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A unique integrated investigation on the effect of meal on neurohumoral mechanisms and blood flow redistribution of the mesenteric circulation during orthostasis was investigated. Food ingestion results in cardiovascular hyperdynamism, reduction in cardiac vagal tone, and baroreflex sensitivity and causes a decrease in α1-adrenoceptor responsiveness only in the venous intrahepatic sinusoids. About 500-mL blood shifts from the mesenteric to the systemic circulation during orthostasis. Accordingly, the orthostatic homeostatic mechanisms are better understood.

The primary goals of medical expulsive therapy are to increase the rate of stone expulsion along the ureter to avoid ureteral obstruction and reduce ureteral colic and thus avoid the need for surgical and more invasive interventions. This review focussed on the findings from in vivo and in vitro animal and human studies that have investigated the pharmacological mechanisms controlling ureteral motility and their translation to current and potentially new clinically used drugs for increasing the rate of stone expulsion along the ureter. The complicated contractility profile of the ureter, which alters with age, tissue segment region, orientation and species contributes to the difficulty of interpreting studies on ureteral pharmacology, which translates to the complexity of discovering ideal drug targets for medical expulsive therapy. Nevertheless, the current drug classes clinically used for patients with stone lodgement include α1 -adrenoceptor antagonists, calcium channel blockers and NSAIDS, whilst there are promising targets for drug development that require further clinical investigations including the phosphodiesterase type 5 enzyme, β-adrenoceptors and 5-HT receptors.

Backround: Intraoperative floopy iris syndrome is a variant of the small pupil syndrome that has been observed during cataract surgery in some patients currently or previously treated with the α1 adrenergic blockers. It is important for cataract surgeons to predict the probable complications, preoperatively. The aim of our study is to evaluate the static and dynamic pupil characteristics of patients treated with silodosin –a selective α1 adrenergic blocker- for Benign Prostate Hypertrophy (BPH) and to compare these values with healthy subjects using an automatic quantitative pupillometry system.Methods: A total of 74 BPH patients treated with silodosin for six months (group 1) and 30 healthy subjects (group 2) were enrolled in this prospective multidisciplinary cross-sectional study. Static and dynamic pupillometric measurements were obtained under optimized conditions and the results were compared between the two groups.Results: Seventy four male patients with a mean age of 63,35±7,21 (46-77) years with BPH treated with silodosin and 30 normal male subjects with a mean age of 63,07±4,73 (52-71) years were analyzed. There were statistically significant differences between the groups with regard to scotopic pupil diameter (PD), high photopic PD, and low photopic PD (pConclusion: Static and dynamic pupil characteristics of subjects treated with silodosin for BPH is different from healthy eyes. In addition, our results may have shed light on understanding the risk for IFIS before cataract surgery and thus surgeons can be on the alert and take precautions.

As heart failure (HF) is a devastating health problem worldwide, a better understanding and the development of more effective therapeutic approaches are required. HF is characterized by sympathetic system activation which stimulates α- and β-adrenoceptors (ARs). The exposure of the cardiovascular system to the increased locally released and circulating levels of catecholamines leads to a well-described downregulation and desensitization of β-ARs. However, information on the role of α-AR is limited. We have performed a systematic literature review examining the role of both cardiac and vascular α1-ARs in HF using 5 databases for our search. All three α1-AR subtypes (α1A, α1B and α1D) are expressed in human and animal hearts and blood vessels in a tissue-dependent manner. We summarize the changes observed in HF regarding the density, signaling and responses of α1-ARs. Conflicting findings arise from different studies concerning the influence that HF has on α1-AR expression and function; in contrast to β-ARs there is no consistent evidence for down-regulation or desensitization of cardiac or vascular α1-ARs. Whether α1-ARs are a therapeutic target in HF remains a matter of debate.

