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Ever since the discovery of rapid eye movement sleep (REMS), studies have been undertaken to understand its necessity, function and mechanism of action on normal physiological processes as well as in pathological conditions. In this review, first, we briefly surveyed the literature which led us to hypothesise REMS maintains brain excitability. Thereafter, we present evidence from in vivo and in vitro studies tracing behavioural to cellular to molecular pathways showing REMS deprivation (REMSD) increases noradrenaline level in the brain, which stimulates neuronal Na-K ATPase, the key factor for maintaining neuronal excitability, the fundamental property of a neuron for executing brain functions; we also show for the first time the role of glia in maintaining ionic homeostasis in the brain. As REMSD exerts a global effect on most of the physiological processes regulated by the brain, we propose that REMS possibly serves a housekeeping function in the brain. Finally, subject to confirmation from clinical studies, based on the results reviewed here, it is being proposed that the subjects suffering from REMS loss may be effectively treated by reducing either noradrenaline level or Na-K ATPase activity in the brain.

The alpha(1) adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the alpha(1) adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known alpha(1) adrenoceptor agonists are alpha(1A) selective, but the discovery of highly selective alpha(1B) and alpha(1D) adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific alpha(1) agonists as well as contributions to our understanding of agonist-receptor interactions.

The aim of this work is to report a detailed study of the presence of α1 AR subtypes in human urinary bladder areas involved in the micturition (i.e. detrusor, trigone and neck), investigating whether or not there are differences between sexes. Methods Urinary bladder specimens were obtained as discarded tissue after cystectomy for vesical carcinoma (17 men and 14 women). Molecular characterization of α1 AR subtypes was done by semi-quantitative RT-PCR. The α1 AR protein expression was studied by saturation binding curves using the α1 AR antagonist 125I-HEAT and by western blot. Analysis of data was performed using the GraphPad PRISM 4 software. Results Results obtained indicated that α1 AR proteins were detectable in each bladder area. In both sexes, the detrusor and the neck expressed similar levels of α1 ARs: respectively, detrusor: 14.6 ± 1.2 in men and 13.1 ± 1.1 fmol/mg prot in women; neck: 16.9±3.2 in men and 17.5 ± 4.1 fmol/mg prot in women. In the trigone, significantly higher α1 ARs were found in women compared to men (20.6 ± 1.1 vs 11.7 ± 0.7 fmol/mg prot). Subtype analysis indicated that in women, each area was endowed with mRNA and protein encoding for each α1 AR subtype. The men detrusor expressed α1A and α1D ARs, while in the trigone and the neck, each subtype was present. Conclusions A selective distribution of α1 ARs did exist between sexes and between the different areas involved in micturition, supporting evidence which indicates a role of different α1 AR subtypes in the pathophysiology of the lower urinary tract symptoms.

Aim Several studies have proposed a role for α1 adrenoceptors (ARs) in ureteral physiology, indicating that they are present in the ureter; however, few studies have been done to identify α1 AR subtypes present in this area. Thus, this study was carried out to characterize the α1 AR subtype gene and protein expression in proximal, medial, and distal region of the human ureter. Methods Molecular characterization of α1 AR subtypes were analyzed by semi-quantitative RT-PCR. α1 AR protein expression was studied by saturation binding curves and by competition binding curves with selective antagonists. Analysis of data was performed using the GraphPad PRISM 4 software. Results Analysis of saturation binding curves revealed a heterogeneous distribution of α1 AR binding sites, the Bmax for the distal ureter was indeed 52.5 ± 5.4 fmol/mg prot, while a lower similar density of α1 ARs was demonstrated in the medial (25.2 ± 1.7 fmol/mg prot) and proximal (23.4 ± 0.4 fmol/mg prot) ureters. Molecular and pharmacological characterization of α1 AR subtypes indicated that each receptor was present, although with differences in terms of the amount expressed. Conclusions Human ureter was endowed with each α1 AR subtype, although α1D and α1A ARs were prevalent over α1B ARs. Radioligand binding results revealed that there were no significant differences in the Kd between ureteral regions, while a heterogeneous distribution of α1 AR binding sites was detected, with the highest density of α1 ARs in the distal ureter and a lower similar density in the medial and proximal ureters. Neurourol. Urodynam. 24:142–148, 2005. © 2005 Wiley-Liss, Inc.

