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We read with interest the article "Samajdar SS, Mukherjee S, Gupta S, et al. Effect of α-blockers on handgrip test response of diastolic blood pressure in hypertensive, benign hypertrophy of prostate patients in a therapeutics clinic, Kolkata: a cross-sectional study. J Assoc Physicians India 2024;72(4):21-23." 1 ., (© Journal of the Association of Physicians of India 2024.)

Abnormal glucose metabolism is a common disease of the endocrine system. The effects of drugs on glucose metabolism have been reported frequently in recent years, and since abnormal glucose metabolism increases the risk of microvascular and macrovascular complications, metabolic disorders, and infection, clinicians need to pay close attention to these effects. A variety of common drugs can affect glucose metabolism and have different mechanisms of action. Hypertension is a common chronic cardiovascular disease that requires long-term medication. Studies have shown that various antihypertensive drugs also have an impact on glucose metabolism. Among them, α-receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers can improve insulin resistance, while β-receptor blockers, thiazides and loop diuretics can impair glucose metabolism. The aim of this review was to discuss the mechanisms underlying the effects of various antihypertensive drugs on glucose metabolism in order to provide reference information for rational clinical drug use., (© 2024 John Wiley & Sons Ltd.)

Introduction: Benign prostatic hyperplasia (BPH) is a condition that affects over 50% of men as they enter their fifth decade of life, often leading to lower urinary tract symptoms (LUTS). Primary treatment options include alpha blockers, 5-alpha reductase inhibitors, and phosphodiesterase-5 inhibitors. However, these medications can have some side effects, and there is a noticeable dearth of information addressing the long-term use of these medications. Thus, the exploration of all treatment modalities helps ensure patients receive personalized and effective care. Consequently, the primary objective of this review is to identify potential emerging medications for the treatment of BPH., Areas Covered: We conducted an extensive review of articles discussing pharmacotherapy for BPH spanning the last 15 years. Our information gathering process involved Scopus, PubMed-MEDLINE, Cochrane, Wiley Online Library Google Scholar, ClinicalTrials.gov, and the PharmaProjects database. This approach ensures that readers gain an in-depth knowledge of the existing therapeutic agents as well as promising avenues for managing BPH., Expert Opinion: BPH treatment targets a patient's specific constellation of symptoms. Therefore, a broad knowledge base encompassing various treatment options is paramount in ensuring optimal treatment. Looking forward, the emphasis on personalization promises to reshape the landscape of BPH treatment and improve patient outcomes.

Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to posttransplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (β-adrenergic blockage), or placebo infusion. Characteristics of participants (5 females/4 males) were as follows: median (range) age 53 (34-63) yr, diabetes duration 29 (18-56) yr, posttransplant 7.0 (1.9-8.4) yr, HbA 1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate was lower with propranolol versus placebo ( P < 0.05). There was no difference in the suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and although levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo ( P < 0.05). Pancreatic polypeptide was greater with phentolamine versus placebo during the euglycemic phase ( P < 0.05), and free fatty acids were lower and the glucose infusion rate was higher with propranolol versus placebo during the hypoglycemic phase ( P < 0.05 for both). These results indicate that neither physiological α- nor β-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic reinnervation of the islet graft is not necessary for posttransplant glucose counterregulation. NEW & NOTEWORTHY Whether adrenergic input to islets is necessary for glucose homeostasis in humans is debated. Here, the adrenergic contribution to intrahepatically transplanted islet cell responses to hypoglycemia in individuals with type 1 diabetes was investigated through α- or β-adrenergic receptor blockade during hyperinsulinemic euglycemic-hypoglycemic clamps. Neither α- nor β-adrenergic blockage affected the suppression of endogenous insulin or activation of glucagon secretion, suggesting that sympathetic reinnervation of islet grafts is not required for posttransplant defense against hypoglycemia.

Introduction: Alpha-adrenergic antagonists are widely prescribed for lower urinary tract symptoms (LUTS), however there has been a report that their use is associated with dementia. Our objective was to investigate if new users of alpha-adrenergic antagonists with varying levels of cognitive impairment had an increased risk of cognitive decline compared to non-users., Methods: This was a retrospective cohort study, utilizing data from the National Alzheimer's Coordinating Center (NACC) data set. After applying relevant exclusion criteria, 916 people who were newly using alpha-antagonist medications were matched with a propensity score to 916 who were not using these medications. The primary outcome was a clinically relevant cognitive decline measured by the Clinical Dementia Rating (CDR) Dementia Staging Instrument or the mini mental state examination (MMSE). Secondary outcomes included scores from other cognitive assessment tools., Results: The matched cohorts did not differ significantly in baseline characteristics. There were no statistically significant differences in baseline or follow-up cognitive scores between those exposed and nonexposed to alpha-adrenergic antagonists. Clinically significant cognitive decline (as defined by the CDR) occurred in 9.72% of the exposed group and 8.19% of the nonexposed group. There was no observed effect of alpha-adrenergic antagonists on cognitive decline, as measured with the CDR (odds ratio [OR] 1.34, p = 0.14) or the MMSE (OR 0.98, p = 0.92). Stratified analyses by cognitive status and apolipoprotein E genotype interaction assessment also demonstrated no significant associations., Conclusion: Alpha-adrenergic antagonists for LUTS do not appear to increase the risk of cognitive decline, offering reassurance to clinicians and patients., (© 2024 The Author(s). Neurourology and Urodynamics published by Wiley Periodicals LLC.)

The basolateral amygdala (BLA) contains adrenergic receptors, which are known to be involved in stress, anxiety, and memory. The objective of this study was to explore whether inhibition of α-adrenergic receptors (by phentolamine, an α-adrenergic receptor antagonist) in the BLA can reduce foot-shock stress-induced anxiety-like behavior, memory deficits, and long-term potentiation (LTP) deficits within the CA1 region of the rat hippocampus. Forty male Wistar rats were assigned to the intact, control, stress (Str), Phent (phentolamine), and Phent + Str groups. Animals were subjected to six shocks on 4 consecutive days, and phentolamine was injected into BLA 20 min before the animals were placed in the foot-shock stress apparatus. Results from the elevated plus maze test (EPM) revealed a reduction in anxiety-like behaviors (by an increased number of entries into the open arm, percentage of time spent in the open arm, and rearing and freezing) among stressed animals upon receiving injections of phentolamine into the BLA. The open-field test results (increased rearing, grooming, and freezing behaviors) were consistent with the EPM test results. Phentolamine infusion into the BLA enhanced spatial memory, reducing errors in finding the target hole and decreasing latency time in the Barnes maze test for stress and nonstress conditions. Injecting phentolamine into the BLA on both sides effectively prevented LTP impairment in hippocampal CA1 neurons after being subjected to foot-shock stress. It has been suggested that phentolamine in the BLA can effectively improve anxiety-like behaviors and memory deficits induced by foot-shock stress., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Although α 1 -adrenoceptor (α 1 -AR) antagonists used to treat benign prostatic hyperplasia can cause ejaculation disorders, the aetiology of this adverse event is still controversial. Therefore, we investigated the effects of antagonists with different affinities for α 1 -AR subtypes on ejaculatory function and their mechanisms of action in normal rats. In the spontaneous seminal emission (SSE) test, systemically administered prazosin, terazosin, tamsulosin and naftopidil decreased the weight of ejaculated seminal material in a dose-dependent manner; the potency order was as follows: tamsulosin > terazosin > prazosin > naftopidil. The selective α 1D -AR antagonist BMY7378 had no effect on SSE. Intrathecal tamsulosin and naftopidil did not inhibit SSE. Tamsulosin, the most potent, was ineffective as a single dose and significantly increased seminal vesicle fluid in rats treated for 2 weeks but did not significantly change retrograde ejaculation. These results indicated that the difference in inhibitory potency of the five α 1 -AR antagonists against SSE was due to the involvement of α 1A -AR subtypes. Our results further suggested that α 1 -AR antagonist-induced ejaculatory dysfunction at the peripheral level was mainly due to the loss of seminal emission, although some retrograde ejaculation may also be involved., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Objective: To assess the ability of intranasal atipamezole to reverse sedative effects of xylazine in dogs., Design: Prospective proof-of-concept study., Setting: University research laboratory., Animal: Six healthy, staff-owned dogs., Interventions: Dogs were sedated with 1.1 mg/kg of xylazine intravenously. The sedation score of each dog was recorded every 5 minutes until they achieved a sedation score of >13/21 for 3 readings. Once achieved, 0.3 mg/kg of atipamezole was administered intranasally using a mucosal atomization device. Sedation scores continued to be recorded every 5 minutes until successful reversal was achieved (<4/21)., Measurements and Main Results: Average times to standing and normal wakefulness after administration of intranasal atipamezole were 6 minutes, 30 seconds and 7 minutes, 20 seconds, respectively., Conclusions: Intranasal atipamezole successfully reversed the sedation effects of xylazine. The findings of this study provide justification for future controlled prospective studies into the potential use of intranasal atipamezole in a variety of settings including exposure to xylazine in operational canines as well as bioavailability studies for optimal dosing., (© Veterinary Emergency and Critical Care Society 2023.)

