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Cardiovascular Research Mar 2023The carotid bodies (CBs) of spontaneously hypertensive (SH) rats exhibit hypertonicity and hyperreflexia contributing to heightened peripheral sympathetic outflow. We...
AIMS
The carotid bodies (CBs) of spontaneously hypertensive (SH) rats exhibit hypertonicity and hyperreflexia contributing to heightened peripheral sympathetic outflow. We hypothesized that CB hyperexcitability is driven by its own sympathetic innervation.
METHODS AND RESULTS
To test this, the chemoreflex was activated (NaCN 50-100 µL, 0.4 µg/µL) in SH and Wistar rats in situ before and after: (i) electrical stimulation (ES; 30 Hz, 2 ms, 10 V) of the superior cervical ganglion (SCG), which innervates the CB; (ii) unilateral resection of the SCG (SCGx); (iii) CB injections of an α1-adrenergic receptor agonist (phenylephrine, 50 µL, 1 mmol/L), and (iv) α1-adrenergic receptor antagonist prazosin (40 µL, 1 mmol/L) or tamsulosin (50 µL, 1 mmol/L). ES of the SCG enhanced CB-evoked sympathoexcitation by 40-50% (P < 0.05) with no difference between rat strains. Unilateral SCGx attenuated the CB-evoked sympathoexcitation in SH (62%; P < 0.01) but was without effect in Wistar rats; it also abolished the ongoing firing of chemoreceptive petrosal neurones of SH rats, which became hyperpolarized. In Wistar rats, CB injections of phenylephrine enhanced CB-evoked sympathoexcitation (33%; P < 0.05), which was prevented by prazosin (26%; P < 0.05) in SH rats. Tamsulosin alone reproduced the effects of prazosin in SH rats and prevented the sensitizing effect of the SCG following ES. Within the CB, α1A- and α1B-adrenoreceptors were co-localized on both glomus cells and blood vessels. In conscious SH rats instrumented for recording blood pressure (BP), the CB-evoked pressor response was attenuated after SCGx, and systolic BP fell by 16 ± 4.85 mmHg.
CONCLUSIONS
The sympathetic innervation of the CB is tonically activated and sensitizes the CB of SH but not Wistar rats. Furthermore, sensitization of CB-evoked reflex sympathoexcitation appears to be mediated by α1-adrenoceptors located either on the vasculature and/or glomus cells. The SCG is novel target for controlling CB pathophysiology in hypertension.
Topics: Rats; Animals; Carotid Body; Rats, Wistar; Tamsulosin; Hypertension; Sympathetic Nervous System; Blood Pressure; Rats, Inbred SHR; Phenylephrine; Prazosin
PubMed: 35048948
DOI: 10.1093/cvr/cvac008 -
Drug Research Jul 2022Acute kidney injury (AKI) is a major medical challenge caused from renal ischemia-reperfusion (IR) injury connected with different cellular events in other distant...
Acute kidney injury (AKI) is a major medical challenge caused from renal ischemia-reperfusion (IR) injury connected with different cellular events in other distant organs. Renal IR-related oxidative stress and inflammation followed by cell apoptosis play a crucial role in IR-induced distant organ pathological damages. Prazosin has shown protective effects against IR-injuries. Thus, the current study intended to investigate the possible protective role of prazosin against the consequents of renal IR in the heart and brain tissues. To reach this goal, rats were randomly divided into 3 groups (n=7): Sham, IR and prazosin pretreatment-IR animals (1 mg/kg intraperitoneally injection of prazosin 45 min before IR induction). After 6 h reperfusion, lipid peroxidation and antioxidant markers levels were evaluated in the both, brain and heart tissue. Moreover, apoptotic pathway in the heart and brain tissues were assessed by western blotting. Accordingly, prazosin pretreatment in IR model rats could significantly increase the antioxidant capacity and attenuate apoptotic pathways by increasing the bcl-2 levels and decreasing the expression of Bax and caspase 3 enzymes (P<0.05). Thus, prazosin suppressed cellular damages of heart and brain tissues post kidney IR by anti-oxidative and anti-apoptotic effects, which suggests the plausible use of prazosin in improving the clinical outcomes during AKI after further investigations.