In this paper, the enantiomers of (±)-1, previously studied as α1 and 5-HT1A ligands, were prepared both by resolution of the racemate and asymmetric synthesis. The enantiomeric purity and absolute configuration were determined by means of HPLC and polarimetric analysis. Enantiomers were evaluated for in vitro 5-HT1A and α1 receptor affinity by binding and functional assays. Results indicate that the two enantiomers are almost equally potent at 5-HT1A and α1 receptor systems and, contrary to WB 4101, the stereoselectivity is poor. As further support to these experimental findings, molecular docking studies on the two enantiomers of (±)-1 have been performed and a comparison with those obtained for 5-HT1A potent agonist (R)-flesinoxan and α1d antagonist (S)-WB 4101 has been drawn.

Alpha1-adrenoceptor antagonists have been shown to provide effective relief from symptoms of benign prostatic hyperplasia (BPH) with attendant improvements in quality of life. Although the alpha1A-adrenoceptor subtype predominates over other subtypes of alpha1 adrenoceptors in the prostate gland, there is no evidence that a subselective alpha-adrenoceptor antagonist provides a clinical advantage over a selective alpha1-adrenoceptor antagonist in the treatment of patients with BPH. The pharmacokinetic profiles of alpha1A-adrenoceptor antagonists and their documented penetration of the blood-brain barrier (CNS adverse effects) preclude a clinical benefit of subselective alpha-adrenoceptor blockers over selective alpha1 blockers.

On a examine la distribution des proteines des sous-types α 1A , α 1B , α 1D des recepteurs adrenergiques-α 1 (RAα 1 ) dans le cerveau, le coeur, le rein et le foie de rats âges de 1 semaine ainsi que dans le cerveau, le coeur, l'aorte, le rein, le foie, le canal deferent, la prostate et les glandes surrenales de rats adultes. Pour ce faire, on a eu recours a la methode de transfert de type Western a l'aide d'anticorps monoclonaux specifiques aux sous-types de recepteurs. Chez les rats nouveau-nes, on a detecte des taux immunoreactifs eleves de RAα 1A et de RAα 1D dans le cerveau et le coeur et de RAα 1B dans le foie et le coeur. Dans les tissus des rats adultes, les taux de proteines des RAα 1B ont ete eleves dans le cerveau, moyens dans le coeur, l'aorte, le foie, le canal deferent et les surrenales, et faibles dans le coeur et la prostate; de plus, l'expression des RAα 1B a ete plus forte dans le cerveau et le coeur que dans les autres tissus, alors que celle des RAα 1D a ete plus marquee dans le cerveau. Les trois sous-types de recepteurs ont augmente avec l'âge dans le cortex cerebral, alors que le taux de RAα 1B a augmente dans le coeur, mais a diminue dans le foie; les taux de RAα 1A et de RAα 1D dans le foie, le rein et le coeur n'ont pas ete influences par l'âge. On conclut que les sous-types de RAα 1 sont exprimes abondamment exprimes dans differents tissus des rats adultes et nouveau-nes.

