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Neurobiology of Stress May 2023Alcohol use disorder (AUD) is characterized by loss of intake control, increased anxiety, and susceptibility to relapse inducing stressors. Both astrocytes and neurons...
Alcohol use disorder (AUD) is characterized by loss of intake control, increased anxiety, and susceptibility to relapse inducing stressors. Both astrocytes and neurons contribute to behavioral and hormonal consequences of chronic intermittent ethanol (CIE) exposure in animal models. Details on how CIE disrupts hypothalamic neuro-glial communication, which mediates stress responses are lacking. We conducted a behavioral battery (grooming, open field, reactivity to a single, uncued foot-shock, intermittent-access two-bottle choice ethanol drinking) followed by Ca imaging in slices of paraventricular nucleus of the hypothalamus (PVN) from male rats exposed to CIE vapor or air-exposed controls. Ca signals were evaluated in response to norepinephrine (NE) with or without selective α-adrenergic receptor (αAR) or GluN2B-containing N-methyl-D-aspartate receptor (NMDAR) antagonists, followed by dexamethasone (DEX) to mock a pharmacological stress response. Expectedly, CIE rats had altered anxiety-like, rearing, grooming, and drinking behaviors. Importantly, NE-mediated reductions in Ca event frequency were blunted in both CIE neurons and astrocytes. Administration of the selective α1AR antagonist, prazosin, reversed this CIE-induced dysfunction in both cell types. Additionally, the pharmacological stress protocol reversed the altered basal Ca signaling profile of CIE astrocytes. Signaling changes in astrocytes in response to NE were correlated with anxiety-like behaviors, such as the grooming:rearing ratio, suggesting tripartite synaptic function plays a role in switching between exploratory and stress-coping behavior. These data show how CIE exposure causes persistent changes to PVN neuro-glial function and provides the groundwork for how these physiological changes manifest in behavioral selection.
PubMed: 37131490
DOI: 10.1016/j.ynstr.2023.100539 -
Philosophical Transactions of the Royal... Jun 2023Atrial fibrillation (AF) is the most common chronic arrhythmia presenting a heavy disease burden. We report a new approach for generating cardiomyocytes (CMs)...
Atrial fibrillation (AF) is the most common chronic arrhythmia presenting a heavy disease burden. We report a new approach for generating cardiomyocytes (CMs) resembling atrial cells from human-induced pluripotent stem cells (hiPSCs) using a combination of Gremlin 2 and retinoic acid treatment. More than 40% of myocytes showed rod-shaped morphology, expression of CM proteins (including ryanodine receptor 2, -actinin-2 and F-actin) and striated appearance, all of which were broadly similar to the characteristics of adult atrial myocytes (AMs). Isolated myocytes were electrically quiescent until stimulated to fire action potentials with an AM profile and an amplitude of approximately 100 mV, arising from a resting potential of approximately -70 mV. Single-cell RNA sequence analysis showed a high level of expression of several atrial-specific transcripts including , , , , , and . Amplitudes of calcium transients recorded from spontaneously beating cultures were increased by the stimulation of -adrenoceptors (activated by phenylephrine and blocked by prazosin) or -adrenoceptors (activated by isoproterenol and blocked by CGP20712A). Our new approach provides human AMs with mature characteristics from hiPSCs which will facilitate drug discovery by enabling the study of human atrial cell signalling pathways and AF. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
Topics: Adult; Humans; Myocytes, Cardiac; Induced Pluripotent Stem Cells; Cell Differentiation; Atrial Fibrillation; Receptors, Adrenergic; G Protein-Coupled Inwardly-Rectifying Potassium Channels
PubMed: 37122218
DOI: 10.1098/rstb.2022.0312 -
BMC Psychiatry Apr 2023As nightmares may be a risk factor for, or symptom of, multiple psychological disorders, some researchers suggest that nightmares should be screened, diagnosed, and...
BACKGROUND
As nightmares may be a risk factor for, or symptom of, multiple psychological disorders, some researchers suggest that nightmares should be screened, diagnosed, and treated. Treatments for nightmares include trauma-focused Cognitive Behavioural Therapy and Image Rehearsal Therapy, and pharmacological interventions such as prazosin and nitrazepam. As recent research has put into question our current understanding of treatment efficacy, there is a need to systematically review findings related to the effectiveness of nightmare treatments to inform best practice. The current review assessed the efficacy of psychosocial treatments of nightmare in all cohorts.