Topics: Acute Kidney Injury; Animals; Antioxidants; Apoptosis; Brain; Ischemia; Kidney; Oxidative Stress; Prazosin; Rats; Reperfusion; Reperfusion Injury
PubMed: 35426094
DOI: 10.1055/a-1806-1453 -
Journal of Applied Physiology... Dec 2022We assessed hypercapnic cerebrovascular reactivity (CVR) and endothelium-dependent function [cerebral shear-mediated dilation (cSMD)] in the internal carotid artery... (Randomized Controlled Trial)
Randomized Controlled Trial
We assessed hypercapnic cerebrovascular reactivity (CVR) and endothelium-dependent function [cerebral shear-mediated dilation (cSMD)] in the internal carotid artery (ICA) with and without systemic α-adrenoreceptor blockade via Prazosin. We hypothesized that CVR would be reduced, whereas cSMD would remain unchanged, after Prazosin administration when compared with placebo. In 15 healthy adults (3 female, 26 ± 4 years), we conducted ICA duplex ultrasound during CVR [target +10 mmHg partial pressure of end-tidal carbon dioxide ([Formula: see text]) above baseline, 5 min] and cSMD (+9 mmHg [Formula: see text] above baseline, 30 s) using dynamic end-tidal forcing with and without α-adrenergic blockade (Prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind, and randomized design. The CVR in the ICA was not different between placebo and Prazosin ( = 0.578). During CVR, the reactivities of mean arterial pressure and cerebrovascular conductance to hypercapnia were also not different between conditions ( = 0.921 and = 0.664, respectively). During Prazosin, cSMD was lower (1.1 ± 2.0% vs 3.8 ± 3.0%; = 0.032); however, these data should be interpreted with caution due to the elevated baseline diameter (+1.3 ± 3.6%; condition: = 0.0498) and lower shear rate (-14.5 ± 23.0%; condition: < 0.001). Therefore, lower cSMD post α-adrenoreceptor blockade might not indicate a reduction in cerebral endothelial function per se, but rather, that α-adrenoreceptors contribute to resting cerebral vascular restraint at the level of the ICA. We assessed steady-state hypercapnic cerebrovascular reactivity and cerebral endothelium-dependent function, with and without α-adrenergic blockade (Prazosin), in a placebo-controlled, double-blind, and randomized study, to assess the contribution of α-adrenergic receptors to cerebrovascular CO regulation. After administration of Prazosin, cerebrovascular reactivity to CO was not different compared with placebo despite lower blood flow, whereas cerebral endothelium-dependent function was reduced, likely due to elevated baseline internal carotid arterial diameter. These findings suggest that α-adrenoreceptor activity does not influence cerebral blood flow regulation to CO and cerebral endothelial function.
Topics: Adult; Female; Humans; Adrenergic Agents; Blood Flow Velocity; Carbon Dioxide; Carotid Artery, Internal; Cerebrovascular Circulation; Hypercapnia; Prazosin; Receptors, Adrenergic, alpha-1; Male; Young Adult
PubMed: 36326471
DOI: 10.1152/japplphysiol.00400.2022 -
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 -
Journal of Feline Medicine and Surgery Dec 2021The aim of this study was to determine if male cats treated with 7 days of prazosin following relief of urethral obstruction (UO) experienced decreased rates of...
OBJECTIVES
The aim of this study was to determine if male cats treated with 7 days of prazosin following relief of urethral obstruction (UO) experienced decreased rates of recurrent urethral obstruction (rUO) within 30 days vs those treated with 7 days of placebo.