Objective: To discuss the role of α-adrenoceptors (α-ARs) in the control of lower urinary tract function with special emphasis on their importance in the pathologically changed blad

Objective: This paper reviews recent studies in animals that examined the effect on lower urinary tract function of α1-adrenoceptor agonists and antagonists. Met

The complexity of the signal transduction pathways linked to α1A-adrenoceptors are becoming clearer. At one time it was thought that the α1A-subtype was linked to the influx of e

Until 1974 it was widely accepted that α-adrenoceptors represented a homogeneous population of receptors. Following the discovery of presynaptic, release-modulating receptors and based on differences

Purpose: The present study evaluated the expression of alpha1-adrenoceptor subtypes in human corpus cavernosum.Materials and Methods: The mRNA encoding alpha1a, and alpha1b and alpha1d subtypes were assessed by RNA-directed complementary cDNA synthesis followed by Taq DNA amplification. The level of alpha1 mRNA was calculated in arbitrary optical density units and normalized with respect to the length of the respective cDNA fragments.Results: We found that alpha1a, alpha1b and alpha1d adrenoceptor subtypes are expressed in human corpus cavernosum, with a predominant expression of the alpha1a subtype.Conclusion: These results suggest that alpha1a-adrenoceptor subtype is important and that understanding the biochemical and functional characteristics of this subtype may lead to the development of specific antagonists in the treatment of impotence.

A series of 2-substituted methyl 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (4), 3-substituted methyl 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (5), 3-substituted methyl 2,3-dihydro-5H-thi...

A series of novel indolylpiperidine derivatives were synthesized and assessed for their pharmacological profiles at alpha1 adrenoceptor subtypes by in vitro binding studies at rat alpha1A and alpha1B receptors. Compound 11 was a potent (Ki=0.63 nM) and selective (approximately 30-fold more selective for the alpha1B receptor than for the alpha1A receptor) alpha1B adrenoceptor antagonist.

In rat aorta, depletion of internal Ca2+ stores by addition of noradrenaline (1 microM) induces a biphasic response (an initial phasic response and a tonic one) mediated by two different intracellular Ca2+ pools. This response cannot be repeated, suggesting a depletion of internal Ca2+ stores sensitive to noradrenaline. In absence of the agonist, this depletion is the signal for the entry of extracellular Ca2+, not only to refill the stores but also, under our experimental conditions, to activate the contractile proteins thus inducing an increase in the resting tone (IRT) that constitutes functional evidence of this Ca2+ entry. The ionic channels involved in the mechanism of the IRT have been studied in the present work. The fact that the addition of nimodipine (10(-15)-10(-11) M) selectively inhibits the IRT suggests that this mechanical response is mediated by Ca2+ influx through dihydropyridine-sensitive Ca2+ channels. Moreover, the inhibitory action of nimodipine is attenuated by glibenclamide (10 microM). Cromakalim (10(-10)-10(-6) M) also inhibits the IRT concentration dependently, and this inhibition is antagonized by glibenclamide (10 microM). These results relate the ATP-dependent K+ channels to the mechanism of the IRT. The refilling of the two internal Ca2+ compartments sensitive to noradrenaline was, like the IRT, altered in presence of the compounds tested, since the subsequent contractile response to noradrenaline was decreased. The present results suggest that nimodipine treatment inhibits the refilling of the Ca2+ compartment responsible for the tonic contraction induced by noradrenaline in Ca2+-free medium, whereas the refilling of the Ca2+ pool responsible for the phasic response to noradrenaline remained unaltered. Both the phasic and tonic responses to noradrenaline in Ca2+-free medium decreased after treatment with cromakalim. We can therefore assume that the refilling of both Ca2+ compartments sensitive to noradrenaline was inhibited. In conclusion, these results are consistent with the contraction of the rat aorta in response to noradrenaline in Ca2+-free medium consisting of an initial phasic response and a tonic one. The former is due to the release of internal Ca2+ from a compartment refilled through a special channel that is cromakalim but not dihydropyridine sensitive. The tonic response is due to Ca2+ release from another compartment refilled through a cromakalim- and dihydropyridine-sensitive Ca2+ channel. The Ca2+ entry through this latter channel intervenes in the IRT observed during the refilling of these stores previously depleted by noradrenaline, and the opening state of this channel is also modulated by ATP-dependent K2+ channels.