METHODS
A systematic search of four databases for peer reviewed journal articles from 2000 onwards produced 69 (35 RCTs, 34 non-RCTs) eligible articles that underwent narrative synthesis.
RESULTS
The results provide strong evidence for exposure and image rehearsal treatments for the reduction of nightmare frequency, severity, and distress, in civilian, military, idiopathic, and posttraumatic stress disorder (PTSD) cohorts. There is emerging evidence that self-guided and brief treatment modalities offer efficient and effective treatment options. There is an urgent need for clinical trials of treatment effectiveness in children.
CONCLUSIONS
The results suggest that treatments for nightmares are most effective when they facilitate a sense of control or mastery by directly targeting the nightmare content and/or the client's emotional responses to the nightmare content.
TRIAL REGISTRATION
A review protocol was registered with PROSPERO (CRD42020204861).
Topics: Humans; Adult; Child; Dreams; Prazosin; Stress Disorders, Post-Traumatic; Cognitive Behavioral Therapy; Treatment Outcome
PubMed: 37085821
DOI: 10.1186/s12888-023-04703-1 -
Minerva Urology and Nephrology Aug 2023Patients on alpha-blockers (ABs) treatment may have an increased risk of adverse events (AEs). Aim of our study was to compare real-life data on neuro-vascular and...
BACKGROUND
Patients on alpha-blockers (ABs) treatment may have an increased risk of adverse events (AEs). Aim of our study was to compare real-life data on neuro-vascular and sexual AEs associated with ABs based on Eudra-Vigilance reported AEs.
METHODS
Eudra-Vigilance (EV) database is the system for managing and analyzing information on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area (EEA). We recorded the number of sexual and neuro-vascular AEs for tamsulosin, alfuzosin, silodosin, prazosin and doxazosin per category and severity until July 30, 2022. Pooled Relative Risk (PRR) was used to compare data between drugs.
RESULTS
Overall the number of AEs were 2842 for Alfuzosin, 11,086 for tamsulosin, 792 for terazosin, 572 for prazosin and 4641 for doxazosin. Different percentages of AEs were obtained for each drug and in different age groups according to EV sub-groups (≤65, 65-85, ≥85). On PRR analysis, the risk of ejaculatory disorders for Silodosin (11%) is 18.5 times higher (PRR 18.5 95%CI; 10.7-31.8; P<0.05) when compared to alfuzosin and the risk of orthostatic hypotension is 2 times lower (PRR=1,84 95%CI 1.32-2.57; P<0.05).
CONCLUSIONS
Real life data is consistent with registry studies regarding side effects related to alpha-blockers. Alfuzosin is safer in terms of ejaculatory disorders while silodosin and tamsulosin in terms of orthostatic hypotension. Clinicians should consider these data when prescribing ABs especially in younger and older patients.
Topics: Humans; Doxazosin; Tamsulosin; Hypotension, Orthostatic; Adrenergic alpha-Antagonists; Prazosin; Urogenital Diseases
PubMed: 37067186
DOI: 10.23736/S2724-6051.23.05225-4 -
Urologia Aug 2023Different strategies have been proposed to treat cytokine storm syndrome (CSS), the final deadly complication of COVID-19. One approach is to target CSS by blocking the...
Different strategies have been proposed to treat cytokine storm syndrome (CSS), the final deadly complication of COVID-19. One approach is to target CSS by blocking the interleukin-6 (IL-6) pathway. A promising group of medications blocking the IL-6 pathway is α-blockers, such as prazosin. First, we hypothesized that Panax ginseng, commonly known as ginseng, can be an effective therapeutic agent in preventing CSS due to its blocking activity on alpha-1 adrenergic receptors (α1-AR). Furthermore, we suggested that herbs with 5α-reductase inhibitory effects, such as Saw palmetto, Nettle root, soya, black pepper, and green tea, can have debilitating impacts on pulmonary function since they can lead to impairment of the lung's ability to regenerate. Thus, we encourage the prospective studies to explore the potential effect of herbal medications, with possible beneficial effects for benign prostatic hyperplasia, during the COVID-19 pandemic since they are commonly consumed.
