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International Journal of Molecular... Sep 2021To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed....
To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed. Blind patch-clamp recording was performed using slice preparations of SG neurons from the spinal cords of adult rats. Spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs, respectively) were recorded. The ratios of the frequency and amplitude of the sIPSCs and sEPSCs following the introduction of naftopidil compared with baseline, and after the application of naftopidil, serotonin (5-HT), and prazosin, compared with noradrenaline (NA) were evaluated. First, the sIPSC analysis indicated that SG neurons reached their full response ratio for NA at 50 μM. Second, they responded to 5-HT (50 μM) with a response ratio similar to that for NA, but prazosin (10 μM) did not change the sEPSCs and sIPSCs. Third, the highest concentration of naftopidil (100 μM) led to two types of response in the SG neurons, which corresponded with the reactions to 5-HT and prazosin. These results indicate that not all neurons were necessarily activated by naftopidil, and that the micturition reflex may be regulated in a sophisticated manner by inhibitory mechanisms in these interneurons.
Topics: Adrenergic alpha-Antagonists; Animals; Excitatory Postsynaptic Potentials; Inhibitory Postsynaptic Potentials; Male; Membrane Potentials; Naphthalenes; Neurons; Norepinephrine; Patch-Clamp Techniques; Piperazines; Prazosin; Rats, Sprague-Dawley; Serotonin; Substantia Gelatinosa; Synaptic Transmission; Rats
PubMed: 34502543
DOI: 10.3390/ijms22179636 -
Asian Journal of Urology Jul 2022Clinical practice guidelines recommend open adrenalectomy (OA) for large pheochromocytoma (LPCC) > 6 cm in size. Although laparoscopic adrenalectomy (LA) for the...
OBJECTIVE
Clinical practice guidelines recommend open adrenalectomy (OA) for large pheochromocytoma (LPCC) > 6 cm in size. Although laparoscopic adrenalectomy (LA) for the treatment of LPCC has been reported, its role remains unclear. This study aimed to compare the effectiveness of LA and OA, and summary the surgical treatment experience.
METHODS
Data concerning LPCC, from January 2010 to June 2019 of a single institution, were retrospectively reviewed. Altogether 82 patients with a tumor larger than 6 cm were included (52 patients in LA group and 30 patients in OA group). Groups were balanced by propensity score matching (PSM) into 15 pairs. Patients' demographics, preoperative characteristics, and prognosis were analyzed.
RESULTS
Before PSM, the OA group had larger tumor sizes (median [interquartile range, IQR]: 8.9 [7.3-10.3] 7.2 [6.7-8.0] cm; =0.000) and higher vanillylmandelic acid level (median [IQR]: 114.3 [67.8-326.4] 66.6 [37.8-145.8] μmol/24 h; =0.004) and needed a higher cumulative dose of prazosin (median [IQR]: 83.5 [37.0-154.0] 38.0 [21.0-81.0] mg; =0.028). After PSM, the baseline data showed no significant differences between both groups. The LA group had relatively more stable blood pressure in surgery, with a lower fluctuation of systolic blood pressure (mean±standard deviation [SD]: 70.9±25.1 107.4±46.2 mmHg, =0.012) and a lower percentage of hemodynamic instability (46.7% 86.7%, =0.020). The LA group had shorter postoperative hospital stays (mean±SD: 6.4±2.7 10.1±3.4 days; =0.003) than the OA group. Differences regarding metastasis rate (6.7% 0, =1.000) were not statistically significant between LA and OA groups. The median (IQR) follow-up time of 82 patients was 72.5 (47.0-103.5) months. Binary logistic regression showed that right-side tumors or those >8 cm in size were independent risk factors of OA.
CONCLUSION
LA is a safe, minimally invasive procedure for LPCC and has relatively better perioperative characteristics in large medical centers. Patients with tumors on the right side or larger than 8 cm are more likely to undergo OA initially.
PubMed: 36035344
DOI: 10.1016/j.ajur.2022.04.004 -
Neuroscience Letters Jan 2021The emission of 50 kHz frequency-modulated ultrasonic vocalizations (FM USVs) in rats has been associated with positive affective states, while a decrease in FM USVs has...