To identify the alpha 1-adrenoceptor subtypes in the human prostatic urethra, we compared the potencies of various alpha 1-adrenoceptor agonists and antagonists in inhibiting [3H]tamsulosin binding to human prostatic urethral membranes with their potencies in inhibiting the binding of (+)-beta-([125I]iodo-4-hydroxyphenyl)ethylaminomethyl-tetralone ([125I]HEAT) to cloned human alpha 1a, alpha 1b and alpha 1d subtypes. The alpha 1A-selective antagonists 5-methylurapidil and (+)niguldipine showed higher affinities for both cloned alpha 1a and urethral alpha 1-adrenoceptors than for cloned alpha 1b- and alpha 1d-adrenoceptors. NS-49, (R)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, recently characterized as an alpha 1A-selective agonist, also showed high affinity for the cloned alpha 1a subtype and urethral alpha 1-adrenoceptors. Prazosin showed lower affinity for alpha 1-adrenoceptors in the human prostatic urethra than for any of the three cloned alpha 1-adrenoceptors. Comparison of the affinities of alpha 1-adrenoceptor agonists and antagonists for human prostatic urethral alpha 1-adrenoceptors to their affinities for the three cloned alpha 1 subtypes indicated a close correlation between the affinities for human urethral alpha 1 and the cloned alpha 1a-adrenoceptors. However, prazosin did not conform to this pattern. These findings suggest that the predominant alpha 1-adrenoceptor in the human urethra is the alpha 1A subtype, and that an alpha 1L subtype which has been characterised by its low affinity for prazosin, may also be present.

1. The pressor action of noradrenaline and its blockade by selective alpha(1)-adrenoceptor antagonists in the pithed mouse were evaluated. 2. Chloroethylclonidine (alpha(1B/D)-adrenoceptor alkylating agent) or BMY 7378 (alpha(1D)-adrenoceptor antagonist), both at 1 mg kg(-1), did not block the increase in blood pressure induced by noradrenaline. 3. 5-Methylurapidil (alpha(1A)-adrenoceptor antagonist), at 0.1 mg kg(-1), displaced the dose-response curve approximately six-fold to the right. 4. The results support the idea that the pithed mouse vasculature express alpha(1A)-adrenoceptors and suggest that it is a good model to study the roles of alpha(1)-adrenoceptors in gene knockout or overexpression.