Oral squamous cell carcinoma (OSCC), a global threatening disease, is reported mostly in the middle and elderly male population. Even though the exact cause of OSCC was not known, consumption of tobacco in any form has been reported in most of OSCC patients. OSCC is a massive invasive type of cancer which easily spreads to the distant organs. Hence treating it at appropriate time is necessary and the rate of OSCC incidence is also constantly increasing. At present, chemoradiation is the only therapy prescribed for OSCC patients which renders various side effects. Hence, the treatment with lesser side effect was of current research interest. Doxazosin (α1 adrenorecptor antagonist) had been proven to render anticancer effect in prostate, renal, hepatic, and ovarian cancers but its role in oral cancer cells was not been elucidated. Therefore, we have assessed the anticancer effect of doxazosin on oral squamous cancer cells via through the induction of apoptosis, and antioxidant property. The cytoprotective effect of doxazosin on normal Vero cells and anticancer effect on oral cancer KB cells were analyzed with MTT assay. Doxazosin antioxidant activity were analyzed by their reactivity with free radicals and metal ions by the method of FRAP, DPPH, chemilumiscence, and ORAC assay. The antioxidant levels were also assessed by TBARS, SOD, and glutathione levels, and later on apoptosis staining techniques like DCFH-DA, Rhodamine 123, and AO/EtBr stain were conducted. Apoptosis was confirmed by estimating the levels of apoptotic proteins in doxazosin-treated KB human oral cancer cells by ELISA method. The results from our study show that doxazosin is a potent antioxidant and it significantly induces apoptosis in human oral cancer by altering various cellular molecules at downstream signaling which has been depict in the results. Our study proves doxazosin as a potent anticancer drug which may be used in the treatment of oral carcinoma, if it is subjected to further research using human clinical trials., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We examined whether the α 1L -adrenoceptor (AR), which shows low affinity (pA 2  < 9) for prazosin (an α 1 -AR antagonist) and high affinity (pA 2  ≈ 10) for tamsulosin/silodosin (α 1A -AR antagonists), is involved in phenylephrine-induced contractions in the guinea pig (GP) thoracic aorta (TA). Intracellular signaling induced by α 1L -AR activation was also examined by focusing on Ca 2+ influx pathways. Tension changes of endothelium-denuded TAs were isometrically recorded and mRNA encoding α-ARs/Ca 2+ channels and their related molecules were measured using RT-quantitative PCR. Phenylephrine-induced contractions were competitively inhibited by prazosin/tamsulosin, and their pA 2 value were calculated to be 8.53/9.74, respectively. These contractions were also inhibited by silodosin concentration-dependently. However, the inhibition was not competitive fashion with the apparent pA 2 value being 9.48. In contrast, phenylephrine-induced contractions were not substantially suppressed by L-765314 (an α 1B -AR antagonist), BMY 7378 (an α 1D -AR antagonist), yohimbine, and idazoxan (α 2 -AR antagonists). Phenylephrine-induced contractions were markedly inhibited by YM-254890 (a Gq protein inhibitor) or removal of extracellular Ca 2+ , and partially inhibited by verapamil (a voltage-dependent Ca 2+ channel (VDCC) inhibitor). The residual contractions in the presence of verapamil were slightly inhibited by LOE 908 (a receptor-operated Ca 2+ channel (ROCC) inhibitor) and strongly inhibited by SKF-96365 (a store-operated Ca 2+ channel (SOCC) and ROCC inhibitor). Among the mRNA encoding α-ARs/SOCC-related molecules, α 1A -AR (Adra1a)/Orai3, Orai1, and Stim2 were abundant in this tissue. In conclusion, phenylephrine-induced contractions in the GP TA can be triggered by stimulation of Gq protein-coupled α 1L -AR, followed by activation of SOCCs and VDCCs.

Purpose: Urolithiasis is a common urinary tract disease with growing prevalence. Alpha1-adrenoceptors (α1-ARs) are abundant in ureteral smooth muscle, distributed with different α1-AR subtypes. α1D-AR is the most widely distributed in the ureter. However, the effect of α1D-AR blockade on ureteric contraction remains unknown., Materials and Methods: We dissected smooth muscle tissues (3 mm×3 mm) from the rat bladder and human ureter, tied silk strips on both tissue ends, and measured contraction in an organ bath chamber. Contraction activity in ureteral smooth muscle cells (USMCs) was immunocytochemically examined using primary rat and human USMC cultures., Results: Using the organ bath system, we determined the inhibitory effects of silodosin, tamsulosin, and naftopidil. Naftopidil significantly decreased contractility of rat bladder tissue; similar results were observed in human ureteral tissue. To confirm ex vivo experimental results in vitro , we examined the phosphorylation of myosin light chain (MLC), a marker of contractility, in a primary human USMC culture. The examined drugs decreased phospho-MLC levels in human USMCs; however, naftopidil profoundly increased MLC dephosphorylation., Conclusions: We studied the effects of naftopidil, an α1D-AR inhibitor, on the ureter. Compared with alpha-blockers, naftopidil significantly relaxed ureteral smooth muscle. Therefore, naftopidil could be an effective therapy for patients with ureteral stones., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

Introduction: Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant pharmacological potential and could be exploited for research by medicinal chemists. It is an indole alkaloid obtained from various natural/synthetic sources. Aims and Results: The research on yohimbine started early, and its use as a stimulant and aphrodisiac by humans has been reported for a long time. The pharmacological activity of yohimbine is mediated by the combined action of the central and peripheral nervous systems. It selectively blocks the pre and postsynaptic α 2 -adrenergic receptors and has a moderate affinity for α 1 and α 2 subtypes. Yohimbine also binds to other behaviourally relevant monoaminergic receptors in the following order: α-2 NE > 5HT-1A>, 5HT-1B > 1-D > D3 > D2 receptors. Conclusion: The current review highlights some significant findings that contribute to developing yohimbine-based drugs. It also highlights the therapeutic potential of yohimbine against selected human diseases. However, further research is recommended on the pharmacokinetics, molecular mechanisms, and drug safety requirements using well-designed randomized clinical trials to produce yohimbine as a pharmaceutical agent for human use.Key MessagesYohimbine is a natural indole alkaloid with significant pharmacological potential.Humans have used it as a stimulant and aphrodisiac from a relatively early time.It blocks the pre- and postsynaptic α2-adrenergic receptors that could be exploited for managing erectile dysfunction, myocardial dysfunction, inflammatory disorders, and cancer.

Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca 2+ current (I CaL ) by noradrenaline (NA). However, the contribution of the adrenoceptor (AR) sub-types to such I CaL -increase is poorly understood, particularly in human. We therefore investigated effects of various broad-action and sub-type-specific α- and β-AR antagonists on NA-stimulated atrial I CaL . I CaL was recorded by whole-cell-patch clamp at 37 °C in myocytes isolated enzymatically from atrial tissues from consenting patients undergoing elective cardiac surgery and from rabbits. NA markedly increased human atrial I CaL , maximally by ~ 2.5-fold, with EC 75 310 nM. Propranolol (β 1  + β 2 -AR antagonist, 0.2 microM) substantially decreased NA (310 nM)-stimulated I CaL , in human and rabbit. Phentolamine (α 1  + α 2 -AR antagonist, 1 microM) also decreased NA-stimulated I CaL . CGP20712A (β 1 -AR antagonist, 0.3 microM) and prazosin (α 1 -AR antagonist, 0.5 microM) each decreased NA-stimulated I CaL in both species. ICI118551 (β 2 -AR antagonist, 0.1 microM), in the presence of NA + CGP20712A, had no significant effect on I CaL in human atrial myocytes, but increased it in rabbit. Yohimbine (α 2 -AR antagonist, 10 microM), with NA + prazosin, had no significant effect on human or rabbit I CaL . Stimulation of atrial I CaL by NA is mediated, based on AR sub-type antagonist responses, mainly by activating β 1 - and α 1 -ARs in both human and rabbit, with a β 2 -inhibitory contribution evident in rabbit, and negligible α 2 involvement in either species. This improved understanding of AR sub-type contributions to noradrenergic activation of atrial I CaL could help inform future potential optimisation of pharmacological AR-antagonism strategies for inhibiting adrenergic AF., (© 2022. The Author(s).)