The emission of 50 kHz frequency-modulated ultrasonic vocalizations (FM USVs) in rats has been associated with positive affective states, while a decrease in FM USVs has been associated with anxiety-like states. We tested the hypothesis in male Sprague-Dawley rats that FM USVs would complement measures of aversive memories (decrease in FM USVs) in a conditioned fear task in which we examined extinction or reconsolidation disruption. In Experiment 1, rats were fear conditioned using low-level footshock followed by extinction while monitoring freezing and FM USVs. In Experiment 2, rats were fear conditioned, the alpha-1 antagonist prazosin was used to disrupt reconsolidation of memory, and freezing and FM USVs were measured. Rats fear conditioned with low-level shock showed minimal freezing that rapidly extinguished, despite a persistent decrease in FM USVs throughout extinction. Prazosin reduced freezing in a memory reactivation-dependent manner as expected, but the reduction in FM USVs after fear conditioning remained decreased, suggesting that an affective component of memory was not impacted by prazosin. These findings indicate that FM USVs may be used as an index of fear- or anxiety-like memory, and their measurement could benefit pre-clinical animal models for assessing reduction of aversive memories.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Avoidance Learning; Conditioning, Classical; Electroshock; Extinction, Psychological; Fear; Male; Memory; Memory Consolidation; Prazosin; Rats, Sprague-Dawley; Ultrasonics; Vocalization, Animal; Rats
PubMed: 33166637
DOI: 10.1016/j.neulet.2020.135458 -
Urology Annals 2023The present retrospective study evaluates the effectiveness and tolerability of alpha-blockers as monotherapy in patients with benign prostatic hyperplasia associated...
Electronic medical records-based retrospective, longitudinal, observational study to understand the patient management of benign prostatic hyperplasia with alpha-blockers monotherapy in Indian population.
OBJECTIVE
The present retrospective study evaluates the effectiveness and tolerability of alpha-blockers as monotherapy in patients with benign prostatic hyperplasia associated with lower urinary tract symptoms (LUTS).
MATERIALS AND METHODS
A total of 335 male patients >50 years were categorized into four groups (Alfuzosin: 166, Silodosin: 67, Tamsulosin: 70, Prazosin: 32). The efficacy evaluated as a change in International Prostate Symptom Score (IPSS), peak flow rate (Qmax), residual urine volume, and relief from LUTS, and tolerability of the various alpha-blockers was assessed across the study group.
RESULTS
At baseline, most of the patients in alfuzosin (60%), silodosin (77%), and tamsulosin (90%) groups presented with severe IPSS (20-35), whereas patients in the prazosin group (69%) presented with a moderate score. At the end of the study, the mean IPSS gradually improved to moderate (41%, 62%, 66%, and 28%) and mild (59%, 38%, 28%, and 72%) in the alfuzosin, silodosin, tamsulosin, and prazosin groups, respectively ( = 0.004), with improvement in mean change in residual urine volume and complete relief from LUTS symptoms with no surgical or radiological interventions. Overall, 194 adverse events (AEs) were observed in 38.8% of patients. Of the total AEs, patients in the alfuzosin, silodosin, tamsulosin, and prazosin groups experienced 21%, 22%, 39%, and 18% of AEs, respectively.
CONCLUSION
The nonselective alpha-adrenergic receptor antagonist, alfuzosin, emerged as noninferior in effectiveness and superior in tolerability than other selective alpha-blockers, silodosin, tamsulosin, and prazosin.
PubMed: 37304518
DOI: 10.4103/ua.ua_114_21 -
International Journal of Molecular... Apr 2022In this study, we examined whether aortic contraction, induced by the alpha-2 adrenoceptor agonist dexmedetomidine, is involved in the transactivation of the epidermal...