Over the last 10 years, the neural code involved in the perception of acoustic communication signals has become a large area of researches. The recent literature suggests that the discrimination between these signals relies more on the temporal organization of neuronal discharges rather than on global changes of firing rate. My PhD thesis aimed at determining to what extent the regulation of cortical inhibition may (i) change the temporal patterns triggered by conspecific and heterospecific vocalizations and (ii) modify the information carried by these patterns on the vocalization identity. Neuronal activity was recorded in the auditory cortex of anesthetized guinea pigs in 16 cortical sites during presentation of a set of vocalizations, and a partial blockage of intra-cortical inhibition was performed by Gabazine application (4 minutes, 10μm). Under these conditions, evoked responses were stronger and the temporal patterns were reinforced. Mutual information quantified at each cortical site was increased but the information computed at the populationnal level did not change, an effect that could be explained by the fact that the redundancy between cortical sites was increased. We then assessed to which extent the noradrenergic modulation can mimic the effects of a partial blockage of inhibitions. Although all the tested drugs modulated both the evoked responses and the spike-timing reliability, none of the noradrenergic agonists used here (α1, α2 and ) induced significant changes in the information carried by neuronal responses. However, the effects induced by phenylephrine, an α1 agonist, seemed to involve an action on the intra-cortical inhibition, which suggests that a noradrenergic modulation of cortical inhibition can operate in the auditory cortex. It is therefore possible to envision that the coordinated action of several neuromodulatory systems modulates cortical inhibition and thus changes the information carried by cortical neurons on the stimuli identity., Depuis quelques années, l’étude du code neuronal impliqué dans la perception des signaux de communication acoustique est devenue un domaine de recherche considérable. La littérature récente de ce domaine suggère que la discrimination entre ces signaux reposerait plutôt sur une organisation des décharges neuronales en motifs temporels que sur des variations globales de taux de décharge. Ma thèse a eu pour objectif de déterminer dans quelle mesure une régulation des inhibitions corticales peut (i) changer les motifs temporels déclenchés par des vocalisations conspécifiques et hétérospécifiques et (ii) modifier l’information portée par ces motifs sur l’identité des vocalisations. Nous avons enregistré l’activité neuronale dans le cortex auditif de cobayes anesthésiés en 16 sites corticaux lors de la présentation d’un jeu de vocalisations, et avons partiellement bloqué les inhibitions corticales par des applications de Gabazine (4minutes, 10µm). Dans ces conditions, les réponses évoquées sont plus fortes et les motifs temporels plus marqués. L’information mutuelle quantifiée au niveau de chaque site cortical est augmentée mais l’information populationnelle au niveau de l’ensemble des 16 sites enregistrés n’est pas modifiée, un effet qui peut s’expliquer par le fait que la redondance entre les sites corticaux est augmentée. Nous avons ensuite évalué dans quelle mesure une modulation noradrénergique était susceptible de mimer les effets d’un blocage partiel des inhibitions. Bien que les agonistes utilisés (α1, α2 et ) aient tous induit des modifications des réponses évoquées et de la reproductibilité des motifs temporels, aucun d’entre eux n’a induit de changements importants de l’information portée par les réponses neuronales aux vocalisations. En revanche, les effets induits par la phenylephrine, un agoniste α1, sont vraisemblablement sous-tendus par une action sur les inhibitions intra-corticales, ce qui rend plausible l’hypothèse d’une modulation noradrénergique des inhibitions corticales. Il est donc envisageable que l’action coordonnée de plusieurs systèmes neuromodulateurs puisse moduler les inhibitions corticales et ainsi changer la quantité d’information portée par les neurones corticaux sur l’identité des stimuli à discriminer.

Objective: To investigate the changes in the α1-adrenoceptor and nerve growth factor (NGF)/NGF precursor (proNGF) pathway in the urethra after diabetes induction. Materials and Methods: Urethral relaxation function was determined by simultaneous recordings of intravesical pressure under isovolumetric conditions and urethral perfusion pressure (UPP) in diabetic rats. The expression of α1-adrenoceptor, NGF, proNGF, low-affinity p75 receptor for neurotrophins (p75NTR) and sortilin in the urethras was measured using real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay and Western blotting. Results: In diabetic rats, the lowest urethral pressure (UPP nadir) during urethral relaxation was significantly higher. Intravenous administration of tamsulosin, an α1-adrenoceptor antagonist, significantly decreased the UPP nadir and baseline UPP in diabetic rats. RT-qPCR and Western blotting studies showed a statistically significant increase of α1a- and α1b-adrenoceptor in the urethras from the diabetic group (p < 0.05). The expression of NGF was significantly decreased in the urethras from the diabetic group while the expression of proNGF was significantly increased (p < 0.05). The p75NTR level in the urethras of diabetic rats was decreased compared with controls (p < 0.05) and there was no significant difference regarding sortilin between the two groups (p > 0.05). Conclusion: This study validated the diabetic urethral dysfunction and furthermore indicated that the increase in the expression of α1-adrenoceptor and changes in the NGF/proNGF pathway may be involved in diabetic urethral dysfunction.

