mice (in vivo exposure to NNK) along with a mouse stress model to explore their independent and combined effects on lung cancer development. In addition, we explored one possible biological pathway by chronic administration of a beta-adrenergic receptor blocker (propranolol). We also tested the use of in vivo imaging for repeated monitoring of tumor development over time. Cohort 1 (n=60) had 4 groups: Home cage control, NNK treatment alone, repeated stress (RS) alone and NNK+RS. Cohort 2 (n=60) had the same 4 groups with the addition of administration of propranolol in drinking water. Cohort 3 (n=48, imaging cohort) had 3 groups: Home cage control, NNK alone and NNK+RS. FVB/N (4-6 wk) were purchased from a commercial supplier and acclimated with gentle handling for two weeks. The repeated stress protocol began week-3 and continued for the duration of the study. It combined two well-established rodent models: social disruption stress via changes in cage mates at the time of cage cleaning (2x/week) and a 90-minute restraint stress immediately prior to cage change (1x/week). NNK or saline treatment began on week-4 (IP; 2x/week; 3 mg/injection) and continued for 4 weeks. 21 weeks after stress initiation, the mice in cohorts 1 and 2 were sacrificed, lungs removed, inflated and tumors counted and sized. Mice in cohort 3 were imaged by Hounsfield-calibrated micro-CT (μCT) at baseline, 14, 19 and 23 weeks. The entire lung space, excluding the heart, was defined as a volumetric region of interests (VOIs). The VOIs were subjected to thresholding to segment the lungs into air space and tissue space compartments. The volume of tissue space of each animal was ratioed against its own baseline tissue space volume. Results from Cohort 1 revealed significantly greater numbers and overall size of lung tumors in stressed mice that received NNK. No significant effects were seen in the absence of NNK. Results from Cohort 2 revealed no significant differences between stressed and unstressed groups treated with propranolol. Cohort 3 revealed a pattern of results with stressed mice generally showing the highest lung tumor volume levels (Hounsfield Units), which reached significance at 19 weeks in preliminary analyses. Conclusion: In this study, we found that repeated stress increased lung tumor burden in female mice treated with NNK, and that a beta-adrenergic pathway may be involved. Citation Format: Frank Jenkins, Laura P. Stabile, Jessie R. Nedrow, Kathryn Day, Joseph D. Latoche, Patrick M. Tarwater, Jessica Manculich, Dana H. Bovbjerg. Effects of repeated psychological stress on NNK-induced lung cancer development in young female mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3391.

Circulating noradrenaline leads to release of neuropeptide Y from cardiac sympathetic nerve terminals via activation of β-adrenergic receptors.

Cardiac disease is marked by sympathoexcitation and elevated levels of noradrenaline (NA) and cotransmitter neuropeptide Y (NPY). Increased NPY levels are associated with a greater risk of ventricular arrhythmias and mortality. Nonetheless, the factors that cause NPY release remain poorly understood. We hypothesized that circulating catecholamines might lead to NPY release from myocardial sympathetic nerve terminals via a β-receptor-mediated mechanism that enhances sympathoexcitation. Ventricular interstitial NA and NPY levels were measured in six Yorkshire pigs after i.v. administration of NA (1mg) and before and after propranolol infusion (1mg/kg). Real-time interstitial NPY levels were measured using ventricular capacitive immunoprobes (CIs) affixed with NPY antibodies and quantified as the change in CI input current (INPY ) upon binding of NPY. Interstitial NA was measured with adjacent fast-scan cyclic voltammetry probes (INA ). A left ventricular pressure catheter and continuous ECGs were used for haemodynamic recordings, and an epicardial 56-electrode sock was used for measurements of activation recovery interval, a surrogate of action potential duration. Upon administration of NA, heart rate and left ventricular pressure increased, and activation recovery interval shortened. Notably, NA significantly increased interstitial myocardial NPY levels. After propranolol, changes in heart rate and activation recovery interval were largely mitigated. The INA increased to a similar extent post-propranolol vs. pre-propranolol, but changes in INPY were significantly reduced post-propranolol. Coronary sinus plasma analyses confirmed fast-scan cyclic voltammetry and CI findings. Hence, this study demonstrates that circulating NA induces NPY release from ventricular sympathetic nerve terminals, the mechanism for which is mediated via β-adrenergic receptors and can be blocked by the non-selective β-blocker, propranolol. KEY POINTS: Cardiovascular disease is characterized by sympathovagal imbalance, with increased plasma noradrenaline (NA) and neuropeptide Y (NPY) concentrations. Increased NPY levels are associated with increased ventricular arrhythmias and mortality in heart failure. Limited data are available on the specific factors that cause NPY release. In this study, fast-scan cyclic voltammetry and capacitive immunoprobes were used to allow for real-time in vivo measurements of interstitial myocardial neurotransmitters and neuropeptides, respectively. Using an in vivo porcine model with cardiac fast-scan cyclic voltammetry and capacitive immunoprobes, it was shown that systemic NA can increase ventricular interstitial NPY levels, suggesting that NA induces NPY release from postganglionic sympathetic nerves. The release of NPY was blocked by administration of the non-selective β-blocker propranolol, suggesting that release of NPY is dependent on activation of β-adrenergic receptors by NA.

