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β-Adrenoceptors are important mediators of smooth muscle relaxation in the urinary bladder, but the concomitant presence of a muscarinic agonist, e.g., carbachol, can attenuate relaxation responses by reducing potency and/or efficacy of β-adrenoceptor agonists such as isoprenaline. Therefore, the present study was designed to explore the subtypes and signalling pathways of muscarinic receptors involved in the attenuation of isoprenaline-induced isolated rat detrusor preparations using novel subtype-selective receptor ligands. In radioligand binding studies, we characterized BZI to be a M(3)-sparing muscarinic agonist, providing selective M(2) stimulation in rat bladder, and THRX-182087 as a highly M(2)-selective antagonist. The use of BZI and of THRX-182087 in the presence of carbachol enabled experimental conditions with a selective stimulation of only M(2) or M(3) receptors, respectively. Confirming previous findings, carbachol attenuated isoprenaline-induced detrusor relaxation. M(2)-selective stimulation partly mimicked this attenuation, indicating that both M(2) and M(3) receptors are involved. During M(3)-selective stimulation, the attenuation of isoprenaline responses was reduced by the phospholipase C inhibitor U 73,122 but not by the protein kinase C inhibitor chelerythrine. We conclude that both M(2) and M(3) receptors contribute to attenuation of β-adrenoceptor-mediated relaxation of rat urinary bladder; the signal transduction pathway involved in the M(3) component of this attenuation differs from that mediating direct contractile effects of M(3) receptors.

PURPOSE: The known importance of testosterone for the development of benign prostatic hyperplasia (BPH) prompted us to test the hypothesis whether polymorphisms of two genes (CYP19A1 and CYP3A4) involved in testosterone metabolism are associated with clinical BPH-parameters. METHODS: A random sample of the population-based Herne lower urinary tract symptoms cohort was analysed. All these men underwent a detailed urological work-up. Two polymorphisms in the CYP19A1 gene [rs700518 in exon 4 (A57G); rs10046 at the 3'UTR(C268T)] and one in the 3'UTR of CYP3A4 [rs2740574 (A392G)] were determined by TaqMan assay from genomic DNA of peripheral blood. These polymorphisms were correlated to clinical and laboratory BPH-parameters. RESULTS: A total of 392 men (65.4 +/- 7.0 years; 52-79 years) were analysed. Mean International Prostate Symptom Score (IPSS; 7.5), Q (max) (15.4 ml/s), prostate volume (31 ml) and prostate specific antigen (PSA) (1.8 ng/ml) indicated a typical elderly population. Both polymorphisms in the CYP19A1 gene were not correlated to age, IPSS, Q (max), prostate volume and post-void residual volume. Serum PSA was higher in men carrying the heterozygous rs10046 genotype (2.0 +/- 0.1 ng/ml) than in those with the CC-genotype (1.7 +/- 0.2 ng/ml, P = 0.012). Men carrying one a mutated allele of the CYP3A4 gene had smaller prostates (27.0 +/- 2.0 vs. 32 +/- 0.8 ml, P = 0.02) and lower PSA levels (1.6 +/- 0.3 vs. 1.9 +/- 0.1 ng/ml). CONCLUSIONS: The inconsistent associations observed herein and for other gene polymorphisms warrant further studies. In general, the data regarding the association of gene polymorphism to BPH-parameters suggest that this disease is caused by multiple rather than a single genetic variant. A rigorous patient selection based on anatomo-pathological and hormonal profile may possible reduce the number of confounders for future studies thus enabling a more detailed assessment of the association between genetic factors and BPH-parameters

Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)–and serum response factor (SRF)–regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)–and transforming growth factor β (TGFβ)–stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders.

Summary Aims: Gender, age, obesity, smoking and alcohol or caffeine intake have been shown or proposed to be risk factors for the prevalence and/or severity of the overactive bladder symptom complex (OAB) or related parameters. We have explored whether any of these factors affect the therapeutic response to a muscarinic receptor antagonist during routine clinical use. Methods: Data were analysed from 3766 OAB patients (77.1% woman, age 62.6 ± 12.8 years) participating in an observational, open-label postmarketing surveillance study of the safety and efficacy of darifenacin. Multiple logistic regression models were applied to explore the effect of potential OAB risk factors on the darifenacin treatment-associated improvement of OAB symptoms, patient’s subjective rating of bladder problems and global efficacy and tolerability. Results: Age and (less consistently) gender were statistically significantly correlated with efficacy parameters, but the extent of their impact was judged to be too small to be clinically relevant. Except for a very small effect of body mass index on urgency episode improvement, none of the lifestyle-associated factors had significant effects on the efficacy of darifenacin. Except for a very small age effect, none of the potential risk factors had significant effects on global tolerability. Discussion and conclusions: We conclude that the efficacy and tolerability of a muscarinic receptor antagonist, such as darifenacin is largely independent of potential OAB risk factors, such as gender, age, obesity, smoking and alcohol or caffeine intake.

Tamsulosin is an alpha(1)-adrenoceptor antagonist used for the treatment of lower urinary tract symptoms that are suggestive of benign prostatic hyperplasia. It is mostly used in a modified-release (M R) Formulation. but an oral controlled absorption system (OCAS) and a 'without-water' tablet formulation are also available in some countries. The oral bioavailability of the MR formulation in the fasted state is close to 100%. Whereas absorption from the MR formulation is affected by concomitant food intake, that of the OCAS formulation is food independent. Tamsulosin exhibits high plasma-protein binding, largely to alpha(1)-acid glycoprotein. It is metabolized, mainly by cytochrome P450 (CYP) 3A4 and CYP2D6 to compounds with low abundance, and 8.7-15% of an oral dose is excreted renally as the parent compound. The pharmacokinetics of tamsulosin are not affected to a major extent by age, and pharmacokinetic alterations in renally impaired patients relate largely to an increased concentration of alpha(1)-acid glycoprotein. Pharmacokinetic alterations with hepatic impairment are also only moderate, thus neither renal nor mild to moderate hepatic impairment ;necessitates dose adjustment. Concomitant exposure to potent CYP3A4 inhibitors can more than double the exposure of tamsulosin. Clinical studies have indicated that despite its lower bioavailability, the OCAS formulation has the same treatment efficacy as the MR formulation but causes somewhat fewer cardiovascular adverse effects