Topics: Male; Humans; Prostatic Hyperplasia; Interleukin-6; Pandemics; Prospective Studies; COVID-19; Adrenergic alpha-Antagonists
PubMed: 37067043
DOI: 10.1177/03915603231162387 -
Pharmaceutical Medicine May 2023Suicide is a serious and growing public health concern yet randomized controlled trials (RCTs) that inform pharmacologic treatment remain limited. We emphasize the... (Review)
Review
Suicide is a serious and growing public health concern yet randomized controlled trials (RCTs) that inform pharmacologic treatment remain limited. We emphasize the overall need for such trials and review the literature to highlight examples of trials that have aimed to study patients at elevated risk of suicide. We discuss key examples of existing psychotropic medication trials as well as psychotherapy intervention studies that can yield important design insights. Medications that have been studied in individuals at risk for suicide include lithium, clozapine, zolpidem, prazosin, ketamine, esketamine, and aripiprazole. While important design challenges should be considered-RCTs to study suicide are feasible and much needed. Issues such as overall trial design, patient-selection criteria, and the scales/tools used to assess suicidality are discussed.
Topics: Humans; Suicidal Ideation; Suicide
PubMed: 37046135
DOI: 10.1007/s40290-023-00467-x -
Hypertension (Dallas, Tex. : 1979) Jun 2023The opioid overdose and opioid use disorder epidemics are concomitant with increased metabolic and CVD risk. Although opioid use disorder causes adverse pregnancy...
BACKGROUND
The opioid overdose and opioid use disorder epidemics are concomitant with increased metabolic and CVD risk. Although opioid use disorder causes adverse pregnancy outcomes, the offspring's cardiovascular health is understudied. We hypothesized that offspring exposed to in utero morphine exposure (IUME) would show increased CVD risk factors and endogenous opioid system dysregulation.
METHODS
Sprague Dawley dams were treated with saline (vehicle, n=10) or escalating doses of morphine (5-20 mg/kg per day, SC, n=10) during gestation. Cardiovascular and metabolic parameters were assessed in adult offspring.
RESULTS
Litter size and pups' birth weight were not different in response to IUME. Female and male IUME offspring showed reduced body length at birth (<0.05) and body weight from weeks 1 to 3 of life (<0.05), followed by a catch-up growth effect. By week 16, female and male IUME rats showed reduced tibia length (<0.05) and fat mass. IUME increases the mean arterial pressure and the depressor response to mecamylamine (5 mg/kg per day, IP) induced by IUME were abolished by a chronic treatment with an alpha-adrenergic receptor blocker (prazosin; 1 mg/kg per day, IP). Although circulating levels of angiotensin peptides were similar between groups, IUME exacerbated maximal ex vivo Ang (angiotensin) II-induced vasoconstriction (<0.05) and induced endothelial dysfunction in a sex-specific manner (<0.05). Proenkephalin, an endogenous opioid peptide that lowers blood pressure and sympathetic-mediated vasoconstriction, showed reduced mRNA expression in the heart, aorta, and kidneys from morphine versus vehicle group (<0.05).
CONCLUSIONS
Among the effects of IUME, neurogenic hypertension, vascular dysfunction, and metabolic dysfunction could be associated with the dysregulation of the endogenous opioid system.
Topics: Pregnancy; Humans; Rats; Animals; Male; Female; Morphine; Analgesics, Opioid; Rats, Sprague-Dawley; Cardiovascular Diseases; Prenatal Exposure Delayed Effects; Hypertension; Angiotensin II; Opioid-Related Disorders
PubMed: 37042247
DOI: 10.1161/HYPERTENSIONAHA.122.20262 -
PLoS Neglected Tropical Diseases Apr 2023Scorpion envenomation is associated with several complications. One of the most serious complications is the cardiac involvement in the form of myocarditis that remains...
BACKGROUND
Scorpion envenomation is associated with several complications. One of the most serious complications is the cardiac involvement in the form of myocarditis that remains the main reason for mortalities associated with scorpion envenomation. The present review aims to elucidate clinical and paraclinical findings associated with scorpion-related myocarditis, and to explore different management strategies and subsequent outcomes.
METHODS
We searched PubMed, Web of Science, Scopus, and Google Scholar for articles related to keywords of myocarditis associated with scorpion envenomation up to May 1, 2022. Each article was carefully reviewed by two independent researchers. In case of disagreement for inclusion, we sought a third researcher opinion.