Adrenergic stimuli are important for corneal epithelial structure and healing. The purpose of the present study was to examine the hypothesis that the lack of a single α1-adrenoceptor (α1-AR) subtype affects corneal epithelial thickness and cell proliferation. Expression levels of α1-AR mRNA were determined in mouse cornea using real-time PCR. In mice devoid of one of the three α1-AR subtypes (α1A-AR−/−, α1B-AR−/−, α1D-AR−/−) and in wild-type controls, thickness of individual corneal layers, the number of epithelial cell layers, and average epithelial cell size were determined in cryosections. Endothelial cell density and morphology were calculated in corneal explants, and epithelial cell proliferation rate was determined with immunofluorescence microscopy. Moreover, the ultrastructure of the corneal epithelium was examined by transmission electron microscopy. Messenger RNA for all three α1-AR subtypes was expressed in whole cornea and in corneal epithelium from wild-type mice with a rank order of abundance of α1A≥ α1B> α1D. In contrast, no α1-AR mRNA was detected in the stroma, and only α1B-AR mRNA was found in the Descemet endothelial complex. Remarkably, corneal epithelial thickness and mean epithelial cell size were reduced in α1A-AR−/−mice. Our findings suggest that the α1A-AR exerts growth effects in mouse corneal epithelial cells.

Correction to the article “Peculiar Aspects in Influence of α1-Adrenoceptor Stimulation on Isolated Rat Heart,” by T. L. Zefirov, I. I. Khabibrakhmanov, N. I. Ziyatdinova, and A. L. Zefirov, Vol. 162, No. 1, pp. 4-6, November 2016

Background: The rapid delayed rectifier K+ current (IKr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. α1-adrenoceptors (α1-AR) activation reduces IKr but, despite the clear relationship between an increase in the sympathetic tone and arrhythmias, the mechanisms underlying the α1-AR regulation of the hERG channel are controversial. Thus, we aimed to investigate the mechanisms by which α1-AR stimulation regulates IKr. Methods: α1-adrenoceptors, hERG channels, auxiliary subunits minK and MIRP1, the non PIP2-interacting mutant D-hERG (with a deletion of the 883-894 amino acids) in the C-terminal and the non PKC-phosphorylable mutant N-terminal truncated-hERG (NTK-hERG) were transfected in HEK293 cells. Cell membranes were extracted by centrifugation and the different proteins were visualized by Western blot. Potassium currents were recorded by the patch-clamp technique. IKr was recorded in isolated feline cardiac myocytes. Results: Activation of the α1-AR reduces the amplitude of IhERG and IKr through a positive shift in the activation half voltage, which reduces the channel availability at physiological membrane potentials. The intracellular pathway connecting the α1-AR to the hERG channel in HEK293 cells includes activation of the Gαq protein, PLC activation and PIP2 hydrolysis, activation of PKC and direct phosphorylation of the hERG channel N-terminal. The PKC-mediated IKr channel phosphorylation and subsequent IKr reduction after α1-AR stimulation was corroborated in feline cardiac myocytes. Conclusions: These findings clarify the link between sympathetic nervous system hyperactivity and IKr reduction, one of the best characterized causes of torsades de pointes and ventricular fibrillation.

Many β-adrenoceptor agonists and antagonists including several clinically used drugs have been reported to also exhibit binding to α1-adrenoceptors. Such promiscuity within the adrenoceptor family appears to occur more often than off-target effects of drugs in general. It should not be considered surprising based on the amino acid homology among the nine adrenoceptor subtypes including the counter-ions for binding the endogenous catecholamines. When β-adrenoceptor ligands also bind to α1-adrenoceptors, they almost always act as antagonists, regardless of being agonists or antagonists at the β-adrenoceptor. The α1-adrenoceptor affinity of β-adrenoceptor ligands in most cases is at least one, and often more log units lower than at their cognate receptor. Consistent evidence from multiple investigators indicates that β-adrenoceptor ligands relatively have the highest affinity for α1A- and lowest for α1B-adrenoceptors. While promiscuity among adrenoceptor subtypes causes misleading interpretation of experimental in vitro data, it is proposed based on the law of mass action that α1-adrenoceptor binding of β-adrenoceptor ligands rarely contributes to the clinical profile of such drugs, particularly if they are agonists at the β-adrenoceptor.