Fesoterodine is an antimuscarinic agent indicated for the treatment of overactive bladder (OAB) symptoms. The objective of this study was to evaluate the efficacy of fesoterodine versus placebo over selected intervals during a 24-hour period in subjects with OAB. In a post hoc analysis, data were analyzed from two randomized, double-blind, placebo-controlled 12-week phase III trials in which subjects with a history of OAB symptoms for 6 months were treated with morning doses of fesoterodine 4 mg, fesoterodine 8 mg, or placebo. These trials are registered at ClinicalTrials.gov (NCT00220363 and NCT00138723). Changes were evaluated in number of micturitions, urgency episodes, urgency urinary incontinence (UUI) episodes, and mean voided volume (MVV) divided into three 8-hour intervals: 08:00-15:59 (daytime), 16:00-23:59 (evening), and 00:00-07:59 (nighttime). Comparisons with placebo were made using analysis of covariance (for least squares mean changes) and Wilcoxon rank sum test (for median percent changes); differences were considered significant at p

Study Type – Symptom prevalence (retrospective cohort) Level of Evidence 2b OBJECTIVES To determine the role of treatment-associated improvement in nocturia in health-related quality of life (HRQL) in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia, and secondarily to confirm the role of nocturia in HRQL at baseline and to compare the effects of watchful waiting, transurethral microwave treatment (TUMT) and transurethral resection of the prostate (TURP) to those of α1-adrenoceptor antagonists (α-blockers) on nocturia. PATIENTS AND METHODS We retrospectively analysed using multiple regression a large single-centre database of patients receiving routine care for treatment-associated alterations of symptoms and HRQL (assessed at baseline, 2611 men) and 6–12 months after initiation of treatment (1258 men). RESULTS Among the symptoms assessed using the International Prostate Symptom Score, nocturia (together with urgency and weak stream) had the strongest correlation with HRQL at baseline and after treatment. Watchful waiting, α-blockers, TUMT and TURP reduced nocturia episodes by a mean (sd) of 7 (53)%, 17 (40)%, 32 (47)% and 75 (23)%, respectively. The treatment-associated improvements in nocturia (together with those of weak stream) had the strongest association with those of HRQL. CONCLUSIONS We conclude that among all LUTS assessed in the IPSS, nocturia has one of the strongest associations with HRQL, and that treatment-associated improvements in nocturia contribute considerably to overall improvements in HRQL.

α1-Adrenoceptor antagonists are the mainstay of medical treatment of male voiding dysfunction which typically is attributed to benign prostatic hyperplasia. While original concepts have assumed that they relieve voiding dysfunction by relaxing prostatic smooth muscle, newer data indicate that their therapeutic effects at least partly occur independent of prostatic relaxation, perhaps involving direct effects on blood vessels, urothelium, afferent nerves, and/or smooth muscle of the urinary bladder. The adverse event profiles differ among α1-adrenoceptor antagonists, with tamsulosin having a particularly good cardiovascular tolerability. While this was originally attributed to its selectivity for α1A-adrenoceptors, it appears that alfuzosin which lacks subtype-selectivity, has a very similar tolerability. In contrast, doxazosin and terazosin, which are chemically and pharmacologically more closely related to alfuzosin than to tamsulosin, appear to have more side effects attributable to the cardiovascular system. More recent data indicate that tolerability differences between α1-adrenoceptor antagonists may at least partly relate to pharmacokinetic rather than to pharmacodynamic differences. Taken together, these data emphasize the idea that concepts about drug efficacy and tolerability despite being highly plausible may not necessarily be true and always require thorough experimental testing. Keywords:: benign prostatic hyperplasia, alfuzosin, doxazosin, tamsulosin, terazosin, lower urinary tract

Purpose Previous studies on associations between voiding dysfunction and quality of life (QoL) have largely been limited to baseline data. Therefore, we have explored associations between Q max and voiding and storage sub-scores of the International Prostate Symptom Score (IPSS) before and after treatment with QoL. Methods Analysis of a single-center database of 2,316 men with voiding dysfunction attributed to benign prostatic hyperplasia undergoing various medical and surgical treatment forms. Results Q max exhibited little correlation with QoL before or after treatment. IPSS inversely correlated with QoL at baseline and after treatment, and IPSS improvements correlated with those of QoL. The associations applied to both the voiding and storage sub-score of the IPSS, with the latter consistently exhibiting somewhat tighter associations. Conclusions Our post-treatment data support the idea of a cause–effect relationship between voiding symptoms and QoL irrespective of treatment form. While both voiding and storage symptoms contribute to this relationship, storage symptoms play a somewhat greater role.

Doxazosin and related, quinazoline-based alpha(1)-adrenoceptor antagonists can induce apoptosis in prostate and various other normal, benign, smooth muscle, endothelial and malignant cells. Such apoptosis-inducing effects occur independently of alpha(1)-adrenoceptor antagonism and typically require much high concentrations than those required for receptor occupancy. Several studies have invested efforts towards the elucidation of the molecular mechanisms underlying doxazosin-induced apoptosis. These include various tumor cells, cardiomyocytes, endothelial cells and bladder smooth muscle cells. While the high concentrations of doxazosin required to induce apoptosis challenge the use of this and related drugs for clinical optimization of apoptosis induction, such quinazoline structure may represent chemical starting points to develop more potent apoptosis-inducing agents free of alpha(1)-adrenoceptor antagonistic action and suitable for cancer treatment with minimal and well-tolerated side effects.

Purpose of review Treatment options for the overactive bladder were recently discussed at the 4th International Consultation on Incontinence (ICI) held in Paris, 5-8 July 2008. This article will overview current thoughts on the pharmacological and clinical basis for the different classes of drugs currently used for the treatment of lower urinary tract symptoms/overactive bladder syndrome/and detrusor overactivity. Individual drugs are not discussed in detail; particular consideration is given to therapeutic aspects of the management of the elderly patient. Recent findings An extensive literature review confirms the rationale for using antimuscarinic drugs, and that the currently used drugs are efficacius with an acceptable tolerability and safety. In patients resistant to antimuscarinics, botulinum toxin may be an alternative - the vanilloids resiniferatoxin and capsaicin have very limited use. New therapeutic options with positive proof-of-concept studies, but with limited clinical experience, are beta(3) adrenoceptor agonists and phosphodiesterase type 5 inhibitors. Positive signals have been found for other classes of drugs (e.g., gonadotropin-releasing hormone antagonists, neurokinin receptor-1 antagonists), but available information is not sufficient for proper assessment. Summary Antimuscarinic drugs remain the first-line treatment of the overactive bladder and a favorable efficacy/tolerability-safety ratio can be confirmed. Promising new alternatives are emerging and future controlled studies will decide their place in the therapeutic arsenal

Ruhe HG, Booij J, Van Weert HC, Reitsma JB, Franssen EJF, Michel MC, Schene AH. Dosisverhoging SSRI’s bij depressie is niet zinvol. Huisarts Wet 2009;52(6):289-96.