Propranolol: a new pharmacologic approach to counter retinopathy of prematurity progression.

Despite the evident progress in neonatal medicine, retinopathy of prematurity (ROP) remains a serious threat to the vision of premature infants, due to a still partial understanding of the mechanisms underlying the development of this disease and the lack of drugs capable of arresting its progression. Although ROP is a multifactorial disease, retinal vascularization is strictly dependent on oxygen concentration. The exposition of the retina of a preterm newborn, still incompletely vascularized, to an atmosphere relatively hyperoxic, as the extrauterine environment, induces the downregulation of proangiogenic factors and therefore the interruption of vascularization (first ischemic phase of ROP). However, over the following weeks, the growing metabolic requirement of this ischemic retina produces a progressive hypoxia that specularly promotes the surge of proangiogenic factors, finally leading to proliferative retinopathy (second proliferative phase of ROP). The demonstration that the noradrenergic system is actively involved in the coupling between hypoxia and the induction of vasculogenesis paved the way for a pharmacologic intervention aimed at counteracting the interaction of noradrenaline with specific receptors and consequently the progression of ROP. A similar trend has been observed in infantile hemangiomas, the most common vascular lesion of childhood induced by pre-existing hypoxia, which shares similar characteristics with ROP. The fact that propranolol, an unselective antagonist of β1/2 adrenoceptors, counteracts the growth of infantile hemangiomas, suggested the idea of testing the efficacy of propranolol in infants with ROP. From preclinical studies, ongoing clinical trials demonstrated that topical administration of propranolol likely represents the optimal approach to reconcile its efficacy and maximum safety. Given the strict relationship between vessels and neurons, recovering retinal vascularization with propranolol may add further efficacy to prevent retinal dysfunction. In conclusion, the strategy of contrasting precociously the progression of the disease appears to be more advantageous than the current wait-and-see therapeutic approach, which instead is mainly focused on avoiding retinal detachment.

Effect of Propranolol on Motor Cortex Excitability in Essential Tremor: An Exploratory Study.

Essential tremor, the world's most prevalent movement disorder, lacks a clear understanding of its pathophysiology. Propranolol, a non-specific beta-blocker capable of crossing the blood-brain barrier, is a primary choice for essential tremor treatment. While its tremor-reducing effects are generally attributed to peripheral actions, various uses hint at central adrenergic effects. Nevertheless, propranolol's precise impact on the central nervous system in essential tremor subjects remains unexplored. In this study, we employed transcranial magnetic stimulation to assess the influence of propranolol on the excitability of the primary motor cortex (M1) in patients with essential tremor, compared to an age- and sex-matched control group. Cortical excitability parameters were measured following placebo and propranolol administration, encompassing resting and active motor thresholds, motor evoked potential characteristics, cortical silent period, and the input/output curve. Distinct effects were observed across the two cortical hemispheres. Essential tremor patients displayed inhibition of the left M1 cortex and heightened excitability in the right M1 cortex four hours after propranolol administration, but not following placebo. These findings suggest potential differential noradrenergic excitatory and inhibitory modulation. However, comprehensive understanding necessitates further investigations, including left-handed participants and more diverse essential tremor subpopulations. This study underscores the need for continued exploration to unravel propranolol's complex effects on motor cortex excitability in essential tremor.