Phenylephrine (PE) is a canonical α 1 -adrenoceptor-selective agonist. However, unexpected effects of PE have been observed in preclinical and clinical studies, that cannot be easily explained by its actions on α 1 -adrenoceptors. The probability of the involvement of α 2 - and β-adrenoceptors in the effect of PE has been raised. In addition, our earlier study observed that PE released noradrenaline (NA) in a [Ca 2+ ] o -independent manner. To elucidate this issue, we have investigated the effects of PE on [ 3 H]NA release and α 1 -mediated smooth muscle contractions in the mouse vas deferens (MVD) as ex vivo preparation. The release experiments were designed to assess the effects of PE at the presynaptic terminal, whereas smooth muscle isometric contractions in response to electrical field stimulation were used to measure PE effect postsynaptically. Our results show that PE at concentrations between 0.3 and 30 µM significantly enhanced the resting release of [ 3 H]NA in a [Ca 2+ ] o -independent manner. In addition, prazosin did not affect the release of NA evoked by PE. On the contrary, PE-evoked smooth muscle contractions were inhibited by prazosin administration indicating the α 1 -adrenoceptor-mediated effect. When the function of the NA transporter (NAT) was attenuated with nisoxetine, PE failed to release NA and the contractions were reduced by approximately 88%. The remaining part proved to be prazosin-sensitive. The present work supports the substantial indirect effect of PE which relays on the cytoplasmic release of NA, which might explain the reported side effects for PE., (© 2022. The Author(s).)

Background: Alpha-adrenoreceptor antagonists or alpha-blockers are used in the treatment of hypertension, in the therapy of benign prostatic hyperplasia and in medical expulsive treatment of ureteral stones. These agents may affect the sexual function, with differences between drugs within the same class, depending on their selectivity for receptor subtypes. The aim of this review was to analyze the effects of alpha-blockers on sexual function., Materials and Methods: We conducted a systematic review and meta-analysis by searching PubMed, EMBASE and other databases for randomized controlled trials (RCTs) reporting sexual adverse effects in patients treated with alpha-blockers. Odds ratios for sexual dysfunction were calculated using random effects Mantel-Haenszel statistics., Results: Out of 608 records retrieved, 75 eligible RCTs were included in the meta-analysis. Compared with placebo, alphablockers were associated with increased odds of ejaculatory disorders both in patients with lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia (BPH) (OR: 7.53, 95% CI: 3.77-15.02, Z = 5.73, p < 0.00001, I2 = 55%) and in patients with ureteral stones (OR: 2.88, 95% CI: 1.50-5.44, Z = 3.19, p < 0.001, I2 = 31%). Uroselective alpha-blockers showed higher odds of ejaculatory disorders. Conversely, nonselective alpha-blockers were not associated with higher odds of ejaculatory dysfunction. Silodosin was associated with increased odds of ejaculatory dysfunction compared with tamsulosin (OR: 3.52, 95% CI: 2.18-5.68, 15 series, 1512 participants, Z = 5.15, p < 0.00001, I2 = 0%). Naftopidil and alfuzosin showed lower odds of ejaculatory dysfunction compared to uroselective alpha-blockers.No statistically significant differences in the odds of erectile dysfunction were observed when alpha-blockers were compared to placebo.

Adrenoceptors are the receptors for catecholamines, adrenaline, and noradrenaline. They are divided in α (α 1 and α 2 ) and β (β 1 , β 2 and β 3 ). α 1 -adrenoceptors are subdivided in α 1A , α 1B and α 1D . Most tissues express mixtures of α 1 -adrenoceptors subtypes, which appear to coexist in different densities and ratios, and in most cases, their responses are probably due to the activation of more than one type. The three subtypes of α 1 -adrenoceptors are G-protein-coupled receptors (GPCR), specifically coupled to G q/11 . Additionally, the activation of these receptors may activate other signaling pathways or different components of these pathways, which leads to a great variety of possible cellular effects. The first clinically used α1 antagonist was Prazosin for Systemic Arterial Hypertension (SAH). It was followed by its congeners, Terazosin and Doxazosin. Nowadays, there are many classes of α-adrenergic antagonists with different selectivity profiles. In addition to SAH, the α 1 -adrenoceptors are used to treat Benign Prostatic Hyperplasia (BPH) and urolithiasis. This antagonism may be part of the mechanism of action of tricyclic antidepressants. Moreover, the activation of these receptors may lead to adverse effects such as orthostatic hypotension, similar to what happens with antidepressants and with some antipsychotics. Structure-activity relationships can explain, in part, how antagonists work and how selective they can be for each one of the subtypes. However, it is necessary to develop new molecules which antagonize the α 1 - adrenoceptors or make chemical modifications in these molecules to improve the selectivity and pharmacokinetic profile and/or reduce the adverse effects of known drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Sudden unexpected death in epilepsy (SUDEP) is a serious and underestimated public health burden. Both clinical and animal studies show that seizure-induced respiratory arrest (S-IRA) is the primary cause of death in SUDEP. Our previous studies demonstrated that atomoxetine, a norepinephrine reuptake inhibitor (NRI), suppresses S-IRA in DBA/1 mice, suggesting that noradrenergic neurotransmission modulates S-IRA. However, it remains unclear which adrenoceptors are implicated in S-IRA in DBA/1 mice., Materials and Methods: Naïve DBA/1 mice exhibit a low incidence of S-IRA, but after primed by acoustic stimulation, they become consistently susceptible to S-IRA. Atomoxetine, adrenoceptor agonists, antagonists or vehicle was intraperitoneally (i.p.) administered alone or in combination, and the effects of drug treatments on S-IRA incidence and seizure behaviors were examined., Key Findings: The incidence of S-IRA in primed DBA/1 mice was significantly reduced by clonidine, an α2 adrenoceptor agonist, as compared with that of the vehicle control. However, compared with the vehicle control, S-IRA was not altered by cirazoline, an α1 agonist. Consistent with previous reports, atomoxetine reduced S-IRA in primed DBA/1 mice. The suppressing effect of atomoxetine on S-IRA was prevented by injection of an α2 adrenoceptor antagonist, yohimbine or atipamezole, but not by prazosin, an α1 antagonist. Administration of α1 or α2 antagonists alone did not promote the incidence of S-IRA in nonprimed DBA/1 mice., Significance: These data demonstrate that noradrenergic neurotransmission modulates S-IRA predominantly via α2 adrenoceptors in DBA/1 mice, indicating that selective activation of α2 adrenoceptors can potentially prevent SUDEP., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Alpha-adrenergic blockers are commonly used as a medical expulsive therapy (MET) for patients with ureteral calculi. The aim of this meta-analysis was to evaluate the efficacy and safety of alpha-adrenergic blockers compared with a placebo when used as a MET., Materials and Methods: We carried out a systematic search of the PubMed, EMBASE, and Web of Science databases, and the Cochrane Library, for relevant articles from inception to November 2020. Our aim was to identify placebo-controlled trails in which patients were randomized to receive either alpha-adrenergic blockers (tamsulosin, alfuzosin, doxazosin, terazosin, naftopidil, or silodosin) or a placebo for the treatment of ureteral calculi., Results: According to strict inclusion criteria, database searches identified 8 placebo-controlled studies that included 2284 patients. Generally, α-blockers had no significant effect on the clearance of stones in the urinary tract (risk ratio [RR] = 1.05; 95% confidence interval [CI] = 1.00-1.11). However, subgroup analysis showed that α-blockers were effective in treating distal urinary tract stones (RR = 1.08; 95% CI = 1.02-1.15). With regards to adverse events, our analysis showed that the combination of MET with α-blockers was likely to cause dizziness (RR = 1.37; 95% CI = 1.06-1.79) and retrograde ejaculation (RR = 3.10; 95% CI = 1.81-5.29)., Conclusion: Although α-blockers cannot improve the overall ureteral stone clearance rate, these drugs are still effective for the treatment of stones in the distal urinary tract. However, the application of α-blockers is likely to cause dizziness and/or retrograde ejaculation., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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.