Background & Aims Colonic musculature contain smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and platelet-derived growth factor receptor α+ cells (PDGFRα+ cells), which are electrically coupled and operate together as the SIP syncytium. PDGFRα+ cells have enriched expression of small conductance Ca2+-activated K+ (SK) channels. Purinergic enteric neural input activates SK channels in PDGFRα+ cells, hyperpolarizes SMC, and inhibits colonic contractions. Recently we discovered that PDGFRα+ cells in mouse colon have enriched expression of α1A adrenoceptors (ARs), which coupled to activation of SK channels and inhibited colonic motility, and α1A ARs were principal targets for sympathetic regulation of colonic motility. Here we investigated whether PDGFRα+ cells in human colon express α1A ARs and share the roles as targets for sympathetic regulation of colonic motility. Methods Isometric tension recording, intracellular recording, and Ca2+ imaging were performed on muscles of the human colon. Responses to α1 ARs agonists or electric field stimulation with AR antagonists and neuroleptic reagents were studied. Results Exogenous or endogenous norepinephrine released from nerve fibers inhibited colonic contractions through binding to α1A ARs or enhanced colonic contractions by acting on α1D ARs. Inhibitory responses were blocked by apamin, an antagonist of SK channels. Phenylephrine, α1 AR agonists, or norepinephrine increased intracellular [Ca2+] in PDGFRα+ cells, but not in ICC, and hyperpolarized SMCs by binding to α1 ARs expressed by PDGFRα+ cells. Conclusions Human colonic contractions are inhibited by α1A ARs expressed in PDGFRα+ cells and activated by α1D ARs expressed in SMC., Graphical abstract

Background Regression of meningioma has been reported after hemorrhage or hormonal withdrawal. Here, we report a case of an incidentally diagnosed meningioma that regressed in association with α1-adrenoceptor antagonist. Case report A 59-year old male patient with an incidentally diagnosed lateral sphenoid wing meningioma was followed with serial magnetic resonance imaging. The tumor with a maximum diameter of 43 mm showed progressive regression, and after 3 years the size was reduced to 22% of the initial volume. During follow-up the patient was treated with an α1-adrenoceptor antagonist (tamsulosin) for benign prostatic hyperplasia. Possible mechanisms are discussed, including our main hypothesis of reduced mitogenic effects through phospholipase C-signal transduction. Conclusion This is the first report of regression of an incidentally diagnosed meningioma associated with α1-adrenoceptor antagonist treatment.

In mammals, the neural control of airway smooth muscle is dominated by a subset of airway vagal preganglionic neurons in the ventrolateral medulla. These neurons are physiologically modulated by adrenergic/noradrenergic projections, and weakened α2-adrenergic inhibition of them is indicated to participate in the pathogenesis and exacerbation of asthma. This study tests whether these neurons are modulated by α1-adrenoceptors, and if so, how. In anesthetized adult rats, microinjection of the α1A-adrenoceptor agonist A61603 (1 pmol) unilaterally into the medullary region containing these neurons caused a significant increase in airway resistance, which was prevented by intraperitoneal atropine (0.5 mg/kg). In rhythmically firing medullary slices of newborn rats, A61603 (10 nM) caused depolarization in both the inspiratory-activated and inspiratory-inhibited airway vagal preganglionic neurons that were retrogradely labeled, and a significant increase in the spontaneous firing rate. Under voltage clamp, A61603 significantly enhanced the spontaneous excitatory inputs to both types of neurons and caused a tonic inward current in the inspiratory-activated neurons along with significantly increased peak amplitude of the inspiratory inward currents. The responses in vitro were prevented by α1A-adrenoceptor antagonist RS100329 (1 μM), which alone significantly inhibited the spontaneous excitatory inputs to both types of the neurons. After pretreatment with tetrodotoxin (1 μM), A61603 (10 or 100 nM) had no effect on either type of neuron. We conclude that in rats, activation of α1-adrenoceptors in the medullary region containing airway vagal preganglionic neurons increases airway vagal tone, and that this effect is primarily mediated by facilitation of the excitatory inputs to the preganglionic neurons.

In this paper, we review reports related to naftopidil since 2011. Naftopidil was approved in Japan as a drug for lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) in 1999. It has three times higher affinity for the alpha-1D adrenergic receptor (α1D-AR) than for the alpha-1A adrenergic receptor (α1A-AR). Although there are several α1 adrenoceptor antagonists, the differences among them with regard to their overall efficacy for LUTS/BPH are unclear. The efficacy of naftopidil for storage symptoms is frequently focused on as a central property of the α1D-AR antagonist.