Background and purpose: Recently, some ligands targeting the sphingosine-1-phosphate receptor subtype 3 (S1P 3 ) have become available. The characterization of these compounds was mainly based on one functional read-out system, although S1 P 3 receptors are known to activate different signal transduction pathways. Therefore, this study pharmacologically characterizes these compounds using different assays. Experimental approach: Using CHO-FlpIn cells expressing the human S1 P 3 receptor the potencies and maximal effects of S1 P, FTY720-P, VPC23019, VPC23153 and VPC24191 were determined in three different assays [inhibition of cAMP accumulation, elevation of intracellular calcium concentrations ([Ca 2+ ] i ) and S1P 3 receptor internalization]. Key results: All compounds tested inhibited forskolin-induced cAMP accumulation, increased [Ca 2+ ] i and induced S1P 3 receptor internalization but with different potencies and maximal effects. S1 P was the most potent compound in all assays followed by FTY720-P. The VPC compounds were generally less potent than S1 P and FTY720-P. Regarding the maximal effects, all compounds except VPC23153, behaved as full agonists in the cAMP accumulation assay. In the calcium assay, FTY720-P, VPC23019 and VPC24191 displayed partial and VPC23153 weak partial agonist activity, relative to S1P. Interestingly, treatment with the G i inactivator Pertussis toxin, did not affect S1 P-induced [Ca 2+ ] i elevations but inhibited those in response to the other compounds, by about 50%. Conclusions and implications: This study demonstrated differential response patterns at the S1 P 3 receptor for a range of ligands. These differences could indicate the presence of functional selectivity at this receptor as FTY720-P and the VPC compounds seemed to signal predominantly via G i - whereas S1P activated G i and G q -coupled pathways.

Nocturia is a prevalent symptom that can adversely affect quality of sleep and overall quality of life leading to morbidity and even mortality. Nocturia can be due to a range of urological conditions and non-urological diseases. Nocturia can be due to an insufficient bladder capacity and/or (nocturnal) polyuria. Some of the possibly underlying non-urological diseases can be life-threatening, implying treatment priorities. Urological treatment options include alpha-adrenoceptor antagonists, muscarinic receptor antagonists and vasopressin receptor agonists. The former two have shown beneficial but small and inconsistent effects in patients assumed to have benign prostatic hyperplasia or overactive bladder, respectively. In contrast, the vasopressin analog desmopressin has consistently shown nocturia improvement in patients with proven polyuria. While supported by lower levels of evidence, lifestyle modifications are generally considered important for nocturia treatment. We conclude that nocturia is a urinary storage symptom with a major impact on patients' lives and a complex pathophysiology.

Although minimally invasive treatments for ureteral stones are efficacious, they are not free of complications and are associated with high cost. Medical expulsive therapy (MET) has recently emerged as an alternative strategy for the initial management of small distal ureteral stones. A MEDLINE search was undertaken to evaluate all currently available data on efficacy and safety of MET therapy in such patients. The specific mechanism of action on the ureteral smooth muscle and the emerging evidence of the efficacy (defined as either an increase in expulsion rate or a decrease in time to expulsion) and low-risk profile suggest that alpha-adrenergic receptor antagonists (alpha-blockers) and calcium channel antagonists should be the initial medical treatment in patients amenable to conservative therapy. NSAIDs and anticholinergics have not shown efficacy as single agents or in combination with alpha-blockers or nifedipine. Corticosteroids may provide a small additive effect when combined with either alpha-blockers or nifedipine.

Anticholinergic therapy is the first-line therapy for overactive bladder (OAB) syndrome. Especially in the last years, the number of available substances has increased because of the launch of solifenacin, darifenacin, and fesoterodine. Additionally, slow-release and transdermal formulations have led to a large variety of available treatment options. The efficacy of all substances has been proven in randomised, double-blind studies, and reviews and meta-analyses have also underlined the efficacy of all available anticholinergics and have been updated regularly. All available drugs are efficacious for OAB treatment, and clinically relevant differences among them have not been proven consistently. Moreover, age, gender, and the type of OAB (dry vs. wet) seem to lack clinically relevant impact on the efficacy of OAB treatment. The various drugs are similar in tolerability, with the exception of more dry mouth and central nervous effects with slow-release oxybutynin. Knowledge of pharmacokinetic properties of the individual substances is important in order to choose the right therapy for each patient

Context Urgency is the core symptom of the overactive bladder symptom complex, but the underlying mechanisms are not fully understood. Objective To review clinical and experimental studies related to how bladder filling and urgency are sensed and what causes urgency and to discuss how this process affects potential therapeutic strategies. Evidence acquisition Review of published reports. Evidence synthesis The definition of urgency as a desire implies that it can only be assessed in cognitively intact patients and that animal studies have to rely on surrogate markers thereof, such as detrusor overactivity (DO); however, DO and urgency are not always associated. While the precise mechanisms of how urgency is sensed remain unclear, accumulating evidence suggests that they may differ from the physiologic sensation of bladder filling. Studies on the neurophysiology of urgency sensing are hampered by reliance on the surrogate marker DO. Functional brain imaging may help to understand the central neurophysiology, but, until now, it has not specifically focused on urgency. With regard to causes of urgency, multiple theories have been forwarded. While none of them has been proven, it should be noted that they are not mutually exclusive, and, in specific patients, different causes may be present. Conclusions The development of improved therapeutic strategies against urgency will be helped by a better understanding of how urgency is perceived and the underlying causes. Rigorous use of existing definitions and the search for reliable surrogate markers will aid such attempts.