In this study, we examined whether aortic contraction, induced by the alpha-2 adrenoceptor agonist dexmedetomidine, is involved in the transactivation of the epidermal growth factor receptor (EGFR) in isolated endothelium-denuded rat aortas. Additionally, we aimed to elucidate the associated underlying cellular mechanisms. The effects of the alpha-2 adrenoceptor inhibitor rauwolscine, EGFR tyrosine kinase inhibitor AG1478, Src kinase inhibitors PP1 and PP2, and matrix metalloproteinase inhibitor GM6001 on EGFR tyrosine phosphorylation and c-Jun NH-terminal kinase (JNK) phosphorylation induced by dexmedetomidine in rat aortic smooth muscles were examined. In addition, the effects of these inhibitors on dexmedetomidine-induced contraction in isolated endothelium-denuded rat aorta were examined. Dexmedetomidine-induced contraction was inhibited by the alpha-1 adrenoceptor inhibitor prazosin, rauwolscine, AG1478, PP1, PP2, and GM6001 alone or by a combined treatment with prazosin and AG1478. AG1478 (3 × 10 M) inhibited dexmedetomidine-induced contraction in isolated endothelium-denuded rat aortas pretreated with rauwolscine. Dexmedetomidine-induced EGFR tyrosine and JNK phosphorylation were inhibited by rauwolscine, PP1, PP2, GM6001, and AG1478. Furthermore, dexmedetomidine-induced JNK phosphorylation reduced upon EGFR siRNA treatment. Therefore, these results suggested that the transactivation of EGFR associated with dexmedetomidine-induced contraction, mediated by the alpha-2 adrenoceptor, Src kinase, and matrix metalloproteinase, caused JNK phosphorylation and increased calcium levels.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Aorta; Dexmedetomidine; ErbB Receptors; Muscle, Smooth, Vascular; Phosphorylation; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Transcriptional Activation; Tyrosine; Yohimbine; src-Family Kinases
PubMed: 35457136
DOI: 10.3390/ijms23084320 -
Frontiers in Pharmacology 2021(TFG) is used as an antidiarrheal traditional medicine in Western Kenya. This study aimed to investigate the antidiarrheal activity of its aqueous extracts and the...
Aqueous Tuber Extracts of (Kotschy ex Schweinf.) Torre and Hillc. (Fabaceae). Possess Significant Antidiarrheal Activity and Spasmolytic Effect Possibly Mediated by Modulation of Nitrous Oxide System, Voltage-Gated Calcium Channels, and Muscarinic Receptors.
(TFG) is used as an antidiarrheal traditional medicine in Western Kenya. This study aimed to investigate the antidiarrheal activity of its aqueous extracts and the putative mechanism (s) of action using Sprague-Dawley rats and New Zealand white rabbits respectively. The antidiarrheal effects of the extract were evaluated in castor oil-induced diarrhea, the castor oil-induced enteropooling, and phenol red gastric motility tests. On the other hand, isolated rabbit's jejunal segments were used to evaluate the spasmolytic effect of TFG on spontaneous contraction, in acetylcholine-induced contraction, in presence of 80mMK, calcium chloride-induced contraction as well as in presence of the following antagonists: naloxone, methylene blue, L-NAME, prazosin, and propranolol in the studies. The data were express as Mean ± S.E.M and analyzed by one-way ANOVA and Tukey's post hoc test in cases of significance which was set at < 0.05. The extract was phytochemically characterized using Liquid chromatography Mass spectroscopy (LC-MS).The extract possessed significant inhibitory effect in the experiments. The extract exhibited significant spasmolytic effect on both spontaneous contraction and in jejunal segment pre-contracted acetylcholine as well as in presence of 80mMK solution. It also attenuated the spasmogenic effect of various concentration of calcium chloride. The extract's spasmolytic effect was, however, significantly attenuated in presence of several antagonists (methylene blue and L-NAME) but the adrenergic blockers (prazosin and propranolol) had no significant effect in the LC-MS identified thirty compounds where Proathocyanidin (11.54%), Syringic acid (7.30%), and 4-Hydroxybenzoic acid (6.19%) had the highest percentage abundance. In conclusion, the results obtained in this study partially validate the traditional uses of the tubers of this plant species as an antidiarrheal. These antidiarrheal effects are probably mediated via modulation of nitrous oxide pathway, voltage gated calcium channels, and muscarinic receptors.