METHODS
All castrated male cats presenting for the first time with UO from May 2014 to August 2017 were eligible for enrollment. Exclusion criteria included the administration of medications or passage of a urinary catheter prior to referral, the presence of heart disease or hypertension requiring medication, prior treatment with glucocorticoids, non-steroidal anti-inflammatory medications, prazosin or phenoxybenzamine, or radiographic identification of cystoliths. Cats were treated with standardized anesthetic and analgesic protocols, standardized indwelling urinary catheter management, and were hospitalized for care. A random numbers table was generated prior to study initiation and cats were randomized to receive either prazosin (0.5 mg PO q12h for 7 days) or placebo in a blinded fashion. A 30-day follow-up with owners via telephone was performed to identify the rate of rUO. Cats that did not receive the full course of study medication were removed from the analysis. The study was unblinded at the end of data collection.
RESULTS
Eighty cats were enrolled and 65 cats completed the study; 12 were excluded because they did not receive the study medication. Sixteen of 65 cats experienced rUO (25%). Of the 16 cats experiencing rUO, five received placebo (n = 5/28 [18%]) and 11 received prazosin (n = 11/37 [30%]). Ten of the cats that experienced rUO reblocked while still hospitalized. There was no significant difference in frequency of rUO in cats treated with prazosin vs placebo ( = 0.27).
CONCLUSIONS AND RELEVANCE
Prazosin administered at 0.5 mg PO q12h did not decrease the rate of rUO in this population of obstructed male cats vs placebo. These results further support evidence suggesting that prazosin may not be beneficial in prevention of feline rUO.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cat Diseases; Cats; Male; Prazosin; Recurrence; Urethral Obstruction
PubMed: 33749375
DOI: 10.1177/1098612X211001283 -
Cardiovascular Therapeutics 2020It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered -adrenoceptors ( -ARs) in skin-lightening... (Review)
Review
It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered -adrenoceptors ( -ARs) in skin-lightening experiments in the frog. Now -ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of -AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by -ARs. In this model system and in the setting of furosemide-induced sodium excretion, -AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal -AR expression in hypertensive animals is elevated, thus supporting a key role for kidney -ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which -ARs activate prohypertensive biochemical systems. While investigating the role of -adrenoceptors ( -ARs) versus -ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney -ARs suppress the postjunctional expression of -ARs. Here, we describe how this finding relates to a broader understanding of the role of -ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of -AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.
Topics: Accidental Falls; Adrenergic alpha-2 Receptor Antagonists; Animals; Antihypertensive Agents; Anxiety; Autonomic Denervation; Blood Pressure; Diuretics; Essential Hypertension; Humans; Hypotension, Orthostatic; Kidney; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Renal Elimination; Renal Reabsorption; Signal Transduction; Sodium; Stress Disorders, Post-Traumatic
PubMed: 32426035
DOI: 10.1155/2020/2478781 -
The American Journal of Psychiatry May 2021Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes.
METHODS
A 12-week, double-blind, randomized, controlled proof-of-concept trial of prazosin (16 mg/day, with a 2-week titration) was conducted in community-recruited adults with current alcohol dependence (N=100) with varying levels of alcohol withdrawal symptoms assessed at treatment entry. Primary outcomes were daily self-reported drinking days and heavy drinking days, and secondary outcomes were average drinks/day and mood, anxiety, craving, and sleep quality ratings.
RESULTS
Modified intent-to-treat analyses indicated a significant interaction of alcohol withdrawal symptom score by treatment by full-dose treatment period (weeks 3-12) for drinking days, heavy drinking days, and average drinks/day. By week 12, participants with high alcohol withdrawal symptoms on prazosin reported 7.07% heavy drinking days and 27.46% drinking days, while those on placebo had 35.58% heavy drinking days and 58.47% drinking days (heavy drinking days: odds ratio=0.14, 95% CI=0.058, 0.333; drinking days: odds ratio=0.265, 95% CI=0.146, 0.481). No such benefit of prazosin was observed in those reporting low or no alcohol withdrawal symptoms. Individuals with high alcohol withdrawal symptoms on prazosin compared with placebo also showed significantly improved anxiety, depression, and alcohol craving over the course of the trial.