The effect of propranolol on post-accident stress and clinical outcomes of burn patients: a clinical trial

Objective:&#x0D; The hypermetabolic response has undoubtedly evolved to help survive burns, but this physiological response has inconsistent consequences and increases the clinical consequences, such as increased heart work and ultimately its decline, decreased immune system function, risk of sepsis, increased long-term hospitalization, which increases the mortality of patients. This study aims to examine the effect of propranolol on post-traumatic stress disorder and clinical outcomes in burn patients.&#x0D; Methods:&#x0D; This was an open-labeled randomized clinical trial in a single center with two parallel groups without placebo control. Propranolol was given 48 hours after starting of resuscitation.&#x0D; Results:&#x0D; In this study, the burn wound of the patients who used propranolol healed faster. In addition, the administration of propranolol reduced the size of the burning surface, the size of the tissue required skin graft, the rejection rate of skin grafts, and also the length of stay in the hospital.&#x0D; Conclusion:&#x0D; Using propranolol in treating burns can play an influential role in the recovery of burn patients, and reduce the post-traumatic stress disorder.

Prevention of activated brown adipose tissue on 18F-FDG-PET scans of young lymphoma patients: results of an ancillary study within the EuroNet-PHL-C2 trial

Activated brown fat (aBAT) is known to affect the evaluation of 18F-FDG PET scans, especially in young patients. The aim of this study was to determine factors influencing the occurrence of aBAT, and to investigate the effectiveness of the two preventive measures, warming and beta-blocker (propranolol) administration. Five-hundred-twenty-eight 18F-FDG-PET scans of 241 EuroNet-PHL-C2 trial patients from 41 nuclear medicine departments in Germany and Czech Republic were screened for aBAT. The occurrence of aBAT was analyzed with patient characteristics (age, sex, body mass index, predisposition to aBAT), weather data at the day of 18F-FDG PET scanning as well as the preventive measures taken. Potentially important factors from univariate analyses were included into a logistic regression model. Warming as a preventive measure was used in 243 18F-FDG-PET scans, propranolol was administered in 36, warming and propranolol were combined in 84, and no preventive measures were taken in 165 scans. Whereas age, sex and body mass index had no clear impact, there was an individual predisposition to aBAT. Logistic regression model revealed that the frequency of aBAT mainly depends on the outside temperature (p = 0.005) and can be effectively reduced by warming (p = 0.004), the administration of unselective beta-blocker or the combination of both. Warming is a simple, cheap and non-invasive method to reduce the frequency of aBAT. However, the effect of warming decreases with increasing outside temperatures. Administration of propranolol seems to be equally effective and provides advantages whenever the positive effect of warming is compromised. The combination of both preventive measures could have an additive effect.

Compromised trigemino-coerulean coupling in migraine sensitization can be prevented by blocking beta-receptors in the locus coeruleus

BackgroundMigraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors.MethodsWe used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague–Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol.ResultsWe found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions’ interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity.ConclusionsAltogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol’s prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing.

Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity

Propranolol, a non-selective beta-blocker medication, has been utilized in the treatment of cardiovascular diseases for several decades. Its hydroxynaphthyl metabolites have been recognized to possess varying degrees of beta-blocker activity due to the unaltered side-chain. This study achieved the successful separation and identification of diastereomeric glucuronic metabolites derived from 4-, 5-, and 7-hydroxypropranolol (4-OHP, 5-OHP, and 7-OHP) in human urine. Subsequently, reaction phenotyping of 5- and 7-hydroxypropranolol by different uridine 5’-diphospho-glucuronosyltransferases (UGTs) was carried out, with a comparison to the glucuronidation of 4-hydroxypropranolol (4-OHP). Among the 19 UGT enzymes examined, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2A1, and UGT2A2 were found to be involved in the glucuronidation of 5-OHP. Furthermore, UGT1A6 exhibited glucuronidation activity towards 7-OHP, along with the aforementioned eight UGTs. Results obtained by glucuronidation of corresponding methoxypropranolols and MS/MS analysis of 1,2-dimethylimidazole-4-sulfonyl (DMIS) derivatives of hydroxypropranolol glucuronides suggest that both the aromatic and aliphatic hydroxy groups of the hydroxypropranolols may be glucuronidated in vitro. However, the analysis of human urine samples collected after the administration of propranolol leads us to conclude that aromatic-linked glucuronidation is the preferred pathway under physiological conditions.