Objectives: To explore associations between the number of vaginal deliveries (primary aim) or gender (secon- dary aim) and overactive bladder (OAB) symptoms as well as their response to treatment with a muscarinic antagonist. Methods: Preplanned secondary analysis of an observational study of solifenacin in OAB patients. Episode frequencies of OAB symptoms, pad use and scores on OAB rating scales were documented in 4450 patients before and after a 12–14 week treatment period with solifenacin 5 or 10 mg. Results: Women without, and with one, two or more than two vaginal deliveries and men were similar in their baseline characteristics. All groups also exhibited rather similar reductions in symptoms and improvements in rating scales upon treatment. Conclusion: These data indicate that solifenacin, and perhaps other muscarinic receptor antagonists, are similarly suitable for the treatment of OAB symptoms in both genders, irrespective of previous vaginal deliveries.

Purpose of review To review evidence and regulatory dosing recommendations for muscarinic receptor antagonists used in the treatment of overactive bladder symptom complex (darifenacin, fesoterodine oxybutynin propiverine solifenacin tolterodine trospium) in special patient populations. Recent findings Growing evidence demonstrates effects of renal impairment, hepatic impairment, genetics and/or comedications on the pharmacokinetics of muscarinic antagonists. They may cause greater exposure in the respective population, which may translate into greater risks for side effects. These possible risks lead to drug-specific regulatory dosing recommendations or even contraindications in certain patient populations. Summary Physicians should be aware of pharmacokinetic alterations in special patient populations and possible associated risks. The evidence-based choice of a muscarinic antagonist in such patients should be guided by its specific pharmacokinetic profile

BACKGROUND: In major depressive disorder, selective serotonin reuptake inhibitors target the serotonin transporter (SERT). Their response rates (30-50%) are modified by SERT promotor polymorphisms (5-HTTLPR). OBJECTIVES: To quantify the relationship between SERT occupancy and response, and whether 5-HTTLPR is a modifier. METHODS: Drug-free depressed outpatients (n=49; both sexes; aged 25-55 years), received paroxetine (20 mg/day). We quantified SERT occupancy with iodine-123-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single-photon emission computed tomography imaging at baseline and after 6 weeks; we genotyped 5-HTTLPR (S, LG, LA). Primary outcomes: percentage decrease in 17-item Hamilton Depression Rating Scale and response (>/=50% decrease of 17-item Hamilton Depression Rating Scale). RESULTS: A significant positive relationship between SERT occupancy and clinical response existed only in the LA/LA genotype (P

Sphingosine-1-phosphate (S1P) signalling via G protein-coupled receptors is important for the regulation of cell function and differentiation. Specific Regulators of G protein Signalling (RGS) proteins modulate the function of these receptors in many cell types including vascular smooth muscle cells (VSMCs). Therefore, we investigated the role of altered expression levels of RGS proteins in S1P receptor function in VSMCs and transfected CHO cells. The mRNA expression of the S1P 1 receptor, RGS4 and RGS16 were down-regulated in VSMCs during phenotypic modulation induced by culturing, whereas mRNA levels of RGS2, RGS3, S1P 2 and S1P 3 receptors were unchanged. Interestingly, the expression level of RGS5 was transiently up-regulated. Despite major alterations in RGS levels, S1P-induced calcium elevation in VSMCs was not altered. Co-transfection of RGS2, RGS3, RGS4, RGS5 and RGS16 into CHO-Flp-In cells stably expressing the S1P 1 or S1P 3 receptor did not modify S1P-induced inhibition of cAMP accumulation to a major extent. Similar results were obtained with SEW2871, a selective S1P 1 receptor agonist. However, the inhibition of cAMP accumulation by the agonist FTY720-P via the S1P 1 receptor was significantly decreased by co-transfection with RGS5. These results indicate that mRNA of the S1P 1 receptor, RGS4, RGS5 and RGS16 is differentially regulated during phenotypic modulation. However, major alterations in RGS protein expression have only limited effect on S1P receptor function.

Aims: To explore possible changes in expression and/or function of alpha(1)- and beta-adrenoceptor subtypes as a cause for bladder dysfunction in a rat model of bladder outlet obstruction (BOO). Methods: BOO was induced in rats by partial urethral ligature. Contraction and relaxation experiments were performed with isolated bladder strips from BOO, sham-operated and non-operated (control) rats 7 days after BOO induction. mRNA expression of alpha(1)- and beta-adrenoceptor subtypes was assessed by quantitative real-time PCR. Results: Receptor-independent contraction or relaxation did not differ between BOO and sham rats. The alpha(1)-agonists methoxamine and A-61,603 caused only weak contraction without major differences between groups. Against KCI-induced tone, the beta-adrenoceptor agonists noradrenaline and isoprenaline caused similar relaxation in BOO and sham rats, whereas relaxation in response to the beta(3)-selective BRL 37,344 was attenuated. Against passive tension, noradrenaline induced relaxation in sham and control rats; in contrast, noradrenaline induced contraction at low concentrations and relaxation at high concentrations in BOO rats. The contraction component was abolished by the alpha(1)-antagonist prazosin. The mRNA expression of alpha(1D)-adrenoceptors was increased in BOO, whereas none of the other receptor mRNAs were up-regulated. Conclusions: In a rat BOO model, weak contraction responses to alpha(1)-agonists and relaxation responses to beta-agonists are not altered to a major extent. Nevertheless, relaxation responses to the endogenous agonist noradrenaline are turned into alpha(1)-adrenoceptor-mediated contraction responses in BOO, possibly due to an up-regulation of alpha(1D)-adrenoceptors. Neurourol. Urodynam. 28:349-355, 2009. (C) 2008 Wiley-Liss, Inc

The airways and the urinary bladder are both hollow organs serving very different functions, i.e. air flow and urine storage, respectively. While the autonomic nervous system seems to play only a minor if any role in the physiological regulation of airway tone during normal breathing, it is important in the physiological regulation of bladder smooth muscle contraction and relaxation. While both tissues share a greater expression of M-2 than of M-3 muscarinic receptors, smooth muscle contraction in both is largely mediated by the smaller M-3 population apparently involving phospholipase C activation to only a minor if any extent. While smooth muscle in both tissues can be relaxed by beta-adrenoceptor stimulation, this primarily involves beta(2)-adrenoceptors in human airways and beta(3)-adrenoceptors in human bladder. Despite activation of adenylyl cyclase by either subtype, cyclic adenosine monophosphate plays only a minor role in bladder relaxation by beta-agonists; an important but not exclusive function is known in airway relaxation. While airway beta(2)-adrenoceptors are sensitive to agonist-induced desensitization, beta(3)-adrenoceptors are generally considered to exhibit much less if any sensitivity to desensitization. Gene polymorphisms exist in the genes of both beta(2)- and beta(3)-adrenoceptors. Despite being not fully conclusive, the available data suggest some role of beta(2)-adrenoceptor polymorphisms in airway function and its treatment by receptor agonists, whereas the available data on beta(3)-adrenoceptor polymorphisms and bladder function are too limited to allow robust interpretation. We conclude that the distinct functions of airways and urinary bladder are reflected in a differential regulation by the autonomic nervous system. Studying these differences may be informative for a better understanding of each tissue