A series of ring-substituted ethyl- and heptyl-linked 4-aminoquinoline dimers were synthesized and evaluated for their affinities at the 3 human α(1)-adrenoceptor (α(1)-AR) subtypes and the human serotonin 5-HT(1A)-receptor (5-HT(1A)-R). We find that the structure-specificity profiles are different for the two series at the α(1)-AR subtypes, which suggests that homobivalent 4-aminoquinolines can be developed with α(1)-AR subtype selectivity. The 8-methyl (8-Me) ethyl-linked analogue has the highest affinity for the α(1A)-AR, 7 nM, and the greatest capacity for discriminating between α(1A)-AR and α(1B)-AR (6-fold), α(1D)-AR (68-fold), and the 5-HT(1A)-R (168-fold). α(1B)-AR selectivity was observed with the 6-methyl (6-Me) derivative of the ethyl- and heptyl-linked 4-aminoquinoline dimers and the 7-methoxy (7-OMe) derivative of the heptyl-linked analogue. These substitutions result in 4- to 80-fold selectivity for α(1B)-AR over α(1A)-AR, α(1D)-AR, and 5-HT(1A)-R. In contrast, 4-aminoquinoline dimers with selectivity for α(1D)-AR are more elusive, since none studied to date has greater affinity for the α(1D)-AR over the other two α(1)-ARs. The selectivity of the 8-Me ethyl-linked 4-aminoquinoline dimer for the α(1A)-AR, and 6-Me ethyl-linked, and the 6-Me and 7-OMe heptyl-linked 4-aminoquinoline dimers for the α(1B)-AR, makes them promising leads for drug development of α(1A)-AR or α(1B)-AR subtype selective ligands with reduced 5-HT(1A)-R affinity.

Metformin is a widely used drug for the treatment of type 2 Diabetes Mellitus. Several studies have also suggested that metformin decreases blood pressure; although an interaction with α-adrenoceptors has been proposed, this mechanism needs to be further investigated. Since α1-adrenoceptors play a significant role to regulate vascular tone, this study has analysed the potential ability of metformin to block α1-adrenoceptors in rat aorta and tail artery. For this purpose, the contractile responses induced by noradrenaline, methoxamine, and phenylephrine were determined in the absence or presence of metformin in rat aorta and tail artery rings. In both arteries, noradrenaline, methoxamine, and phenylephrine produced concentration-dependent contractile responses. Interestingly, the contractile responses to noradrenaline, methoxamine, and phenylephrine were significantly and differentially blocked by metformin (1, 3.1 and/or 10 mM) but not by vehicle. These results suggest that metformin is capable to block α1-adrenoceptors and may explain, at least in part, the anti-hypertensive effect observed in several clinical trials.

A series of 1,4-disubstituted piperazine derivatives with α 1 -adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity in vitro and in vivo. Most of them displayed strong antiarrhythmic activity in the adrenaline induced model of arrhythmia and in the rat coronary artery ligation-reperfusion model. Their antiarrhythmic effect is mainly related to α 1 -adrenolytic properties. Among them one compound showed characteristics similar to quinidine in different arrhythmia models as well as electrocardiogram (ECG) studies which suggests that it possesses not only α 1 -adrenoceptor blocking properties but also affinity for cardiac Na + and K + channels, similar to class IA antiarrhythmic agents. Two other compounds revealed some antioxidant effects. Another compound (MH-79) is particularly promising since it displayed a strong antiarrhythmic effect without the influence on ECG record.

Damage to salivary gland after radiotherapy for head and neck malignant tumours can lead to irreversible oral complaints, which severely impair quality of life. The protective effect of α1-adrenoceptor activation on the salivary glands after irradiation has previously been demonstrated. However, the exact mechanism remains unclear. In this study, we investigated the underlying cytoprotective mechanism of α1-adrenoceptor activation in rat submandibular glands after irradiation.Rats were locally irradiated using a linear accelerator in the head and neck region with a dose of 20Gy. After irradiation, phenylephrine (5mg/kg) was injected intraperitoneally for 7 successive days and the submandibular glands were then collected. The antiapoptotic effect of phenylephrine on the gland was examined by TUNEL, the proliferative cellular nuclei antigen (PCNA) was determined by immunohistochemistry, and the activation of c-Jun N-terminal kinase (JNK) was detected by Western blot.The irradiation only group showed severe atrophy, increased apoptosis, enhanced cell proliferation, and the phosphorylation of JNK was markedly increased by 26.89% (P0.05), compared to the control. The phenylephrine-treated group, however, showed remarkably alleviated atrophy, decreased apoptosis, and further increased cell proliferation, and the phosphorylation of JNK was markedly decreased by 36.00% (P0.05), compared to the irradiation only group.The data showed that the underlying protective mechanism of α1-adrenoceptor activation in irradiated gland might be related to improved cell proliferation, inhibited cell apoptosis, and depressed activation of JNK. It could be helpful in protecting salivary glands against irradiation damage.