Effect of propranolol on temporomandibular joint pain in repeatedly stressed rats.

Stress substantially increases the risk of developing painful temporomandibular disorders (TMDs) by influencing the release of endogenous catecholamines. Propranolol, an antagonist of β-adrenergic receptors, has shown potential in alleviating TMD-associated pain, particularly when the level of catecholamines is elevated. The aim of this study was to explore whether intra-articular propranolol administration is effective in diminishing temporomandibular joint (TMJ) pain during repeated stress situations. Additionally, we investigated the effect of repeated stress on the expression of genes encoding β-adrenoceptors in the trigeminal ganglion. In the present study, rats were exposed to a stress protocol induced by sound, then to the administration of formalin in the TMJ (to elicit a nociceptive response), followed immediately afterward by different doses of propranolol, after which the analgesic response to propranolol was evaluated. We also assessed the levels of beta-1 and beta-2 adrenergic receptor mRNAs (Adrb1 and Adrb2, respectively) using reverse transcription-quantitative PCR (RT-qPCR). Our findings revealed that propranolol administration reduces formalin-induced TMJ nociception more effectively in stressed rats than in non-stressed rats. Furthermore, repeated stress decreases the expression of the Adrb2 gene within the trigeminal ganglion. The findings of this study are noteworthy as they suggest that individuals with a chronic stress history might find potential benefits from β-blockers in TMD treatment.

Development of a Hydroxypropyl-β-Cyclodextrin-Based Liquid Formulation for the Oral Administration of Propranolol in Pediatric Therapy.

Propranolol (PPN) is widely used in children to treat various cardiovascular diseases. The availability of a suitable PPN solution should avoid recourse to extemporaneous preparations of unknown/limited stability, as commonly made in hospital pharmacies. However, the development of pediatric PPN solutions is hindered by their instability to light and stability at pH ≈ 3, bitter taste, and the need to improve palatability and avoid co-solvents, flavoring agents, or preservatives that are potentially toxic. In this study, cyclodextrin (CD) complexation has been exploited to develop a safe, stable, and palatable oral pediatric solution of PPN. An initial screening among various CDs allowed us to select HPβCD for its good complexing ability and no toxicity. Drug-HPβCD physical mixtures or co-ground systems (1:1 or 1:2 mol:mol) were used to prepare 0.2% w/v drug solutions. Photo stability studies evidenced the protective effect of HPβCD, revealing a reduction of up to 75% in the drug degradation rate after 1 h of exposure to UV radiation. Storage stability studies showed unchanged physical-chemical properties and almost constant drug concentration after 6 months and under accelerated conditions (40 °C), despite the less aggressive pH (≈5.5) of the solution. The electronic tongue test proved that the HPβCD taste-masking properties improved the formulation palatability, with a 30% reduction in drug bitterness.

Sex-dependent noradrenergic modulation of premotor cortex during decision making.

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.

Chronic administration of a norepinephrine antagonist prevents and partially reverses escalation of cocaine self-administration.