Objective: Storage symptoms significantly deteriorate the quality of life in men with benign prostate enlargement (BPE). Muscarinic receptor antagonists (MRAs) and β3-adrenergic receptors agonists alone, or in combination with selective α1-alpha-antagonists, are considered the most effective medicines relieving storage symptoms. The aim of this study was to analyze the pharmacotherapy of storage symptoms in men with BPE, and their compliance with the European Association of Urology (EAU) guidelines., Patients and Methods: The survey was conducted in 2018 by 261 urologists among 24,613 men with lower urinary tract symptoms (LUTS) and BPE treated pharmacologically. Data concerning recent severity of non-neurological LUTS, storage symptoms and pharmacotherapy were collected., Results: Storage symptoms were reported by 12,356 patients (50.2%) with BPE, more frequently nocturia (75.8%), than urinary urgency (57.8%) and frequency (44.3%). Patients with storage symptoms were more frequently prescribed with MRAs and mirabegron (43.1% vs. 5.0% and 2.4% vs. 0.3%, respectively; p<0.001). Of note, 54.5% of patients with storage symptoms were treated neither with MRAs, nor β3-adrenergic receptors agonists. In the subgroup with storage symptoms, the increasing severity of LUTS accounted for more frequent prescription of MRA (2.1% vs.  29.1% vs. 42.8% in patients with mild, moderate, and severe LUTS, respectively). Decision tree analysis revealed that patients with urinary urgency and urinary frequency, as well as younger ones with urinary urgency but without urinary frequency, were more frequently prescribed with MRAs., Conclusions: Urinary urgency and frequency are associated with increased utilization of MRAs in men with BPE in everyday clinical practice. The attitude of Polish urologists toward management of persistent storage symptoms in BPE patients is in line with the EAU guidelines.

Objective: Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/β 2 -adrenergic drugs affect joint destruction in adjuvant-induced arthritis., Methods: Complete Freund's adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the β 2 -adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization., Results: On D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint., Conclusion and Significance: Our findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bellinger, Wood, Wergedal and Lorton.)

In brain astrocytes, noradrenaline (NA) has been shown to up-regulate IL-6 production via β-adrenoceptors (ARs). However, the underlying intracellular mechanisms for this regulation are not clear, and it remains unknown whether α-ARs are involved. In this study, we investigated the AR-mediated regulation of IL-6 mRNA levels in the cultured astrocytes from rat spinal cord. NA, the α 1 -agonist phenylephrine, and the β-agonist isoproterenol increased IL-6 mRNA levels. The phenylephrine-induced IL-6 increase was accompanied by an increase in ERK phosphorylation, and these effects were blocked by inhibitors of PKC and ERK. The isoproterenol-induced IL-6 increase was accompanied by an increase in CREB phosphorylation, and these effects were blocked by a PKA inhibitor. Our results indicate that IL-6 increases by α 1 - and β-ARs are mediated via the PKC/ERK and cAMP/PKA/CREB pathways, respectively. Moreover, conditioned medium collected from astrocytes treated with the α 2 -AR agonist dexmedetomidine, increased IL-6 mRNA in other astrocytes. In this study, we elucidate that α 1 - and α 2 -ARs, in addition to β-ARs, promote IL-6 transcription through different pathways in spinal cord astrocytes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background/aims: The NMDA receptor plays a key role in the pathogenesis of neurodegenerative disorders including Alzheimer's and Huntington's disease, as well as depression and drug or alcohol dependence. Due to its participation in these pathologies, the development of selective modulators for this ion channel is a promising strategy for rational drug therapy. The prototypical negative allosteric modulator ifenprodil inhibits selectively GluN2B subunit containing NMDA receptors. It was conformationally restricted as 2-methyl-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol, which showed high GluN2B affinity and inhibitory activity. For a better understanding of the relevance of the functional groups and structural elements, the substituents of this 3-benzazepine were removed successively (deconstruction). Then, additional structural elements were introduced (reconstruction) with the aim to analyze, which additional modifications were tolerated by the GluN2B receptor., Methods: The GluN2B affinity was recorded in radioligand receptor binding studies with the radioligand [ 3 H]ifenprodil. The activity of the ligands was determined in two-electrode voltage clamp experiments using Xenopus laevis oocytes transfected with cRNA encoding the GluN1-1a and GluN2B subunits of the NMDA receptor. Docking studies showed the crucial interactions with the NMDA receptor protein., Results: The deconstruction approach showed that removal of the methyl moiety and the phenolic OH moiety in 7-positon resulted in almost the same GluN2B affinity as the parent 3-benzazepine. A considerably reduced GluN2B affinity was found for the 3-benzazepine without further substituents. However, removal of one or both OH moieties led to considerably reduced NMDA receptor inhibition. Introduction of a NO 2 moiety or bioisosteric replacement of the phenol by a benzoxazolone resulted in comparable GluN2B affinity, but almost complete loss of inhibitory activity. An O-atom, a carbonyl moiety or a F-atom in the tetramethylene spacer led to 6-7-fold reduced ion channel inhibition., Conclusion: The results reveal an uncoupling of affinity and activity for the tested 3-benzazepines. Strong inhibition of [ 3 H]ifenprodil binding by a test compound does not necessarily translate into strong inhibition of the ion flux through the NMDA receptor associated ion channel. 3-(4-Phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine- 1,7-diol (WMS-1410) shows high GluN2B affinity and strong inhibition of the ion channel. Deconstruction by removal of one or both OH moieties reduced the inhibitory activity proving the importance of the OH groups for ion channel blockade. Reconstruction by introduction of various structural elements into the left benzene ring or into the tetramethylene spacer reduced the NMDA receptor inhibition. It can be concluded that these modifications are not able to translate binding into inhibition., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Significance: After a dilated eye examination, many patients experience symptoms of prolonged light sensitivity, blurred vision, and cycloplegia associated with pharmacological mydriasis. Phentolamine mesylate ophthalmic solution (PMOS) may expedite the reversal of mydriasis in patients, potentially facilitating return to functional vision and reducing barriers to obtaining dilated eye examinations., Purpose: The protracted reversal time after pharmacologically induced pupil dilation impairs vision. We tested the hypothesis that PMOS rapidly reduces pupil diameter in this acute indication., Methods: In this double-masked placebo-controlled, randomized, two-arm crossover phase 2b trial, we evaluated the effects of one drop of 1% PMOS applied bilaterally in subjects who had their pupils dilated by one of two common mydriatic agents: 2.5% phenylephrine or 1% tropicamide. End points included change in pupil diameter, percent of subjects returning to baseline pupil diameter, and accommodative function at multiple time points., Results: Thirty-one subjects completed the study (15 dilated with phenylephrine and 16 with tropicamide). Change in pupil diameter from baseline at 2 hours after maximal dilation with 1% PMOS was -1.69 mm and was significantly greater in magnitude compared with placebo for every time point beyond 30 minutes (P < .05). At 2 hours, a greater percentage of study eyes given 1% PMOS returned to baseline pupil diameter compared with placebo (29 vs. 13%, P = .03), which was this also seen at 4 hours (P < .001). More subjects treated with PMOS in the tropicamide subgroup had at least one eye returning to baseline accommodative amplitude at 2 hours (63 vs. 38%, P = .01). There were no severe adverse events, with only mild to moderate conjunctival hyperemia that resolved in most patients by 6 hours., Conclusions: Phentolamine mesylate ophthalmic solution at 1% reversed medically induced pupil dilation more rapidly than placebo treatment regardless of which mydriatic was used (adrenergic agonists and cholinergic blockers) with a tolerable safety profile., Competing Interests: Conflict of Interest Disclosure: The publication of this article was sponsored by Ocuphire Pharma, Inc. ARM, MPS, RMJ, KC, JEY, SAK, and ATA are or were employees, directors/officers, or paid consultants for Ocuphire Pharma. PMK, MBM, ESL, JSP, and GDH are on the medical advisory board for Ocuphire Pharma. PMK, SAF, SMM, and SRK were principal investigators for this clinical trial funded by Ocuphire Pharma. CBS serves as Chief Medical Officer of Oculos Development Services, LLC, which was the contract research organization for this clinical trial. The authors indicated that they have no other conflicts of interest with regard to the content of this article. The authors listed report a financial conflict of interest (PMK, SAF, SMM, SRK, CBS, ARM, MPS, RMJ, KC, JEY, SAK, ATA, MBM, GDH, ESL, and JSP). The sponsor (Ocuphire) provided financial and material support and participated in study design, analysis, and interpretation. The authors were responsible for the preparation of this article and the decision to submit this article for publication. Each of the authors had (full/limited) access to the study data and takes full responsibility for their presentation in this article., (Copyright © 2021 American Academy of Optometry.)