PubMed: 33796023
DOI: 10.3389/fphar.2021.636879 -
Antibiotics (Basel, Switzerland) Nov 2022is a Gram-negative orofecal transmitted pathogen that causes a wide diversity of local and systemic illnesses. utilizes several interplayed systems to regulate its...
is a Gram-negative orofecal transmitted pathogen that causes a wide diversity of local and systemic illnesses. utilizes several interplayed systems to regulate its invasion and pathogenesis: namely, quorum sensing (QS) and type three secretion system (T3SS). In addition, could sense the adrenergic hormones in the surroundings that enhance its virulence. The current study aimed to evaluate the ability of α-adrenoreceptor antagonist prazosin to mitigate the virulence of serovar Typhimurium. The prazosin effect on biofilm formation and the expression of , , , and T3SS-type II encoding genes was evaluated. Furthermore, the prazosin intracellular replication inside macrophage and anti-virulence activity was evaluated in vivo against . . The current finding showed a marked prazosin ability to compete on SdiA and QseC and downregulate their encoding genes. Prazosin significantly downregulated the virulence factors encoding genes and diminished the biofilm formation, intracellular replication inside macrophages, and in vivo protected mice. To sum up, prazosin showed significant inhibitory activities against QS, T3SS, and bacterial espionage, which documents its considered anti-virulence activities.
PubMed: 36358239
DOI: 10.3390/antibiotics11111585 -
Molecular Pain 2021Neuropeptide W (NPW) messenger ribonucleic acid (mRNA) and NPBW1 and/or NPBW2 mRNA are expressed in the descending pain inhibitory system. In the present study, we...
Neuropeptide W (NPW) messenger ribonucleic acid (mRNA) and NPBW1 and/or NPBW2 mRNA are expressed in the descending pain inhibitory system. In the present study, we examined whether NPW microinjected into the descending pain inhibitory system, such as the periaqueductal gray (PAG), locus coeruleus (LC), and rostral ventromedial medulla (RVM), produces an analgesic effect using a rat formalin test. Microinjections of NPW into the PAG ipsilateral and contralateral to the formalin-injected side, LC ipsilateral and contralateral to the formalin-injected side, and RVM produced an analgesic effect. In the RVM study, the analgesic effect was antagonized by WAY100135, a 5-HT antagonist, and enhanced by prazosin, an α1 antagonist, and SB269970, a 5-HT antagonist. Naloxone, an opioid antagonist, also antagonized the effect of NPW in the RVM study. In the ipsilateral LC study, the analgesic effect was antagonized by WAY100135, idazoxan, an α2 antagonist, and naloxone and was enhanced by prazosin and SB269970. In the contralateral LC study, the analgesic effect was antagonized by prazosin, idazoxan, SB269970, and naloxone. The analgesic effect was antagonized by WAY100135, SB269970, idazoxan, and naloxone in the ipsilateral and contralateral PAG studies. These findings strongly suggest that NPBW1/W2 activation by NPW microinjection into the RVM, LC, and PAG affect the descending pain modulatory system and produce anti-nociceptive and pro-nociceptive effects in the rat formalin test.
Topics: Analgesics; Animals; Formaldehyde; Injections; Ligands; Locus Coeruleus; Male; Medulla Oblongata; Neuropeptides; Pain; Periaqueductal Gray; Rats, Sprague-Dawley; Receptors, Neuropeptide; Rats
PubMed: 33573476
DOI: 10.1177/1744806921992187 -
European Urology Focus Jan 2022Sexual dysfunction is a common side effect of medical therapy for benign prostatic hyperplasia (BPH), whereas prostatic urethral lift (PUL) offers safe and effective...
BACKGROUND
Sexual dysfunction is a common side effect of medical therapy for benign prostatic hyperplasia (BPH), whereas prostatic urethral lift (PUL) offers safe and effective relief of lower urinary tract symptoms while preserving sexual function.
OBJECTIVE
To compare the long-term impact on sexual health of PUL or daily medical therapy of doxazosin or finasteride alone or in combination in BPH patients.