The urinary bladder stores urine for most of the day, a process facilitated by beta-adrenergic receptor-mediated detrusor relaxation and alpha(1)-adrenergic receptor-mediated contraction of the bladder neck. Physiological voiding is caused by detrusor contraction induced by muscarinic receptor stimulation. This manuscript reviews data on alterations of alpha(1)- and beta-adrenergic and of muscarinic responsiveness of the detrusor related to gender, developmental maturation, ageing and pathophysiological conditions such as diabetes, arterial hypertension and bladder outlet obstruction, all of which can be associated with alterations of bladder function such as bladder overactivity. The existing data show that none of the conditions associated with bladder overactivity exhibit increased muscarinic receptor responsiveness which could explain the clinical observations; while not being fully consistent, they if anything show a reduced responsiveness. On the other hand, more limited data demonstrate that alpha(1)-adrenergic responsiveness may be enhanced and beta-adrenergic responsiveness reduced in states associated with bladder overactivity. However, the existing data are too sparse and/or too inconsistent to allow definitive conclusions. Thus, alterations distinct from those of autonomic receptors may be better candidates to explain bladder dysfunction.

Two groups of drugs, alpha blockers and 5-alpha-reductase inhibitors (5ARI), are currently widely used for the medical treatment of benign prostatic syndrome (BPS). Alpha blockers are characterized by a rapid onset of efficacy. If given at an adequate dose, all alpha blockers have a similar efficacy, yet quantitative differences regarding side effects exist. The onset of clinical efficacy of 5ARIs is delayed and dependent on prostate volume. Symptom improvement is generally less pronounced than with alpha blockers, yet this difference declines with time. 5ARI, in contrast to alpha blockers, reduce prostate volume and the risk of long-term BPS complications such as prostate surgery or acute urinary retention. The combination therapy of alpha blockers and 5ARI is superior to either monotherapy; however, this superiority becomes evident only after prolonged (>1 year) therapy. Because of additive side effects, this combination should be reserved for BPS patients with a high risk of progression. Regarding plant extracts, no definitive recommendation can be given because of a limited number of high-quality clinical trials. The use of antimuscarinics in men with BPS with a dominance of storage symptoms and without significant obstruction is promising, although further trials, particularly with a longer study duration, are required.

Agonists and antagonists of G protein-coupled receptors are important drugs for the treatment of cardiovascular disease, but the therapeutic response of any given patient remains difficult to predict because of large interindividual variability. Among the factors potentially contributing to such variability, we have reviewed the evidence for a role of pharmacodynamic pharmacogenetics ( i.e., polymorphisms in the cognate receptors for such drugs as well as other proteins potentially modifying their action). Based upon the availability of data and the prevalence of use, we have focused on ligands at adrenergic and angiotensin II receptors ( including the indirectly acting angiotensin-converting enzyme inhibitors). The vast majority of gene polymorphisms reviewed here have shown only inconsistent effects on drug action, which does not make these polymorphisms useful genetic markers to predict treatment responses. We conclude that considerable additional research, partly involving other types of study than those available now, will be necessary to allow a definitive judgment whether pharmacodynamic pharmacogenetic markers are useful in an individualized approach to cardiovascular therapy. Moreover, we predict that even such additional research will result in only few cases where the promise of tailored treatment can be fulfilled; however, some of these few cases may be of major clinical relevance

The new version of the German guidelines for assessing benign prostatic hyperplasia (BPH) was written in 2006 and 2007 by experts of the BPH working group on behalf of the German Association of Urology and Federation of German Urologists. The full version is expected to be published in 2008. Recommendations for assessing BPH were modified and updated and include patient history, symptom questionnaires, physical examination, urine analysis, prostate-specific antigen, uroflowmetry, ultrasound examination of the urinary bladder (including postvoid residual urine), and ultrasound examination of the upper urinary tract or creatinine measurement. Optional tests are voiding diary, pressure-flow studies, ultrasound measurement of detrusor wall thickness, urethrocystography, and urethrocystoscopy. For the first time, tests for the differential diagnosis of bladder symptoms and BPH are described. Furthermore, the latest knowledge was added on disease progression, indications for urodynamic assessment, and ultrasound measurement of detrusor wall thickness for evaluating bladder outlet obstruction. International quality standards were applied in order to increase the guidelines' value; all tests were judged using the levels of evidence and grades of recommendation of the U.S. Department of Health and Human Services classification

Objective Stress urinary incontinence (SUI) occurs in men and women. Pharmacologic treatment of female SUI has been beneficiary but the role of drug treatment in male SUI is controversial. This review evaluates the drug classes, the effects of these drugs in trials with male SUI, and the levels of evidence of the individual trials. Methods A systematic literature review was conducted searching for studies on male SUI published between 1966 and 2007. In retrieved articles, reference lists were hand-searched to identify additional articles. The level of evidence was judged according to the Oxford classification. Results This search found nine articles providing evidence that α-adrenoceptor agonists (ephedrine, phenylpropanolamine, midodrine), β 2 -adrenoceptor agonists (clenbuterol), and serotonin-noradrenaline reuptake inhibitors (imipramine, duloxetine) have a potentially beneficial effect on male SUI. Most trials used only small numbers of patients and a mixed study population (men and women). The evidence level of most studies was low due to the lack of randomisation (case series or cohort studies, level 4). In contrast, the first high-level study to provide evidence in the treatment of male SUI was with duloxetine, a selective serotonin and noradrenaline reuptake inhibitor (randomised controlled study, level 1b). However, only one well-designed study has been published so far. Conclusions One high-level study with duloxetine in combination with pelvic floor muscle training shows preliminary but promising results in the treatment of male SUI. These results have to be confirmed in larger and well-designed trials to allow definite recommendations for the pharmacologic treatment of male SUI.