Aim: We hypothesize that excess norepinephrine (NE) modulates NCC activity via an α1 adrenoceptor pathway to drive the development of salt-sensitive hypertension (HTN). Methods: Male Sprague-Dawley (SD) rats receiving a continuous s.c. saline or NE (600ng/min) infusion and naïve Dahl Salt-Sensitive (DSS) rats were fed a 0.6% (NS) or 8% NaCl (HS) diet for 14 or 21 days respectively (N=4/gp). On day 14 (SD) or 21 (DSS) MAP and NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg) infusion) and expression (via immunoblotting) was assessed. Additional groups of NE infused SD and DSS rats received a propranolol (9.9mg/kg/day; s.c.) or prazosin (2.5mg/kg/day; oral) and a NS or HS diet for 14 or 21 days. Results: SD rats exhibit HS evoked suppression of NCC expression and activity. In contrast, NE infused SD rats and DSS rats exhibit HTN and fail to suppress NCC expression and activity during HS-intake. β-adrenoceptor antagonism (confirmed pharmacologically) reduced MAP in NE infused SD and DSS rats, but failed to decrease NCC activity or expression. In contrast α1-adreoceptor antagonism (confirmed pharmacologically) abolished the salt-sensitive component of HTN and restored dietary sodium evoked suppression of NCC activity and expression in NE infused SD rats and DSS rats. Conclusion: Our data suggests NE activates α, but not β, adrenoceptors to prevent dietary sodium evoked suppression of NCC activity and the development of salt-sensitive hypertension. The PATHWAY-2 Trial reported a primary role of sodium retention in resistant HTN suggesting α1-adreoceptor antagonism represents a new therapeutic approach for resistant and sympathetically mediated HTN.

Because hypertension related alterations occur in the properties of α(1)-adrenoceptor in several mammalian tissues and hypertension may impact ejaculatory function, we investigated hypertension related alterations in the functional, biochemical and molecular properties of α(1)-adrenoceptor in the rat seminal vesicle and vas deferens. Spontaneous seminal emission in male spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats was studied during the 3-day observation period. The characteristics of α(1)-adrenoceptor in the seminal vesicle and epididymal and prostatic portion of vas deferens of the two strains were determined using an isolated muscle bath, radioligand receptor binding and real-time reverse transcription-polymerase chain reaction techniques. SHRs had significantly higher serum testosterone than WKY rats. However, the daily mean number of ejaculatory plugs emitted and their dry weight in SHRs were significantly lower than those in WKY rats. Although there was no significant difference in the properties of α(1)-adrenoceptor in the prostatic portion of vas deferens between SHRs and WKY rats, the maximum contractile responses to phenylephrine, total α(1)-adrenoceptor density and expression of α(1A)-adrenoceptor mRNA were significantly higher in the seminal vesicle and epididymal portion of vas deferens of SHRs vs. WKY rats. Our data demonstrate the presence of hypertension related alterations in serum testosterone and in α(1)-adrenergic responsiveness of the rat seminal vesicle and vas deferens and suggest that ejaculatory function in SHRs does not mirror these hypertension related alterations.

Significant inter-individual variability exists in responses of human dorsal hand veins to activation of α-adrenoceptors. Simultaneous graded infusions of the α1- and α2-adrenoceptor agonists phenylephrine (3.66–8000 ng/min) and dexmedetomidine (0.0128–1000 ng/min) were given into dorsal veins of both hands and responses of 75 subjects were analyzed to assess whether a subject's sensitivity to phenylephrine (ED50) predicts his sensitivity to dexmedetomidine. Individual ED50 estimates of dexmedetomidine and phenylephrine ranged between 0.06–412 and 14.2–7450 ng/min and exhibited only a weak positive relationship (r2 = 0.074, P = 0.018). Finger temperature, body mass index, age and phenylephrine sensitivity together accounted for about 30% of dexmedetomidine ED50 variation (r2 = 0.315, P