DESIGN, SETTING, AND PARTICIPANTS
This was a comparative analysis of sexual function outcomes from PUL studies (L.I.F.T. [n=107], Crossover [n=42], and MedLift [n=39]) and the Medical Therapy of Prostatic Symptoms (MTOPS) trial. The men included were sexually active with International Prostate Symptom Score ≥13, Qmax ≤12ml/s, and prostate volume 30-80 cm. MTOPS subjects completed the Brief Male Sexual Function Inventory, while PUL subjects completed the International Index of Erectile Function and the Male Sexual Health Questionnaire for Ejaculatory Function.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Mean percentage changes from baseline in erectile, ejaculatory, and sexual satisfaction domains were compared at 12, 24, 36, and 48 mo.
RESULTS AND LIMITATIONS
PUL significantly improved erectile function through 24 mo, and ejaculatory function and sexual satisfaction across all time points. Medical therapy did not improve sexual function at any time point. Finasteride significantly decreased erectile function at 48 mo, and combined therapy significantly reduced ejaculatory function at 12 and 24 mo. Comparatively, PUL was superior to finasteride in preserving erectile function at 24 and 48 mo, and superior to doxazosin and combined therapy at 12 mo. PUL outperformed all three medical therapies at all time points in improving ejaculatory function and sexual satisfaction. Limitations include the use of distinct patient-reported questionnaires and narrowed data on comorbidities that influence male sexual function.
CONCLUSIONS
Indirect comparison reveals that PUL is superior to BPH medical therapy in preserving erectile and ejaculatory function and sexual satisfaction.
PATIENT SUMMARY
In our non-head-to-head study, only patients undergoing PUL for an enlarged prostate experienced improvements in sexual health. Conversely, patients on medical therapy experienced worsening of erectile and ejaculatory function.
Topics: Doxazosin; Erectile Dysfunction; Finasteride; Humans; Male; Prostate; Prostatic Hyperplasia
PubMed: 33436276
DOI: 10.1016/j.euf.2020.12.013 -
Pharmacology Research & Perspectives Aug 2020α1-adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants and...
α1-adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants and antipsychotics have been reported to have α1 affinity. This study examined 101 clinical drugs and laboratory compounds to build a comprehensive understanding of α1-adrenoceptor subtype affinity and selectivity. [3H]prazosin whole-cell binding was conducted in CHO cells stably expressing either the full-length human α1A, α1B, or α1D-adrenoceptor. As expected, doxazosin was a high-affinity nonselective α1-antagonist although other compounds (eg, cyclazosin, 3-MPPI, and ARC239) had higher affinities. Several highly α1A-selective antagonists were confirmed (SNAP5089 had over 1700-fold α1A selectivity). Despite all compounds demonstrating α1 affinity, only BMY7378 had α1D selectivity and no α1B-selective compounds were identified. Phenoxybenzamine (used in pheochromocytoma) and dibenamine had two-component-binding inhibition curves at all three receptors. Incubation with sodium thiosulfate abolished the high-affinity component suggesting this part is receptor mediated. Drugs used for hypertension and BPH had very similar α1A/α1B/α1D-adrenoceptor pharmacological profiles. Selective serotonin reuptake inhibitors (antidepressants) had poor α1-adrenoceptor affinity. Several tricyclic antidepressants (eg, amitriptyline) and antipsychotics (eg, chlorpromazine and risperidone) had high α1-adrenoceptor affinities, similar to, or higher than, α blockers prescribed for hypertension and BPH, whereas others had poor α1 affinity (eg, protriptyline, sulpiride, amisulpiride, and olanzapine). The addition of α blockers for the management of hypertension or BPH in people already taking tricyclic antidepressants and certain antipsychotics may not be beneficial. Awareness of the α-blocking potential of different antipsychotics may affect the choice of drug for those with delirium where additional hypotension (eg, in sepsis) may be detrimental.
Topics: Adrenergic alpha-Antagonists; Animals; Antidepressive Agents; Antipsychotic Agents; CHO Cells; Cricetulus; Humans; Receptors, Adrenergic, alpha-1
PubMed: 32608144
DOI: 10.1002/prp2.602