Objective: in light of recent interest in the use of muscarinic receptor antagonists for the treatment of male lower urinary tract symptoms, understanding how such drugs work not only on the bladder but also on the prostate is important. Methods: A literature review was conducted to identify studies on the cholinergic innervation and presence and function of muscarinic acetylcholine receptors in the human prostate. Results: The available studies demonstrate a dense cholinergic innervation within both stromal. and epithelial compartments of the prostate. Concomitantly, the human prostate expresses muscarinic receptors at densities exceeding those of alpha(1)-adrenoceptors. They mainly belong to the M-1 subtype and are found on epithelial cells, but a smaller population of M-2 receptors is found on stromal cells. Both populations have been shown to be functional in signal transduction assays. However, in line with the sparse receptor density on stromal smooth muscle cells, contractile responses of the prostate are only small. Data from prostate cancer cell lines and from botulinum toxin injections into the benign prostate raise the possibility that muscarinic receptors may promote prostatic growth. Animal data suggest that muscarinic receptors may be of primary importance in the genesis of prostatic secretions, but this needs to be confirmed in humans. Conclusions: Taken together it appears that direct effects on the prostate need to be considered when using muscarinic receptor antagonists in men. They may primarily involve alterations of glandular secretion and prostatic growth. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved

Urinary bladder function is known to mature during fetal and postnatal development, including changes in neurotransmitter regulation of detrusor contraction. However, only few experimental data are available about muscarinic receptor antagonist function in the urinary bladder from young animals. In the present study, we compare the muscarinic receptor-mediated contractions in juvenile and adult porcine detrusor and the effects of antimuscarinic compounds. Urinary bladders from young (8–12 weeks; 12- to 35-kg body weight) and mature pigs (>40 weeks; >100 kg) were compared. Muscarinic receptor expression was assessed by real time polymerase chain reaction and radioligand binding. Muscle contraction was measured with a force transducer; L-type Ca2+ currents (I Ca,L) of isolated detrusor myocytes were recorded with standard voltage clamp technique. Juvenile and adult detrusor expressed similar quantities of the messenger RNA of M2 and M3 receptors. The number of [3H]QNB-binding sites and their affinity for the radioligand were also similar between juvenile and adult detrusor. In contrast, maximum contractile responses to the muscarinic receptor agonist carbachol were slightly larger in juvenile than adult bladders. On the other hand, carbachol was slightly less potent in juvenile than in adult tissue. The M3 antagonist DAU 5884 and the spasmolytic drug propiverine inhibited contractile responses with comparable efficacies and potencies in juvenile and adult tissue. I Ca,L was somewhat smaller in juvenile than in adult cells. Taken together, these data suggest that expression and function of M2 and M3 receptors are similar in the detrusor of juvenile and mature pigs. Therefore, similar responses to antimuscarinic compounds could be expected in young and adult patients.

The sphingolipid metabolites sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) can be involved in cellular growth and apoptosis, by both receptor-dependent and -independent mechanisms. We investigated the role of S1P and SPC in intracellular Ca2+ elevation, cell proliferation and cell death in DU 145 and PC3 hormone-refractory prostate cancer cell lines. S1P and SPC increased intracellular Ca2+ levels, most likely in a receptor-independent manner. Surprisingly, both S1P and SPC did not stimulate but rather reduced cell growth through induction of apoptosis. Therefore, antagonists targeted against S1P, SPC and their receptors do not appear to be promising new approaches in the treatment of hormone-refractory prostate cancer.

The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M-3 subtype, with the M-2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by beta-adrenoceptors, in most species involving a strong beta(3)-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M-3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of beta-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to beta-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in beta-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and beta-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder

Conditions associated with hypertrophy of the urinary bladder have repeatedly been associated with an increased urinary excretion of transforming growth factor ( TGF)beta in both rats and patients. Because TGF beta can have both growth- promoting and - inhibiting effects, we have studied its effects on cell growth and death in primary cultures of rat bladder smooth muscle cells. TGF beta 1, TGF beta 2, or TGF beta 3 did not cause apoptosis, but all three isoforms inhibited DNA synthesis with similar potency (EC50 of approximately 0.1 ng/ ml) and efficacy. Such inhibition was antagonized by a specific TGF beta receptor antagonist and independent of the presence of serum. Mitogen- activated protein kinases ( MAPKs) are involved in the control of cell growth, and all three TGF beta isoforms inhibited activation of the extracellular signal- regulated kinase, c- Jun NH 2- terminal kinase, and p38 MAPK subfamilies. Nevertheless, the inhibitory effects of the TGF beta isoforms on DNA synthesis were not affected by presence of inhibitors of the three MAPK pathways. TGF beta did not alter cell size as measured by flow cytometry or mitochondrial activity, an integrated measure of cell size and number. We conclude that our data do not support the hypothesis that TGF beta is a mediator of rat bladder hypertrophy.

Agonist exposure can cause internalisation of G-protein coupled receptors (GPCRs), which may be a part of desensitisation but also of cellular signaling. Previous methods to study internalisation have been tedious or only poorly quantitative. Therefore, we have developed and validated a quantitative method using a sphingosine-1-phosphate (S1P) receptor as a model. Because of a lack of suitable binding studies, it has been difficult to study S1P receptor internalisation. Using a N-terminal HisG-tag, S1P(1) receptors on the cell membrane can be visualised via immunocytochemistry with a specific anti-HisG antibody. S1P-induced internalisation was concentration dependent and was quantified using a microplate reader, detecting either absorbance, a fluorescent or luminescent signal, depending on the antibodies used. Among those, the fluorescence detection method was the most convenient to use. The relative ease of this method makes it suitable to measure a large number of data points, e.g. to compare the potency and efficacy of receptor ligands.