Astrocytes are glial cells with numerous fine processes which are important for the functions of the central nervous system. The activation of β-adrenoceptors induces process formation of astrocytes via cyclic AMP (cAMP) signaling. However, the role of α-adrenoceptors in the astrocyte morphology has not been elucidated. Here, we examined it by using cultured astrocytes from neonatal rat spinal cords and cortices. Exposure of these cells to noradrenaline and the β-adrenoceptor agonist isoproterenol increased intracellular cAMP levels and induced the formation of processes. Noradrenaline-induced process formation was enhanced with the α 1 -adrenoceptor antagonist prazosin and α 2 -adrenoceptor antagonist atipamezole. Atipamezole also enhanced noradrenaline-induced cAMP elevation. Isoproterenol-induced process formation was not inhibited by the α 1 -adrenoceptor agonist phenylephrine but was inhibited by the α 2 -adrenoceptor agonist dexmedetomidine. Dexmedetomidine also inhibited process formation induced by the adenylate cyclase activator forskolin and the membrane-permeable cAMP analog dibutyryl-cAMP. Moreover, dexmedetomidine inhibited cAMP-independent process formation induced by adenosine or the Rho-associated kinase inhibitor Y27632. In the presence of propranolol, noradrenaline inhibited Y27632-induced process formation, which was abolished by prazosin or atipamezole. These results demonstrate that α-adrenoceptors inhibit both cAMP-dependent and -independent astrocytic process formation., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Heart failure (HF) is associated with neurohumoral activation, which in turn leads to an increased peripheral resistance. In mesenteric vasculature, perivascular innervation plays relevant role maintaining vascular tonus and resistance. Therefore, we aimed to determine the possible alterations in superior mesenteric artery (SMA) perivascular innervation function in HF rats. HF was induced by coronary artery occlusion in male Wistar rats, and sham-operated (SO) rats were used as controls. After 12 wk, a greater vasoconstrictor response to electrical field stimulation (EFS) was observed in endothelium-intact and endothelium-denuded SMA of HF rats. Alpha-adrenoceptor antagonist phentolamine diminished this response in a higher magnitude in HF than in SO animals. However, the noradrenaline (NA) reuptake inhibitor desipramine increased EFS-induced vasoconstriction more in segments from HF rats. Besides, EFS-induced NA release was greater in HF animals, due to a higher tyrosine hydroxylase expression and activity. P2 purinoceptor antagonist suramin reduced EFS-induced vasoconstriction only in segments from SO rats, and adenosine 5'-triphosphate (ATP) release was lower in HF than in SO. Moreover, nitric oxide (NO) synthase inhibitor N ω -nitro-L-arginine methyl ester (L-NAME) enhanced EFS-induced vasoconstriction in a similar extent in both groups. HF was not associated with changes in EFS-induced NO release or the vasodilator response to NO donor sodium nitroprusside. In conclusion, HF postmyocardial infarction enhanced noradrenergic function and diminished purinergic cotransmission in SMA and did not change nitrergic innervation. The net effect was an increased sympathetic participation on the EFS-induced vasoconstriction that could help to understand the neurotransduction involved on the control of vascular tonus in HF. NEW & NOTEWORTHY This study reinforces the pivotal role of noradrenergic innervation in the regulation of mesenteric vascular tone in a rat model of heart failure. Moreover, our results highlight the counteracting role of ATP and NA reuptake, and help to understand the signaling pathways involved on the control of vascular tonus and resistance in heart failure postmyocardial infarction.

Oxalis pes-caprae L. is a plant of the Oxalidaceae family, from which several compounds have been previously identified. Recently, we showed that an Oxalis pes-caprae L. extract inhibits the vasopressor effect of noradrenaline. In this work we aimed to explore the mechanisms involved in this effect. The results confirmed that the flavonoid fraction present in the extract inhibits noradrenaline-induced contractions and that this effect is concentration-dependent. Also, a parallel shift to the right in the noradrenaline concentration-response curve was observed, suggesting a decrease in efficacy and also in potency. Together these results support the assumption that the extract could exert a non-competitive antagonism on the α-adrenergic receptors. However, experiments in the presence of competitive antagonists for α-adrenergic receptor sub-types (i.e. prazosin, yohimbine and phentolamine) showed that the effect may not be directly mediated by α-adrenergic receptors. Thus, the interaction of this extract with the adrenergic system remains to be confirmed.

Acute respiratory distress syndrome (ARDS), characterized by acute hypoxic respiratory dysfunction or failure, is a manifestation of multiple organ failure in the lung, and the most common risk factor is sepsis. We previously showed that blocking α 2 -adrenoceptor (α 2 -AR) could attenuate lung injury induced by endotoxin in rats. α 2A -adrenoceptor (α 2A -AR), a subtype of α 2 -AR plays a key role in inflammatory diseases, but the mechanism remains unknown. Here, we explored the effect of BRL-44408 maleate (BRL), a specific α 2A -AR antagonist, on cecal ligation puncture (CLP)-induced ARDS in rats and the underlying mechanism. Preadministration of BRL-44408 maleate significantly alleviated CLP-induced histological injury, macrophage infiltration, inflammatory response, and wet/dry ratio in lung tissue. However, there was no statistical difference in survival rate between the CLP and CLP+BRL groups. Extracellular regulated protein kinase (ERK1/2), p38MAPK, and p65 were activated in the CLP group, and BRL-44408 maleate inhibited the activation of these signal molecules, c-Jun N-terminal kinase (JNK) and protein kinase A (PKA) showed no changes in activation between these two groups. BRL-44408 maleate decreased lipopolysaccharide (LPS)-induced expression of cytokines in NR8383 rat alveolar macrophages and reduced phosphorylation of ERK1/2, p38MAPK, and p65. JNK and PKA were not influenced by LPS. Together, these findings suggest that antagonism of α 2A -AR improves CLP-induced acute lung injury and involves the downregulation of ERK1/2, p38MAPK, and p65 pathway independent of the activation of JNK and PKA., (© 2020 Wiley Periodicals, Inc.)

Objective: The α1D-adrenoreceptor (α1D-AR) is involved in angiotensin II-induced vascular remodeling and hypertension. Whether α1D-AR plays a role in hypertension-associated cardiac hypertrophy is unclear. Here we investigated effects of BMY 7378, a selective α1D-AR antagonist, on cardiac status in aged spontaneously hypertensive rats (SHR)., Methods: Male SHR were studied during the phase of developing hypertension (5 and 10 weeks old) and once hypertension was established (20 and 30 weeks old) to assess the evolution of cardiac hypertrophy. Age-matched WKY rats were studied as controls. Thirty-week-old SHR were treated for 4 weeks with BMY 7378 (10 mg/kg per day, o.a.), or captopril (angiotensin-converting enzyme inhibitor, 40 mg/kg per day, o.a.) (as a positive control). Blood pressure and cardiac function were measured in vivo, cardiac hypertrophy by histology, and α1D-AR protein expression by immunofluorescence., Results: By 30 weeks of age, SHR exhibited significant hypertension and cardiac hypertrophy. BMY 7378 and captopril decreased blood pressure and improved hemodynamic parameters and cardiac function in treated SHR vs. untreated SHR (P < 0.05). Histology showed increased cardiomyocyte size, fibrosis, and left ventricular hypertrophy in SHR hearts. BMY 7378 ameliorated fibrosis and cardiac hypertrophy, but had no effect on cardiomyocyte size in SHR. Effects of BMY 7378 were associated with increased α1D-AR protein expression in SHR., Conclusion: Our data indicate that pharmacological antagonism of α1D-AR reduces blood pressure and associated cardiac hypertrophy in aged SHR. These findings suggest that the α1D-AR plays a pathophysiological role in the development of hypertension and cardiac target organ damage in SHR.