In the search for new hypotesive agents a series of aroxyalkyl derivatives of 2-methoxyphenylpiperazine was obtained. The aim of the present study was to examine their hypotensive properties and to evaluate their mechanism of action. In the study their hypotensive activity after i.v. and p.o. administration, influence on the pressor responses to adrenaline, noradrenaline and methoxamine, direct spasmolytic and vasorelaxant effects were assessed. In the next step two compounds which were the most active and selective for α(1)-adrenoceptors were evaluated for their α(1)-adrenoreceptor subtypes selectivity in functional bioassays. The data from our experiments indicate that the hypotensive activity of tested aroxyalkyl derivatives of 2-methoxyphenylpiperazine is mainly a result of their α(1)- or α(1)/α(2)-adrenoceptor blocking properties. The two most active compounds showed to be the competitive antagonists of α(1)-adrenoceptors with stronger activity at α(1D)-, α(1A)- and α(1L)- and weaker at α(1B)-subtype.

In the search for new hypotensive agents a series of pyrrolidin-2-one derivatives was obtained with α-adrenoceptor blocking properties. The aim of the present study was to examine the possible involvement of other mechanisms in the observed hypotensive properties. In the present study the affinities for β1-adrenoreceptors, vasorelaxant effect and the involvement in NO pathway of pyrrolidin-2-one derivatives were assessed. In the next step compounds were also evaluated for their α1-adrenoreceptor subtypes in functional bioassays. The data from our experiments indicate that the hypotensive activity of tested pyrrolidin-2-one derivatives is a result of their α-adrenoceptor blocking properties and the compounds have stronger antagonist potency for the α1D- than for α1B-subtype. Among investigated compounds EP-46 is the most potent and selective antagonist for the α1D- and α1A- than for α1B-subtype. Compound EP-43 can enhance NO production additionally.

We have evaluated the part played by the mitochondrial ATP-sensitive potassium (mK(ATP)) channels on effect of alpha(1)-adrenoceptor activation by noradrenaline in ischemia-induced ventricular arrhythmia.Anesthetized rats were subjected to 25 minutes of regional ischemia, and infarct size (IS) and ischemia-induced ventricular arrhythmia were measured. Group I served as saline control with ischemia (n = 9). In group II (n = 9), the ischemic period was preceded by three short episodes of ischemia, followed by reperfusion. In group III, noradrenaline (2 microg/kg, IV, n = 9) was injected prior to ischemia. In group IV, an alpha(1)-adrenoceptor blocker (prazosin, 0.5 mg/kg, IV, n = 6) was administrated prior to noradrenaline injection. In Groups V and VI, rats received a specific mitochondrial K(ATP) channel inhibitor [5-hydroxydecanoic acid (5-HD), 10 mg/kg, IV, n = 6] prior to or after noradrenaline injection. Ischemic preconditioning (IPC) and noradrenaline markedly reduced incidences of ventricular fibrillation (VF) (0%, 0% vs. 55.5% in control, P0.05) and ventricular tachycardia (VT) (11%, 44.5% vs. 100% in control, P0.001 and P0.05), duration of VF + VT (3 +/- 1 seconds, 4.7 +/- 2.1 seconds vs. 52.9 +/- 6 seconds in control, P0.001), number of VF + VT episodes (1.7 +/- 1.7, 5.75 +/- 2.4 vs. 60.5 +/- 8 in control, P0.001), severity of arrhythmias (0.3 +/- 0.3, 1.7 +/- 0.5 vs. 3.9 +/- 0.3 in control rats, P0.001 and P0.01), and IS (13.6 +/- 1.8%, 18.2 +/- 1.5% vs. 49.6 +/- 2.4% in control, P0.001). Administration of prazosin or 5-HD prior to or after noradrenaline injection intensified incidences of VF (66.6%, 66.6% and 50%, P0.05) and VT (100%, 100%, and 100%, P0.05), duration of VF + VT episodes (70.2 +/- 10.5 seconds, 69.8 +/- 6.75 seconds, and 60.8 +/- 14.9 seconds, P0.001), number of VF + VT episodes (56 +/- 16.4, 67 +/- 11, and 45 +/- 3.5, P0.01, P0.001, and P0.05), severity of arrhythmias(3.8 +/- 0.3, 4 +/- 0.5, and 3.7 +/- 0.2, P0.01, P0.05, and P0.01), and IS (45.5 +/- 3%, 46.8 +/- 3.4%, and 43 +/- 2.5%, respectively, P0.001) compared with the noradrenaline-treated group.Prazosin or 5-HD treatment eliminated the beneficial effects of noradrenaline on arrhythmogenesis and infarct size.