UNLABELLED The sphingomyelin metabolites ceramide, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) are emerging modulators of vascular tone. While ceramide appears to act primarily intracellularly, S1P and SPC appear to mainly work via specific receptors, although those for SPC have not yet been defined unequivocally. Each of the sphingomyelin metabolites can induce both vasoconstriction and vasodilatation and, in some cases--ceramide on the one hand, and S1P and SPC on the other hand--have opposite effects on vascular tone. The differences in effects between vessels may relate to the relative roles of endothelial and smooth muscle cells in mediating them, as well as to the distinct expression patterns of S1P receptors among vascular beds and among endothelial and smooth muscle cells. Recent evidence suggests that vascular tone is not only modulated by sphingomyelin metabolites which are exogenously added or reach the vessel wall via the bloodstream but also by those formed locally by cells in the vessel wall. Such local formation can be induced by known vasoactive agents such as angiotensin II and may serve a signalling function. CONCLUSION We conclude that sphingomyelin metabolites are important endogenous modulators of vascular function, which may contribute to the pathophysiology of some diseases and be targets for therapeutic interventions.

Muscarinic acetylcholine receptors, particularly M 3 receptors, are physiologically the most important mechanism to induced urinary bladder smooth muscle contraction. Their prototypical signaling response is a stimulation of phospholipase C (PLC), and this also has been shown in the urinary bladder. Nevertheless, it has remained controversial whether PLC signaling mediates bladder contraction induced by muscarinic receptor agonists. Studies in favor and against a role for PLC differed in their experimental protocol (single versus repeated concentration-response curves within a single preparation) and in the PLC inhibitors that have been used. We have now tested whether previous differential conclusions regarding a role for PLC are related to inhibitors and/or experimental protocols. In a single curve protocol, U-73,122 [1-[6-[((17β)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1 H -pyrrole-2,5-dione] did not attenuate carbachol responses. In a repeated curve protocol, ET-18-OCH 3 (1- O -octadecyl-2- O -methyl- sn -glycero-3-phosphorylcholine) lacked significant inhibition relative to vehicle time controls. In contrast, D609 ( O -tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt) depressed maximal carbachol effects but also nonspecifically inhibited contraction induced by KCl. Neomycin did not affect the carbachol-induced rat urinary bladder contraction. We conclude that previously reported differences relate to the use of inhibitors rather than experimental protocols and that the overall data do not support a role for PLC in M 3 muscarinic receptor-mediated rat bladder contraction.

Having observed a large variation in the number and type of original preclinical publications for newly registered drugs, we have explored whether longitudinal trends and/or factors specific for certain drugs or their manufacturers may explain such variation. Our analysis is based on 1954 articles related to 170 newly approved drugs. The number of preclinical publications per compound declined from a median of 10.5 in 1991 to 3 in 2011. A similar trend was observed for the number of in vivo studies in general, but not in the subset of in vivo studies in animal models of disease. The percentage of compounds with studies using isolated human cells or cell lines almost doubled over time from 37 to 72%. Number of publications did not exhibit major differences between compounds intended for human versus veterinary use, therapeutic areas, small molecules versus biologicals, or innovator versus follow-up compounds; however, some companies may publish fewer studies per compound than others. However, there were qualitative differences in the types of models being used depending on the therapeutic area; specifically, compounds for use in oncology very often used isolated cells and cell lines, often from human origin. We conclude that the large variation in number and type of reported preclinical data is not easily explained. We propose that pharmaceutical companies should consistently provide a comprehensive documentation of the preclinical data they generate as part of their development programs in the public domain to enable a better understanding of the drugs they intend to market.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is frequently used as loading control in immunoblot experiments (Hsu et al. 2014; Oldenburger et al. 2014; Wang et al. 2014). We have recently reported a study on the homologous desensitization of human β3-adrenoceptors stably expressed in human embryonic kidney cells (Michel-Reher and Michel 2013). As part of that study, we have used immunoblots to determine the effect of treatment with the β-adrenoceptor agonist isoprenaline (10 μM for 24 h) on the abundance of several G-proteinα-subunits at the protein level. After analysis of these G-proteins, the blots were stripped and reprobed with a GAPDH antibody (mouse monoclonal IgG, Bioconnect MAB-374, 1:2,000,000). GAPDH immunoreactivity was quantified using a secondary antibody (Lumilight plus kit, Roche Applied Science) by an LAS3000 (Fujifilm, Dusseldorf, Germany) using AIDA software (version 3.52, Raytest, Straubenhardt, Germany). Data were obtained from ten blots, each with four pairs of samples from isoprenalineand vehicle-treated cells, resulting in 40 pairs of GAPDH quantification with and without isoprenaline treatment. During our initial analysis of the G-protein data, we noted that expression of the data relative to GADPH abundance tended to increase variance. As recently discussed (Motulsky 2014), normalization should only been performed for good reasons. As normalization for GADPH abundance did not improve the variance of G-protein expression, we had decided to report the non-normalized data (Michel-Reher and Michel 2013). We have now analyzed GADPH data from that study to explore whether isoprenaline treatment may have altered its expression at the protein level. This indicated a 32 % lower expression of GADPH protein in isoprenaline—as compared to vehicle-treated cells (173 vs. 254 arbitrary units; mean difference 80 (95 % confidence interval=35–127, t=3.541, df= 39, p

Bladder dysfunction is common in the general population (Stewart et al. 2010) and even more so among patients seeing a physician for any reason (Goepel et al. 2002). It often manifests as lower urinary tract symptoms (LUTS), a term originally coined to describe voiding and storage symptoms in men with benign prostatic hyperplasia (BPH) but now more universally used to describe any type of voiding and storage symptoms in both sexes. Studies into possible causes of urinary bladder dysfunction have long focused on detrusor smooth muscle cells (Turner and Brading 1999). More recently, it became clear that several other types of cells and organs contribute to regulating detrusor smooth muscle function. These include the urothelium (Andersson and McCloskey 2014; Michel 2015), afferent nerves (Michel and Igawa 2015; Yoshimura et al. 2014b), and the central and autonomic nervous systems (Fowler and Griffiths 2010; Yoshimura et al. 2014a). Alterations in any of these may at least partly be responsible for detrusor dysfunction and, accordingly, be potential targets for the treatment of bladder dysfunction. As highlighted by an article in this issue of Naunyn-Schmiedeberg’s Archives of Pharmacology (Bayrak et al. 2015), there is an additional suspect, the bladder vasculature. This article will discuss the currently available experimental and clinical evidence for a role of the vasculature in causing bladder dysfunction, and how existing and emerging treatments may modulate bladder function by acting on blood vessels. Due to a similarity in concept, data on prostate perfusion will also be discussed to some extent.