To investigate the possible relationship between the bladder mucosal expression of α(1)-adrenoceptor (AR) mRNAs, storage symptoms and urodynamic findings in patients with lower urinary symptoms (LUTS) and benign prostatic obstruction (BPO).Mucosa was obtained from the posterior bladder wall from 20 patients with a diagnosis of LUTS and BPO undergoing prostatectomy. α(1)-AR subtype mRNA was quantified using competitive real-time reverse transcription-polymerase chain reaction. A preoperative video urodynamic study measured volumes for first desire to void (FDV) and strong desire to void (SDV). Patients were divided into group 1, with volumes for FDV ≤ 200 ml or SDV ≤ 300 ml, and group 2, with volumes FDV ≥ 201 ml and SDV ≥ 301 ml. Preoperative and postoperative international prostate symptom score (IPSS) and Overactive Bladder Symptom Score (OABSS) were evaluated.The group 1 FDV (141.0 ± 13.5 ml) was significantly lower than that of group 2 (299.0 ± 48.1 ml). Similarly, the SDV for group 1 (247.0 ± 21.9 ml) was also significantly lower than for group 2 (444.0 ± 32.5 ml). There were no significant differences between groups 1 and 2 with respect to mucosal α(1a)- and α(1b)-AR mRNA levels. However, group 1 patients had significantly more α(1d)-mRNA than those in group 2. No relationship between the expression of α(1)-AR mRNAs and preoperative or postoperative OABSS or IPSS was detected.There was a relationship between the expression of α(1d)-AR mRNA in the bladder mucosa and storage-phase urodynamics in LUTS/BPO patients, suggesting a role of α(1D)-ARs in bladder sensation.

Finding effective chemotherapeutic agents for clinical use is a long-lasting goal in medicinal chemistry. In this study, we report a new class of α1-adrenoceptor (α1-AR) antagonists. Specifically, we describe the synthesis and the blocking activities toward α1-AR of 7-(2-hydroxypropoxy)-3,4-dihydroisoquinolin-1(2H)-one 1 and its structurally perturbed analogs 2–11 that were designed according to the principle of bioisosterism. Their structures were identified with IR, 1H NMR, MS, HRMS and elemental analysis. The blocking activities of compounds 1–11 were evaluated on isolated rat anococcygeus muscles. The results indicated that these compounds showed moderate to good activities. Among them, compound 1 exhibited the highest activity that was comparable to those of known α1-AR antagonists tamsulosin and DDPH (1-(2,6-dimethylphenoxy)-2-(3,4-di- methoxyphenylethylamino)propane hydrochloride) and thus may be exploitable as a lead compound for the discovery of promising α1-AR antagonists.

Xiao, Daliao, Xiaohui Huang, Lawrence D. Longo, and Lubo Zhang. PKC regulates α1-adrenoceptor-mediated contractions and baseline Ca2+ sensitivity in the uterine arteries of nonpregnant and pregnant sheep acclimatized to high alttude hypoxia. High Alt. Med. Biol. 11:153–162, 2010.—Chronic hypoxia has a profound effect on uterine artery adaptation to pregnancy. The present studies tested the hypothesis that pregnant kinase C (PKC) differentially regulates α1-adrenoceptor-mediated contractions and Ca2+ sensitivity in the uterine arteries of nonpregnant and pregnant sheep acclimatized to high altitude hypoxia. Uterine arteries were isolated from nonpregnant (NPUA) and near-term pregnant (PUA) ewes maintained at high altitude (3801 m, Pao2 ∼60 torr) for 110 days. Phorbol 12,13-dibutyrate (PDBu) decreased phenylephrine-induced contractions in PUA but not in NPUA, which was partly inhibited by the PKC inhibitor GF109203X. Additionally, GF109203X shifted the concentration–response curve of phenylephrine-induced contractions to the right in PUA. In β-escin-permeabilized arteries, Ca2+-induced increases in 20-kDa myosin light chain phosphorylation (MLC20-P) were similar in NPUA and PUA. However, Ca2+ produced a concentration-dependent increase in the ratio of tension to MLC20-P in PUA, as compared with NPUA. PKC inhibition decreased Ca2+-induced contractions in both NPUA and PUA. PDBu induced contractions of PUA in the absence of changes in MLC20-P, which was not affected by PD098059. There was a significant increase in the basal activity of PKCɛ in PUA, but not in NPUA, in hypoxic sheep, as compared with normoxic animals. The results demonstrate that the inhibitory effect of PKC on α1-adrenoceptor-mediated contractions of uterine arteries is preserved in pregnant sheep at high altitude. However, the PKC-mediated thin-filament regulatory pathway is upregulated, resulting in increased baseline Ca2+ sensitivity in the uterine artery during pregnancy at high altitude.