Objective: The present study systematically reviewed the safety of combined treatment with an alpha blocker and phosphodiesterase-5 inhibitor., Materials and Methods: The study was performed according to the PRISMA statement. The included studies were randomized controlled trials that included at least one group on alpha-blocker monotherapy and one group on a combined treatment with an alpha blocker and phosphodiesterase-5 inhibitor. The primary endpoints were the hemodynamic effects of the two groups, specifically the clinically significant changes and a positive orthostatic test. The secondary endpoints were the adverse events of the two treatment modalities., Results: A total of 6687 studies were screened, and 19 randomized controlled trials were eligible for the meta-analysis. The combined treatment more often produced a clinically significant hemodynamic change with an MD of 4.73 (CI 1.25, 17.94; I 2  = 0%; p = 0.02), but the positive orthostatic test was similar between the groups with an MD of 1.64 (CI 0.36, 7.47; I 2  = 50%; p = 0.52). The meta-analysis of adverse events favored alpha-blocker monotherapy with an OD of 0.5 (CI 0.32, 0.78; I 2  = 44%; p = 0.002). However, if we consider only the adverse events due to hypotension, the result was similar between the two groups with an OD of 0.97 (CI 0.58, 1.64; I 2  = 0%; p = 0.92)., Conclusion: The combined treatment may produce a clinically significant hemodynamic change. The combination of alpha blocker and phosphodiesterase-5 inhibitor was safe because it did not increase the rate of adverse events due to hypotension.

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., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Electrical field stimulation (EFS) induces contractions of both snake aorta and human umbilical cord vessels (HUCV) which were dependent on the presence of the endothelium. This study aimed to establish the nature of the mediator(s) responsible for EFS-induced contractions in HUCV. Rings with or without endothelium from human umbilical artery (HUA) or vein (HUV) were mounted in organ bath chambers containing oxygenated, heated Krebs-Henseleit's solution. Basal release of dopamine (DA), noradrenaline, and adrenaline was measured by LC-MS-MS. Cumulative concentration-response curves were performed with dopamine in the absence and in the presence of L-NAME or of dopamine antagonists. EFS studies were performed in the presence and absence of L-NAME, the α-adrenergic blockers prazosin and idazoxan, and the dopamine antagonists SCH-23390 and haloperidol. Tyrosine hydroxylase (TH) and dopa-decarboxylase (DDC) were studied by immunohistochemistry and fluorescence in situ hybridizations. Basal release of dopamine requires an intact endothelium in both HUA and HUV. TH and DDC are present only in the endothelium of both HUA and HUV as determined by immunohistochemistry. Dopamine induced contractions in HUA only in the presence of L-NAME. Dopamine-induced contractions in HUV were strongly potentiated by L-NAME. The EFS-induced contractions in both HUA and HUV were potentiated by L-NAME and inhibited by the D2-like receptor antagonist haloperidol. The α-adrenergic antagonists prazosin and idazoxan and the D1-like receptor antagonist SCH-23390 had no effect on the EFS-induced contractions of HUA and HUV. Endothelium-derived dopamine is a major modulator of HUCV reactivity in vitro., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Sympathetic vasoconstriction is mediated by α-adrenergic receptors under resting conditions. During exercise, increased sympathetic nerve activity (SNA) is directed to inactive and active skeletal muscle; however, it is unclear what mechanism(s) are responsible for vasoconstriction during large muscle mass exercise in humans. The aim of this study was to determine the contribution of α-adrenergic receptors to sympathetic restraint of inactive skeletal muscle and active skeletal muscle during cycle exercise in healthy humans. In ten male participants (18-35 yr), mean arterial pressure (intra-arterial catheter) and forearm vascular resistance (FVR) and conductance (FVC) were assessed during cycle exercise (60% total peak workload) alone and during combined cycle exercise + handgrip exercise (HGE) before and after intra-arterial blockade of α- and β-adrenoreceptors via phentolamine and propranolol, respectively. Cycle exercise caused vasoconstriction in the inactive forearm that was attenuated ~80% with adrenoreceptor blockade (%ΔFVR, +81.7 ± 84.6 vs. +9.7 ± 30.7%; P = 0.05). When HGE was performed during cycle exercise, the vasodilatory response to HGE was restrained by ~40% (ΔFVC HGE, +139.3 ± 67.0 vs. cycle exercise: +81.9 ± 66.3 ml·min -1 ·100 mmHg -1 ; P = 0.03); however, the restraint of active skeletal muscle blood flow was not due to α-adrenergic signaling. These findings highlight that α-adrenergic receptors are the primary, but not the exclusive mechanism by which sympathetic vasoconstriction occurs in inactive and active skeletal muscle during exercise. Metabolic activity or higher sympathetic firing frequencies may alter the contribution of α-adrenergic receptors to sympathetic vasoconstriction. Finally, nonadrenergic vasoconstrictor mechanisms may be important for understanding the regulation of blood flow during exercise. NEW & NOTEWORTHY Sympathetic restraint of vascular conductance to inactive skeletal muscle is critical to maintain blood pressure during moderate- to high-intensity whole body exercise. This investigation shows that cycle exercise-induced restraint of inactive skeletal muscle vascular conductance occurs primarily because of activation of α-adrenergic receptors. Furthermore, exercise-induced vasoconstriction restrains the subsequent vasodilatory response to hand-grip exercise; however, the restraint of active skeletal muscle vasodilation was in part due to nonadrenergic mechanisms. We conclude that α-adrenergic receptors are the primary but not exclusive mechanism by which sympathetic vasoconstriction restrains blood flow in humans during whole body exercise and that metabolic activity modulates the contribution of α-adrenergic receptors.

While alpha-blockers are commonly used to reduce lower urinary tract symptoms in prostate cancer patients receiving radiotherapy, their impact on response to radiotherapy remains unknown. Therefore, this pilot study aimed to retrospectively determine if alpha-blockers use, influenced response to radiotherapy for localised prostate cancer. In total, 303 prostate cancer patients were included, consisting of 84 control (alpha-blocker naïve), 72 tamsulosin and 147 prazosin patients. The main outcomes measured were relapse rates (%), time to biochemical relapse (months) and PSA velocity (ng/mL/year). Recurrence free survival was calculated using Kaplan-Meier analysis. Prazosin significantly reduced biochemical relapse at both two and five-years (2.72%, 8.84%) compared to control (22.61%, 34.52%). Recurrence free survival was also significantly higher in the prazosin group. This remained after multivariable analysis (HR: 0.09, 95% CI: 0.04-0.26, p < 0.001). Patients receiving prazosin had a 3.9 times lower relative risk of biochemical relapse compared to control. Although not statistically significant, tamsulosin and prazosin extended recurrence free survival by 13.15 and 9.21 months respectively. We show for the first time that prazosin may reduce risk of prostate cancer recurrence and delay time to biochemical relapse and provides justification for prospective studies to examine its potential as an adjunct treatment option for localised prostate cancer.

Competing Interests: Declaration of competing interest None.

Objective: To determine the impact of epidural phentolamine on the duration of anaesthesia following epidural injection of lidocaine-epinephrine., Study Design: Blinded randomized experimental study., Animals: A group of 12 adult ewes weighing 25.7 ± 2.3 kg and aged 8-9 months., Methods: All sheep were administered epidural lidocaine (approximately 4 mg kg -1 ) and epinephrine (5 μg mL -1 ). Of these, six sheep were randomized into three epidural treatments, separated by 1 week, administered 30 minutes after lidocaine-epinephrine: SAL: normal saline, PHE1: phentolamine (1 mg) and PHE2: phentolamine (2 mg). The other six sheep were administered only epidural lidocaine-epinephrine: treatment LIDEP. Each injection was corrected to 5 mL using 0.9% saline. Noxious stimuli were pinpricks with a hypodermic needle and skin pinch with haemostatic forceps to determine the onset and duration of sensory and motor block. Heart rate, noninvasive mean arterial pressure (MAP), respiratory rate and rectal temperature were recorded., Results: The onset times were not different among treatments. Duration of sensory block was significantly shorter in SAL (57.5 ± 6.2 minutes), PHE1 (60.7 ± 9.0 minutes) and PHE2 (62.0 ± 6.7 minutes) than in LIDEP (81.7 ± 13.4 minutes) (p < 0.05). Duration of motor blockade was significantly shorter in PHE1 (59.4 ± 5.4 minutes) and PHE2 (54.3 ± 4.0 minutes) than in SAL (84.8 ± 7.0 minutes) and LIDEP (91.5 ± 18.2 minutes) (p < 0.01). MAP in PHE2 was decreased at 10 minutes after administration of phentolamine (p < 0.05)., Conclusion and Clinical Relevance: Epidural administration of 5 mL normal saline after epidural injection of lidocaine-epinephrine reduced the duration of sensory but not motor block in sheep. Epidural administration of phentolamine diluted to the final volume of 5 mL diminished both the duration of sensory and motor block in sheep administered epidural lidocaine-epinephrine., (Copyright © 2020 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