CONCLUSIONS
The findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and for associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of prazosin's efficacy in the treatment of AUD.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Alcohol Abstinence; Alcoholism; Anxiety; Central Nervous System Depressants; Counseling; Craving; Depression; Double-Blind Method; Ethanol; Female; Humans; Male; Middle Aged; Prazosin; Proof of Concept Study; Self-Help Groups; Sleep Wake Disorders; Substance Withdrawal Syndrome; Treatment Outcome
PubMed: 33207935
DOI: 10.1176/appi.ajp.2020.20050609 -
Translational Cancer Research Sep 2019Osteosarcoma is a primary malignant bone tumor that frequently occurs in adolescents and children, its high aggressiveness and rapid metastasis often resulting in poor...
BACKGROUND
Osteosarcoma is a primary malignant bone tumor that frequently occurs in adolescents and children, its high aggressiveness and rapid metastasis often resulting in poor prognoses. In previous studies, Prazosin has been shown to possess anti-proliferative properties against prostate cancer and glioblastoma cells. In our study, we investigated Prazosin's underlying mechanisms and its effects on the biological behaviors of osteosarcoma cells.
METHODS
Osteosarcoma cell lines MG63 and 143B were treated with different concentrations of Prazosin, and a CCK8 assay assessed its effect on cell viability. Colony formation, Transwell and flow cytometry assays were used to examine its effects on cell proliferation, cell migration, and cell invasion and apoptosis, respectively. The expression of relevant proteins was then examined using western blotting.
RESULTS
Our data showed that Prazosin dose-dependently reduced the viability of MG63 and 143B cells and significantly inhibited their clonogenic ability. Moreover, Prazosin attenuated the cell migration and invasion abilities of MG63 and 143B cells when compared with the NC group. It also accelerated cell apoptosis in mitochondrial pathways by regulating Bcl-2/Bax axis and caspase 3. Furthermore, Prazosin treatment inactivated the Akt/mTOR pathway by down-regulating Akt and mTOR phosphorylation (p-Akt, p-mTOR) and the expression of P70 and cyclin D1.
CONCLUSIONS
Our data highlights the fact that Prazosin inhibits cell growth, inhibits the motility of osteosarcoma cells, and promotes apoptosis, suggesting that Prazosin is a potential anti-cancer agent in osteosarcoma therapy.
PubMed: 35116948
DOI: 10.21037/tcr.2019.09.03 -
Journal of Clinical Hypertension... Sep 2022There is emerging evidence that α1-blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood... (Review)
Review
There is emerging evidence that α1-blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood pressure control. However, there are several special indications. Benign prostatic hyperplasia is a compelling indication of α1-blockers, because of the dual treatment effect on both high blood pressure and lower urinary tract symptoms. Many patients with resistant hypertension would require α1-blockers as add-on therapy. Primary aldosteronism screen is a rapidly increasing clinical demand in the management of hypertension, where α1-blockers are useful for blood pressure control in the preparation for the measurement of plasma aldosterone and renin. Nonetheless, α1-blockers have to be used under several considerations. Among the currently available agents, only long-acting α1-blockers, such as doxazosin gastrointestinal therapeutic system 4-8 mg daily and terazosin 2-4 mg daily, should be chosen. Orthostatic hypotension is a concern with the use of α1-blockers especially in the elderly, and requires careful initial bedtime dosing and avoiding overdosing. Fluid retention is potentially also a concern, which may be overcome by combining an α1-blocker with a diuretic.
Topics: Adrenergic alpha-Antagonists; Aged; Aldosterone; Antihypertensive Agents; Diuretics; Doxazosin; Humans; Hypertension; Renin
PubMed: 36196467
DOI: 10.1111/jch.14556 -
Pharmaceutics Mar 2021Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in... (Review)
Review
Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.
PubMed: 33810493
DOI: 10.3390/pharmaceutics13040450