The genetic function approximation (GFA) algorithm has been used to derive a three-term QSAR equation able to correlate the structural properties of arylpiperazine derivatives with their affinity toward the alpha1 adrenoceptor (alpha1-AR). The number of rotatable bonds, the hydrogen-bond properties, and a variable belonging to a topological family of descriptors (chi) showed significant roles in the binding process toward alpha1-AR. The new model was also compared to a previous pharmacophore for alpha1-AR antagonists and a QSAR model for alpha2-AR antagonists with the aim of finding common or different key determinants influencing both affinity and selectivity toward alpha1- and alpha2-AR.

Induction of apoptosis by α1-adrenoceptor antagonists in benign prostatic hyperplasia and prostate cancer

Selectivity of tamsulosin and terazosin to functional alpha1-adrenoceptors was examined. Both drugs competitively inhibited the contractile responses to noradrenaline in different tissues where the responses were mediated through the alpha1D-, alpha1B- or alpha1L-subtype. Together with the affinities obtained in the binding study with cloned (alpha1a, alpha1b, alpha1d) and native (alpha1A and alpha1B) subtypes, the selectivity of tamsulosin was alpha1Aalpha1L, alpha1Dalpha1B. Terazosin had lower affinity at various subtypes than tamsulosin, but showed relatively high selectivity to the alpha1D-subtype. In the human prostate, tamsulosin was more than 30-fold higher in affinity than terazosin in functional and binding studies.

Recently, alpha(1)-adrenoceptors (alpha(1)-ARs) have been reported to play a prominent role in the growth of a variety of cells; however, little is known about prostate growth and subtype-specific effects on cell proliferation. We examined the role of alpha(1d)-AR in prostate growth and the effect of subtype-selective alpha(1)-AR antagonist, naftopidil, which has relatively higher affinity for alpha(1d)-AR, on prostate growth in vitro and in vivo.First, we examined the effect of naftopidil on the cell proliferation of PrEC, PrSC, and PrSMC using WST-1 assay. Second, we performed real-time RT-PCR to quantify each alpha(1)-AR subtype mRNA expression level in a benign prostate hyperplasia (BPH) model rat, which was recently established to pathologically resemble human BPH patients. In addition, naftopidil was given to this model orally for 21 days and the proliferative and apoptotic indexes measured. Third, 18 BPH patients were administered naftopidil for 12 weeks and the proliferative and apoptotic indexes were compared before and after naftopidil administration.Naftopidil significantly inhibited cell proliferation dose-dependently in all cell lines that expressed alpha(1d)-AR mRNA. The expression level of alpha(1d)-AR during the growth process of the prostate in the BPH model rat was significantly higher than that in the normal prostate (P0.001). Naftopidil administration inhibited cell proliferation without apoptosis in the BPH model rat and BPH patients.alpha(1d)-AR may play an important role in the regulation of cellular proliferation in the prostate, and alpha(1d)-AR blockage by naftopidil may not only improve lower urinary tract symptoms but also inhibit prostate growth in BPH patients.

tension of approximately 1 mN was applied to preparations that were then left to equilibrate for 60-90 min until spontaneous phasic contractions, which were stable in both amplitude and frequency, were generated. 24 patients (median age 65.1 +/9.3 years) pathologically diagnosed with BPH were used on data analysis. RESULTS: Spontaneous contractions were observed at a frequency of 10.1 +/9.5 5min-1. The amplitude and the rate of the spontaneous contractions were increased by phenylephrine 1.0μM, and were decrease by SIN-1 10μM. The spontaneous contractions