It has been reported that the beta-adrenergic receptor blocker (propranolol) and the a-adrenergic receptor (AR) blocker (phentolamine) both can inhibit human endothelial cell (EC) angiogenesis in vitro. However, it is unknown whether this inhibition also acts on pericytes. The present study aimed to determine how pericytes react to treatment with an a-/β- AR blocker. In the study, cell proliferation assays and scratch assay were performed to assess the effect of phentolamine or propranolol on cell proliferation and migration. Western blot and ELISA were employed to determine changes in VEGF-A and Ang-1 expression levels. The results indicated that the nonselective a-/β- AR blocker inhibited the proliferation, migration, and secretion of pericytes. The use of the nonselective a-/β- AR blocker might have an impact on vascularization and vascular maturation. Our research suggests the rational use of nonselective a-/β- AR blockers to treat angiogenesis-dependent diseases.

Impairment of corneal nerves can result in the development of ocular surface diseases such as aqueous tear deficiency and neurotrophic keratopathy. This study investigates oral nicergoline, an α-adrenoceptor antagonist shown to enhance endogenous secretion of nerve growth factor (NGF) by the lacrimal gland, as a potential therapy for these conditions. Five female spayed Beagle dogs received a 2-week course of oral nicergoline (10 mg twice daily). Drug safety was evaluated with ophthalmic and physical examinations, blood pressure monitoring, bloodwork, and urinalysis. The effect of nicergoline on the ocular surface was assessed with corneal esthesiometry, Schirmer tear test-1, and tear film breakup time. Drug effect on NGF levels was assessed by collecting tears and blood at baseline and completion of therapy using a bead-based immunoassay and an enzyme-linked immunosorbent assay. Although nicergoline was well tolerated in all dogs, it did not have a significant impact on corneal sensitivity, tear production, or tear stability. Of note, NGF was below the limit of quantification in all tear samples and was only detected in 8/20 serum samples with no significant difference between levels at baseline (189.4 ± 145.1 pg/mL) and completion of therapy (149.4 ± 79.4 pg/mL). Further validation of NGF analytical assays is warranted before nicergoline is investigated in clinical patients., (© 2019 American College of Veterinary Ophthalmologists.)

Benign prostatic hyperplasia (BPH) is an aging-related and progressive disease linked to an up-regulation of α 1 -adrenoceptors. The participation of EGF receptors (EGFR) in the GPCRs' signalosome has been described but so far data about the contribution of these receptors to prostatic stromal hyperplasia are scanty. We isolated and cultured vimentin-positive prostate stromal cells obtained from BPH patients. According to intracellular Ca 2+ measurements, cell proliferation and Western blotting assays, these cultured hyperplastic stromal cells express functional α 1- adrenoceptors and EGFR, and proliferate in response to the α 1- adrenoceptor agonist phenylephrine. Interestingly, in these cells the inhibition of EGFR signaling with GM6001, CRM197, AG1478 or PD98059 was associated with full blockage of α 1 -adrenoceptor-mediated cell proliferation, while cell treatment with each inhibitor alone did not alter basal cell growth. Moreover, the co-incubation of AG1478 (EGFR inhibitor) with α 1A/ α 1D -adrenoceptor antagonists showed no additive inhibitory effect. These findings highlight a putative role of EGFR signaling to α 1 -adrenoceptor-mediated human prostate hyperplasia, suggesting that the inhibition of this transactivation cascade could be useful to reduce BPH progression., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Psychostimulants, including methylphenidate (MPH), improve cognitive processes dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. In both humans and animals, systemic MPH improves certain cognitive processes, such as working memory, in a narrow inverted-U-shaped manner. In contrast, other processes, including attention-related, are improved over a broader/right-shifted dose range. The current studies sought to elucidate the potential circuit and receptor mechanisms underlying the divergent dose-dependent procognitive effects of psychostimulants. We first observed that, as with working memory, although sustained attention testing was highly dependent on multiple frontostriatal regions, only MPH infusion into the dorsomedial PFC improved task performance. Importantly, the dose-response curve for this action was right-shifted relative to working memory, as seen with systemic administration. Additional studies examined the receptor mechanisms within the PFC associated with the procognitive actions of MPH across working memory and sustained attention tasks. We observed that PFC α2 and D1 receptors contributed to the beneficial effects of MPH across both cognitive tasks. However, α1 receptors only contributed to MPH-induced improvement in sustained attention. Moreover, activation of PFC α1 receptors was sufficient to improve sustained attention. This latter action contrasts with the impairing actions of PFC α1 receptors reported previously for working memory. These results provide further evidence for a prominent role of the PFC in the procognitive actions of MPH and demonstrate the divergent dose sensitivity across cognitive processes aligns with the differential involvement of PFC α1 receptors.

Purpose: To examine the utility of electronic health records from a routine care setting in assessing comparative effectiveness of fourth-line anti-hypertensive drugs to treat resistant hypertension., Methods: We conducted a cohort study using the Clinical Practice Research Datalink: a repository of electronic health records from UK primary care. We identified patients newly prescribed fourth-line anti-hypertensive drugs (aldosterone antagonist , beta-blocker, or alpha-blocker). Using propensity score-adjusted Cox proportional hazards models, we compared the incidence of the primary outcome (composite of all-cause mortality, stroke, and myocardial infarction) between patients on different fourth-line drugs. AA was the reference drug in all comparisons. Secondary outcomes were individual components of the primary outcome, blood pressure changes, and heart failure. We used a negative control outcome, Herpes Zoster, to detect unmeasured confounding., Results: Overall, 8639 patients were included. In propensity score-adjusted analyses, the hazard ratio for the primary outcome was 0.81 (95% CI, 0.55-1.19) for beta-blockers and 0.68 (95% CI, 0.46-0.96) for alpha-blockers versus AA. Findings for individual cardiovascular outcomes trended in a more plausible direction, albeit imprecise. A trend for a protective effect for Herpes Zoster across both comparisons was seen., Conclusions: A higher rate of all-cause death in the AA group was likely due to unmeasured confounding in our analysis of the composite primary outcome, supported by our negative outcome analysis. Results for cardiovascular outcomes were plausible, but imprecise due to small cohort sizes and a low number of observed outcomes., (© 2019 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.)