To examine the mechanism underlying improvements in nocturia by α(1)-blockers, we investigated whether the α(1)-blocker naftopidil acts on nocturia with sleep disturbance using a frequency/volume chart (FVC).A total of 56 male patients with lower urinary tract symptoms were enrolled. The inclusion criteria were as follows: eight or more points on the I-PSS; three or more points on the I-PSS score for nocturia; and prostate volume larger than 20 ml. Patients received 50 mg of naftopidil once daily for 4 weeks, and non-responders received 75 mg for another 4 weeks. All patients were examined, and their data entered into FVC for 2 days before and after administration of naftopidil. Quality of sleep was also evaluated using modified Pittsburgh sleep quality index (PSQI).Patients with sleep quality scores of three or four were assigned to sleep disturbance group (n = 33), while those with scores of less than three were assigned to non-disturbance group (n = 23). After administration of naftopidil, total I-PSS decreased and nocturia score decreased from 3.5 to 2.6 (P0.01). Total mean score of modified PSQI in sleep disturbance group became significantly lower after administration of naftopidil (from 16.9 to 14.0; P0.01). Naftopidil significantly decreased nocturnal urine volume, resulting in a decrease in the nocturnal polyuria index in both sleep disturbance and non-disturbance groups.These results suggest that α(1)-blockers have the ability to normalize sleep disorders. Naftopidil improved nocturnal polyuria regardless of the presence of sleep disturbance, meaning that it might directly reduce nocturnal urine production.

The activity of various 1-(3-(4-arylpiperazin-1-yl)-propyl)-pyrrolidin-2-ones α1-adrenergic receptors (α1-ARs) antagonists, was described using the quantitative structure–activity relationship (QSAR) model by applying it to 49 compounds. The molecular descriptors of the α1-ARs antagonists were obtained by quantum chemical calculations combined with molecular modeling calculations. The obtained model explains more than 88% of the variance and it was successfully validated by four tests (LOO, LMO, external test and Y-scrambling test). Statistical analysis shows that the α1-ARs activity of the studied compounds depends mainly on the PCR and Qindex descriptors.

Some of the cardiac properties of the partial beta-agonist prenalterol may indicate a contribution from alpha 1-adrenergic stimulation. We therefore studied whether prenalterol interacted with alpha 1-adrenoceptors in rat myocardium. Combination with propranolol did not reveal an alpha 1-adrenergic inotropic effect of prenalterol in papillary muscles. Neither did prenalterol block the alpha 1-adrenergic response to phenylephrine. In myocardial cells, prenalterol inhibited 3H-prazosin binding to alpha 1-adrenoceptors only at very high concentrations. Prenalterol thus exhibited no functionally important interactions with alpha 1-adrenoceptors in myocardium, and its properties cannot be accounted for in terms of contribution from alpha 1-adrenergic effects.

This study was performed to characterize the α1-adrenoceptor subtypes in mouse ureters as regards gene expressions and contractile functions.The mRNAs for these subtypes were quantified by the real-time quantitative reverse transcription polymerase chain reaction. In a functional study, α1-adrenoceptor antagonists were evaluated against the noradrenaline-induced contraction in mouse isolated ureteral preparations.In mouse ureter, the relative mRNA expression levels for α1a-, α1b- and α1d-adrenoceptors were 74.5, 14.3 and 11.2%, respectively. Adrenaline and noradrenaline each produced a concentration-dependent phasic contraction (pD 2 values, 5.73±0.05 and 5.69±0.06, respectively). Prazosin (non-selective α1-adrenoceptor antagonist), silodosin (selective α1A-adrenoceptor antagonist), and BMY-7378 (selective α1D-adrenoceptor antagonist) all shifted the concentration–response curve for noradrenaline to the right, the rank order of potencies (apparent pA 2 values) being silodosin (9.32±0.11)prazosin (8.55±0.10)BMY-7378 (6.06±0.15). The α1A-adrenoceptor antagonist silodosin was thus much more effective than the α1D-adrenoceptor antagonist BYM-7378.Our results demonstrate that in mouse ureters: the mRNA for the α1A-adrenoceptor was more prevalent than those for the α1B- and α1D-adrenoceptors, and that among these subtypes, the α1A-adrenoceptor plays the major role in noradrenaline-induced contraction.