Anxiety is a critical component of the development and maintenance of drug addiction; however, anti-anxiety medications such as benzodiazepines and beta-blockers (β-adrenergic receptor antagonists) are not used for the treatment of substance use disorder, except for the management of acute withdrawal syndrome. Preclinical studies have shown that beta-blockers may reduce stress-induced relapse; however, the effect of beta blockers on the escalation and maintenance of drug intake has not been tested. To address this issue, we chronically administered the β-adrenergic receptor antagonist propranolol during the escalation or maintenance of cocaine intake in a model of extended access (6h) to cocaine self-administration (0.5mg/kg). The behavioural specificity of propranolol was tested using a non-drug reward (saccharin). Daily administration of propranolol (15 mg/kg) prevented the development of escalation of cocaine self-administration and partially reversed self-administration after the establishment of escalation of intake. Moreover, propranolol dose-dependently decreased the motivation for cocaine tested under a progressive ratio schedule of reinforcement during the development of escalation and after maintenance. Finally, propranolol administration had no effect on the escalation and maintenance of saccharin self-administration. These results demonstrate that chronic treatment with propranolol provides therapeutic efficacy in reducing cocaine self-administration during the development and after the establishment of escalation of cocaine self-administration in an animal model relevant to cocaine use disorder. These results suggest that beta blockers should be further investigated as a target for medication development for the treatment of cocaine use disorder.

Drugs possessing aryloxypropanamine pharmacophore, duloxetine, dapoxetine and propranolol, increase allopregnanolone in rat brain: Possible involvement of allopregnanolone in their central nervous system effects

Allopregnanolone (AP) is a neurosteroid synthesized in the brain and a positive allosteric modulator of γ-aminobutyric acid (GABA) type A receptors. Some drugs possessing the aryloxypropanamine (AOPA) pharmacophore, such as fluoxetine, exert their central nervous system (CNS) effects by increasing the brain AP. Although duloxetine (DLX), dapoxetine (DPX), atomoxetine (ATX) and propranolol (PRL) also possess the AOPA pharmacophore and are used to treat some psychiatric disorders, the capabilities of these drugs to increase the brain AP and the possible involvement of AP in their CNS effects remain to be fully elucidated. To clarify these points, we first developed a method for quantifying AP in the rat brain by liquid chromatography/electrospray ionization-tandem mass spectrometry. Analysis of the changes in the brain AP levels using this method revealed that the intraperitoneal administration of DLX (10 mg/kg), DPX (10 mg/kg) and PRL (20 mg/kg) significantly increased the brain AP (DLX: < 0.40–2.74 ng/g tissue, DPX: 1.48–3.83 ng/g tissue and PRL: < 0.40–2.09 ng/g tissue) compared to the saline administration (<0.40 ng/g tissue). These results suggested the possible involvement of the GABAergic neurosteroid, AP, in the central actions of DLX, DPX and PRL. In contrast, ATX (10 mg/kg) did not affect the AP levels in the brain. In addition, the brain and serum AP levels had a remarkably high positive correlation after the administration of DLX, DPX and PRL. Thus, this study proposed the AP-related novel mechanism of actions of DLX, DPX and PRL in the CNS.

Microinjection of NMDA-neurotoxin into the superior salivatory nucleus of the rat: Short-term secretory and long-term drinking behavior effects

The anatomical location of the superior salivatory nucleus (SSN), the site of origin of the parasympathetic preganglionic cell bodies that innervate the submandibular-sublingual salivary glands, is well established in rats. However, as of yet there is no functional data that convincingly shows the secretory nature of this region. Previous studies have not been able to differentiate between interventions on efferent or afferent fibers connected to the SSN versus interventions on the salivatory nucleus itself. Taking advantage of the fact that salivatory neurons express NMDA-receptors on their somas, in the present study SSN cell bodies were activated and lesioned sequentially by means of intracerebral application of NMDA-neurotoxin. In exp. 1 two effects, a short- and a long-term effect, were observed following NMDA administration. The first effect was high submandibular-sublingual saliva secretion during the hour following administration of the neurotoxin and the second was a profound change in drinking behavior once the animals recovered from the lesion. Thus, on post-surgery days 16, 17 and 18, the rats exhibited hyperdipsia in the presence of dry food but not in the presence of wet food. In expt. 2 results showed that saliva hypersecretion observed after NMDA-microinjection was completely blocked by the administration of atropine (a cholinergic blocker) but not after the administration of dihydroergotamine plus propranolol (α and β-adrenergic blockers, respectively). From a functional perspective, these data suggest that the somata of the parvocellular reticular formation control the secretory activity of the submandibular-sublingual salivary glands and thus constitute the SSN.