Introduction: The involvement of serotonin (5-HT) in increased lower urinary tract symptoms in aging is unclear. We sought to compare voiding function and 5-HT induced detrusor contraction between young and aged rats., Methods: This study used young (2- to 3-month-old) and aged (26- to 30-month-old) male Fischer 344 rats. 1. Rats were housed in individual metabolic cages, and then the total volume of urination, volume per micturition, voiding frequency, and voiding interval were analyzed. 2. Using urinary bladder body strips, developed tension was recorded after cumulative addition of 5-HT (1-100 nM) in the absence or presence of tetrodotoxin (1 μM), and in the presence of tetrodotoxin with ketanserin (0.3-3 μM) or naftopidil (1 and 3 μM). We examined the effects of atropine, ketanserin, and naftopidil on electrical field stimulation (EFS)-induced contraction., Results: 1. Compared to young rats, aged rats exhibited decreased voiding frequency and increased volume per micturition, but total volume of urination (normalized to body weight) did not differ. Moreover, voiding interval was significantly prolonged in aged rats during the active period. 2. In the presence of tetrodotoxin, pEC 50 of 5-HT were significantly lower in aged rats than in young rats (P < 0.01), but the maximal response to 5-HT was not altered in the aged bladder. Ketanserin inhibited 5-HT-induced contraction in both groups, while suppression by naftopidil was relatively limited, especially in aged rats. EFS induced neurogenic contraction in a frequency-dependent manner. Atropine-resistant contraction was not inhibited by naftopidil, but was potentiated by ketanserin., Conclusions: Urination intervals were extended in aged rats, indicating that urination rhythm changed. In the senescent rat bladder, 5-HT induced detrusor contraction, but the effect of 5-HT and the naftopidil-sensitive contractile force were weaker than those in young rats. Additionally, 5-HT did not contribute to the increase in atropine-resistant EFS-induced contractions in aged rats., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Stress-induced prothrombotic changes are mediated by the sympathetic nervous system and critically involved in mental triggering of acute coronary syndromes, but the underlying psychobiology is not fully understood. We tested the hypothesis that a norepinephrine (NE) infusion to mimic effects of stress-induced NE release on blood coagulation elicits prothrombotic changes and examined to what extent these would be mediated by an alpha-adrenergic mechanism., Methods and Results: In a single-blind placebo-controlled within-subjects design, 24 middle-aged, non-smoking, non-obese and normotensive men participated in three experimental trials with an interval between one and two weeks. Each trial applied two sequential infusions of 1 and 15 min duration with varying substances [i.e., saline as placebo, the non-specific α-blocker phentolamine (2.5 mg/min), and NE (5 μg/min)]: trial 1=saline + saline; trial 2=saline + NE, and trial 3=phentolamine + NE. Plasma levels of clotting factor VIII activity (FVIII:C), fibrinogen, and D-dimer were assessed from blood samples collected immediately before and 1 min and 20 min after infusion procedures. Compared to saline + saline, saline + NE induced increases over time in FVIII:C, fibrinogen, and D-dimer levels. With phentolamine + NE, fibrinogen levels remained increased compared to saline + saline, but changes in FVIII:C and D-dimer levels were no more different. Coagulation changes did not differ between saline + NE and phentolamine + NE., Conclusions: NE infusion activates blood coagulation. The resulting prothrombotic state could be one psychobiological mechanism underlying mental triggering of acute coronary syndromes. Blockade of α-adrenergic receptors partly attenuated NE effects on coagulation and could be implied to have preventive potential in susceptible individuals., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Locus coeruleus (LC) noradrenergic neurons afferents release noradrenaline (NA) in the cerebellar cortex for modulating cerebellar neuronal circuitry function. Our previous study found that NA inhibited the spontaneous simple spikes activity of cerebellar Purkinje cells (PC) through activation of molecular layer interneurons (MLIs) in vivo in mice. We here examined the effects of NA on spontaneous complex spikes (CSs) activity of cerebellar PC in urethane-anesthetized mice by electrophysiology recording technique and pharmacological methods. Our results showed that cerebellar surface perfusion of NA significantly reduced the number of spikelets and the area under curve (AUC) of the spontaneous CSs. Application of nonselective adrenergic receptor (AR) antagonist, phentolamine, abolished the NA-induced inhibition of CSs. However applying a nonselective β-AR blocker, propranolol, failed to prevent the NA-induced inhibition of CSs activity. The NA-induced inhibition of CSs activity was not blocked by α1-AR antagonist, prazosin, but it was abolished by α2-AR antagonist, yohimibine. Moreover, application of α2-AR agonist, UK14304 induced a depression of CSs activity and mimicked the NA-induced inhibition of CS activity. These results indicate that NA regulates spontaneous CSs activity of cerebellar PCs via activation of α2-AR in vivo in mice. Our present results suggest that noradrenergic neurons of LC may modulate the outputs of cerebellar PCs via inhibition of CSs activity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction between dibucaine and epinephrine, phentolamine, a nonselective α-adrenergic antagonist, was added to the mixture., Methods: We assessed sensory blockade with these drugs by injecting 0.6 mL of drug-in-saline in the dorsal thoracolumbar area of rats; pinprick of the "wheal" formed by the injectate was the area targeted for stimulation to elicit a cutaneous trunci muscle reflex. The sensory block of dibucaine was compared with that of bupivacaine or epinephrine. Drug-drug interactions were analyzed by isobologram. Phentolamine was added to investigate the antinociceptive effect of dibucaine coinjected with epinephrine., Results: We demonstrated that dibucaine, epinephrine, and bupivacaine produced dose-dependent skin antinociception. On the median effective dose (ED50) basis, the potency was higher for epinephrine (mean, 0.011 [95% confidence interval {CI}, 0.007-0.015] μmol) than for dibucaine (mean, 0.493 [95% CI, 0.435-0.560] μmol) (P < .01), while there were no significant differences between dibucaine and bupivacaine (mean, 0.450 [95% CI, 0.400-0.505] μmol). On the equipotent basis (75% effective dose, median effective dose, and 25% effective dose), sensory block duration provoked by epinephrine was greater (P < .01) than that provoked by dibucaine or bupivacaine. Coadministration of dibucaine with epinephrine produced a synergistic nociceptive block, whereas phentolamine blocked that synergistic block., Conclusions: The preclinical data indicated that there is no statistically significant difference between the potency and duration of dibucaine and bupivacaine in this model. Epinephrine synergistically enhances the effects of dibucaine, while phentolamine partially blocked those effects. α-Adrenergic receptors play an important role in controlling synergistic analgesic effect of dibucaine combined with epinephrine.

α2-Adrenoceptors (α2-AR) found in the cardiomyocyte's sarcolemma represent a very important negative feedback for control of myocardial contractility by endogenous catecholamines. Earlier, we showed that the endogenous neurotransmitter agmatine in micromolar concentrations via α2-AR activates the nitric oxide (NO) synthesis, enhancing the Ca 2+ pumping into sarcoplasmic reticulum (SR). In the millimolar doses it inhibits Ca 2+ sequestration by SR Ca 2+ ATPase (SERCA), acting through the first type of imidazoline receptors. Here, we study the functional activity of agmatine, as well as a specific α2-agonist, guanabenz, in respect to spontaneous Ca 2+ -transients in SHR cardiomyocytes of the early age (2-2.5 months), and adulthood animals (8-9 months). α2-mediated cardioprotective effect was almost twofold decreased in SHR cardiac cells compared to normotensive rats of the corresponding age, despite the fact that both α2A- and α2B-AR protein levels were significantly increased in SHR cardiomyocytes. NO-mediated facilitation of SERCA activity is substantially reduced in SHR cardiomyocytes vs. normotensive rats. These data suggest that the SHR phenotype starting from early age shows signs of the impaired sarcolemmal α2-AR signaling, which can aggravate the development of this cardiovascular pathology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Effects of stress on the reward system are well established in the literature. Although previous studies have revealed that stress can reinstate extinguished addictive behaviors related to cocaine, the effects of stress on the rewarding memory of cocaine are not fully understood. Here, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem-reward circuitry using a cocaine-induced conditioned place preference (CPP) paradigm combined with restraint stress in rats. The rats exposed to 30-minute restraint stress immediately before posttest exhibited significantly larger CPP scores compared with non-stressed rats. Intra-laterodorsal tegmental nucleus (LDT) microinjection of a β or α2 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Consistent with this observation, intra-LDT microinjection of a β or α2 adrenoceptor agonist before posttest increased cocaine CPP. Additionally, intra-ventral tegmental area (VTA) microinjection of antagonists for the muscarinic acetylcholine, nicotinic acetylcholine or glutamate receptors attenuated the stress-induced enhancement of cocaine CPP. Finally, intra-medial prefrontal cortex (mPFC) microinjection of a D1 receptor antagonist also reduced the stress-induced enhancement of cocaine CPP. These findings suggest a mechanism wherein the LDT is activated by noradrenergic input from the locus coeruleus, leading to the activation of VTA dopamine neurons via both cholinergic and glutamatergic transmission and the subsequent excitation of the mPFC to enhance the memory of cocaine-induced reward value., (© 2018 Society for the Study of Addiction.)

Naftopidil, an α-1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α-1 adrenoceptor inhibitor. We examined the incorporation of 5-bromo-2'-deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme-linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound-healing assay, and mRNA expressions of type IV collagen and α-smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin-induced lung fibrosis in mice were evaluated using histology, micro-computed tomography, and surfactant protein-D levels in serum. Naftopidil, dose-dependently but independently of phenoxybenzamine, inhibited 5-bromo-2'-deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α-smooth muscle actin in one normal lung fibroblast line. Histological and micro-computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein-D levels in bleomycin-induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)