Aim: This study investigated the impact of hypertension combined with diabetic nephropathy on rat renal α1-adrenoceptor subtype composition. Methods: In streptozotocin-induced diabetic spontaneously hypertensive rats (SHR), diabetic nephropathy developed as reflected by increased kidney index, plasma creatinine, albumin excretion, creatinine clearance and fractional excretion of Na+ (all p < 0.05). Renal vasoconstrictions caused by electrical stimulation of renal nerves and intrarenally administered noradrenaline (α-adrenoceptor agonist), phenylephrine (α1-adrenoceptor agonist) and methoxamine (α1A-adrenoceptor agonist) were determined in the presence and absence of intrarenally administered amlodipine (Ca2+ channel blocker), 5-methylurapidil (α1A-adrenoceptor antagonist), chloroethylclonidine (α1B-adrenoceptor antagonist) and BMY 7378 (α1D-adrenoceptor antagonist). Results: In diabetic nephropathy SHR, there was a significant (all p < 0.05) attenuation of all adrenergically induced vasoconstrictor responses in the antagonists, except chloroethylclonidine, which caused a significant (all p < 0.05) enhancement of the responses. Conclusion: The data demonstrated that there was a functional coexistence of α1A- and α1D-adrenoceptors in the renal vasculature of SHR irrespective of the presence of diabetic nephropathy. However, there was a minor contribution of pre-synaptic α-adrenoceptors to the adrenergically mediated vasoconstrictor responses in the diabetic nephropathy SHR.

The mechanisms underlying actions of dihydroxyphenylalanine (L-DOPA) in Parkinson's disease remain to be fully elucidated. Noradrenaline formed from L-DOPA may stimulate alpha(1)-adrenoceptors. We assessed the involvement of alpha(1)-adrenoceptors in actions of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques. In each animal, the minimal dose of L-DOPA required to alleviate parkinsonian symptoms was defined (12.5-25 mg/kg p.o.). The effects of coadministration of the alpha(1)-adrenoceptor antagonist prazosin ([4-(4-amino-6,7-dimethoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone) on motor activity, parkinsonism, and dyskinesia were assessed. Antiparkinsonian benefit was accompanied by mild dyskinesia. L-DOPA also elicited hyperactivity, i.e., activity greater than that seen in normal animals. Coadministration of prazosin (0.16-0.63 mg/kg p.o.) with L-DOPA did not significantly affect either its antiparkinsonian actions or dyskinesia. However, prazosin significantly and dose-dependently attenuated L-DOPA-induced activity, reducing it to a level equivalent to that of normal animals. More specifically, during periods of pronounced L-DOPA-induced activity, prazosin attenuated the total and duration of activity by 80 and 76%, respectively. These actions of prazosin were expressed in the absence of sedation. Although activation of alpha(1)-adrenoceptors plays no major role in the antiparkinsonian and dyskinetic effects of L-DOPA per se, it does contribute to the induction of hyperactivity. alpha(1)-Adrenoceptors may be involved in pathological responses to L-DOPA treatment, including the dopamine dysregulation syndrome.

Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging men leading to lower urinary tract symptoms (LUTS). α1-Adrenoceptors (α1ARs) antagonists (blockers) have become a mainstay of LUTS treatment because they relax prostate smooth muscle and decrease urethral resistance, as well as relieving bladder LUTS symptoms. A review of key recent clinical trials suggests new insights into the role of specific α1AR subtypes in the treatment of LUTS.

Background To study the influence of the changes in the α1-adrenergic receptor and NGF/ProNGF pathway on the diabetic urethral function. Methods A total of 20 female Wistar rats were divided into two groups equally at random. Urethral function was examined by recordings of bladder pressure and urethral perfusion pressure (UPP). The expression of α1-adrenergic receptor in the urethra was measured via RT-qPCR and ELISA method. The expression of nerve growth factor (NGF) in the urethra was measured via RT-qPCR and ELISA method. The expression of proNGF, P75NTR and sortilin in the urethra was measured by western blotting. Results The lowest urethral pressure (UPP nadir) during urethral relaxation was higher in diabetic rats. The UPP nadir and baseline UPP in diabetic rats was significantly decreased by intravenous administration of the α1-adrenoceptor antagonist (tamsulosin). The α1a and α1d adrenergic receptor in the urethra of the diabetic group was significantly increased via RT-qPCR and western blotting (P0.05). Conclusions The increase in the expression of α1-adrenoceptor and changes of the NGF/ProNGF pathway in the diabetic urethral was a possible mechanism of the diabetic urethral dysfunction.

In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.