RESULTS
A total of 703 cases from 30 case reports and 34 case series were included in our review. Myocarditis associated with scorpion envenomation was usually reported in children presenting with cardiopulmonary symptoms including pulmonary edema (60.7%) and shock or hypotension (45.8%). The most common ECG findings are sinus tachycardia (82%) followed by ST-T changes (64.6%). The management typically included inotropes (especially dobutamine), prazosin, diuretics, nitroglycerine and digoxin, when indicated. Mechanical ventilation was required in 36.7% of the patients. Mortality in confirmed scorpion-related myocarditis cases is estimated at 7.3%. Almost all survived cases showed rapid recovery and improvement in the left ventricular function.
CONCLUSION
Even though myocarditis associated with scorpion envenomation is rare, it remains a serious and in some of cases a fatal consequence of scorpion sting. In case of relative presentations, particularly in envenomed children, diagnosis of myocarditis should be considered. Early screening using serial cardiac markers and echocardiography can guide the treatment. Prompt treatment that focuses on cardiogenic shock and pulmonary edema usually results in a favorable outcome.
Topics: Child; Humans; Animals; Scorpion Stings; Myocarditis; Pulmonary Edema; Dobutamine; Respiration, Artificial; Scorpions
PubMed: 37018229
DOI: 10.1371/journal.pntd.0011219 -
International Journal of Molecular... Mar 2023Secretion of melatonin, a natural hormone whose receptors are present in the ciliary epithelium, displays diurnal variation in the aqueous humor (AH), potentially...
Secretion of melatonin, a natural hormone whose receptors are present in the ciliary epithelium, displays diurnal variation in the aqueous humor (AH), potentially contributing to the regulation of intraocular pressure. This study aimed to determine the effects of melatonin on AH secretion in porcine ciliary epithelium. The addition of 100 µM melatonin to both sides of the epithelium significantly increased the short-circuit current (Isc) by ~40%. Stromal administration alone had no effect on the Isc, but aqueous application triggered a 40% increase in Isc, similar to that of bilateral application without additive effect. Pre-treatment with niflumic acid abolished melatonin-induced Isc stimulation. More importantly, melatonin stimulated the fluid secretion across the intact ciliary epithelium by ~80% and elicited a sustained increase (~50-60%) in gap junctional permeability between pigmented ciliary epithelial (PE) cells and non-pigmented ciliary epithelial (NPE) cells. The expression of MT receptor was found to be >10-fold higher than that of MT and MT in porcine ciliary epithelium. Aqueous pre-treatment with MT/MT antagonist luzindole failed to inhibit the melatonin-induced Isc response, while MT antagonist prazosin pre-treatment abolished the Isc stimulation. We conclude that melatonin facilitates Cl and fluid movement from PE to NPE cells, thereby stimulating AH secretion via NPE-cell MT receptors.
Topics: Swine; Melatonin; Aqueous Humor; Pigment Epithelium of Eye; Epithelium; Epithelial Cells; Carrier Proteins; Ciliary Body; Animals
PubMed: 36982863
DOI: 10.3390/ijms24065789 -
Marine Drugs Mar 2023Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely...
Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely due to the downfall of peripheral arterial resistance through direct or indirect effects on adrenergic signaling. TTX is a high-affinity blocker of voltage-gated Na (Na) channels. In arteries, Na channels are expressed in sympathetic nerve endings, both in the intima and media. In this present work, we aimed to decipher the role of Na channels in vascular tone using TTX. We first characterized the expression of Na channels in the aorta, a model of conduction arteries, and in mesenteric arteries (MA), a model of resistance arteries, in C57Bl/6J mice, by Western blot, immunochemistry, and absolute RT-qPCR. Our data showed that these channels are expressed in both endothelium and media of aorta and MA, in which and were the most abundant transcripts, suggesting that murine vascular Na channels consist of Na1.2 channel subtype with Naβ1 auxiliary subunit. Using myography, we showed that TTX (1 µM) induced complete vasorelaxation in MA in the presence of veratridine and cocktails of antagonists (prazosin and atropine with or without suramin) that suppressed the effects of neurotransmitter release. In addition, TTX (1 µM) strongly potentiated the flow-mediated dilation response of isolated MA. Altogether, our data showed that TTX blocks Na channels in resistance arteries and consecutively decreases vascular tone. This could explain the drop in total peripheral resistance observed during mammal tetrodotoxications.
Topics: Mice; Animals; Tetrodotoxin; Aorta; Mesenteric Arteries; Mammals; Voltage-Gated Sodium Channel beta-1 Subunit
PubMed: 36976245
DOI: 10.3390/md21030196