We have compared the ability of three radioligands, [(125)I]-cyanopindolol, [(3)H]-CGP 12,177 and [(3)H]-dihydroalprenolol, to label the three human beta-adrenoceptor subtypes. Saturation and competition binding experiments were performed using membrane preparations from Chinese hamster ovary cells stably transfected with the three subtypes. While [(3)H]-CGP 12,177 had very similar affinity for beta(1)- and beta(2)-adrenoceptors (about 40 pM), [(125)I]-cyanopindolol and [(3)H]-dihydroalprenolol had 4- to 6-fold higher affinity for beta(2)- as compared to beta(1)-adrenoceptors (10 vs 45 and 187 vs 1,021 pM, respectively). The affinity of [(125)I]-cyanopindolol at beta(3)-adrenoceptors was considerably lower (440 pM) than at the other two subtypes. The beta(3)-adrenoceptor affinity of [(3)H]-CGP 12,177 and [(3)H]-dihydroalprenolol was so low that it could not be estimated within the tested range of radioligand concentrations (up to 4,000 pM and 30,000 pM for [(3)H]-CGP 12,177 and [(3)H]-dihydroalprenolol, respectively). We conclude that all three radioligands are ill-suited to label beta(3)-adrenoceptors, particularly in preparations co-expressing multiple subtypes. In the absence of alternatives, [(125)I]-cyanopindolol appears the least unsuitable to label beta(3)-adrenoceptors. There is a need for high-affinity radioligands which are either selective for beta(3)-adrenoceptors or reasonably non-selective among all three beta-adrenoceptor subtypes.

Background and purpose: The thiazolidine carboxylic acid, BML-241, has been proposed as a lead compound in development of selective antagonists at the sphingosine-1-phosphate receptor (S1P3), based on its inhibition of the rise in intracellular calcium concentrations ([Ca2+]i) in HeLa cells overexpressing S1P receptors. We have studied the antagonistic properties of BML-241 for the S1P3 receptor in more detail. Experimental approach: Chinese hamster ovary (CHO) cells stably transfected with the S1P3, S1P2 or α1A-adrenoceptors were used to investigate the effect of BML-241 on increases in [Ca2+]i mediated via different receptors. CHO-K1 cells were used to study ATP-induced [Ca2+]i elevations. Effects on S1P3-mediated inhibition of forskolin-induced cAMP accumulation and on binding to α1A-adrenoceptors were also investigated. In addition, the effect of BML-241 on contractions of rat mesenteric artery induced by phenylephrine was studied in an organ bath. Key results: High concentrations of BML-241 (10 μM) inhibited the rise in [Ca2+]i induced by S1P3 and S1P2 receptor stimulation; lower concentrations were ineffective. This high concentration of BML-241 also inhibited [Ca2+]i increases via P2 (nucleotide) receptor or α1A-adrenoceptor stimulation. Moreover, BML-241 (10 μM) inhibited α1-adrenoceptor-mediated contraction of rat mesenteric artery but did not displace [3H]-prazosin from α1A-adrenoceptors in concentrations up to 100 μM. BML-241 (10 μM) did not affect the S1P3-mediated decrease of forskolin-induced cAMP accumulation. Conclusions and Implications: We conclude that BML-241 is a low potency, non-selective inhibitor of increases in [Ca2+]i, rather than a specific antagonist at the S1P3 receptor. British Journal of Pharmacology (2006) 149, 277–282. doi:10.1038/sj.bjp.0706872

Background The temporal relations between the onset of echocardiographic changes and clinical diagnosis of right ventricular (RV) failure are unresolved. We have characterized such relations in a rat monocrotaline (MCT) model of RV failure. Methods Eight-week-old male Wistar rats were injected with MCT (60 mg/kg) or vehicle and underwent serial echocardiography. RV free-wall thickness (RVWT), pulmonary artery acceleration time normalized to cycle length (PAAT/CL), RV end-diastolic diameter (RVEDD), and tricuspid annular plane systolic excursion (TAPSE) were measured. Results Significant differences in echocardiographic parameters between MCT-treated and control rats were found as early as 14 days before RV failure for RVWT, 10 days for PAAT/CL, and 7 days for RVEDD and TAPSE. The time intervals between the onset of changes in RVWT, PAAT/CL, RVEDD, and TAPSE and diagnosis of RV failure were 11.3 ± 0.8, 10.9 ± 0.7, 6.5 ± 0.5, and 5.4 ± 0.7 days, respectively. The sequence of echocardiographic changes was consistent in all animals during development of RV failure. Conclusions Pulmonary hypertension (assessed by PAAT/CL) and RV free-wall thickening (characterized by RVWT) precede RV dilation and RV systolic dysfunction (measured by RVEDD and TAPSE, respectively). Echocardiographic analysis permits accurate determination of the stage of disease development in MCT-induced RV failure.

Tamsulosin is an α1-adrenergic receptor antagonist. For many years, it has been available in a modified-release (MR) capsule formulation only, but recently, an oral-controlled absorption system (OCAS) tablet formulation has been introduced. Tamsulosin is an effective treatment for patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia for many years. The overall tolerability of tamsulosin 0.4 mg MR is comparable to placebo and is not affected by cardiovascular comorbidity or concomitant medication. The tamsulosin 0.4 mg OCAS tablet has a smoothened pharmacokinetic profile compared with the 0.4 mg MR capsule. While the efficacy of tamsulosin OCAS and tamsulosin MR are comparable, the OCAS formulation appears to have minor advantages regarding tolerability, which may become clinically relevant if the MR capsule is taken on an empty stomach.

1 We have systematically reviewed the presence, functional responses and regulation of alpha(1)-, alpha(2)- and beta-adrenoceptors in the bladder, urethra and prostate, with special emphasis on human tissues and receptor subtypes. 2 Alpha(1)-adrenoceptors are only poorly expressed and play a limited functional role in the detrusor. Alpha(1)-adrenoceptors, particularly their alpha(1A)-subtype, show a more pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, particularly in elderly men with enlarged prostates. Alpha(1)-adrenoceptor agonists are important in the treatment of symptoms of benign prostatic hyperplasia, but their beneficial effects may involve receptors within and outside the prostate. 3 Alpha(2)-adrenoceptors, mainly their alpha(2A)-subtype, are expressed in bladder, urethra and prostate. They mediate pre-junctional inhibition of neurotransmitter release and also a weak contractile effect in the urethra of some species, but not humans. Their overall post-junctional function in the lower urinary tract remains largely unclear. 4 Beta-adrenoceptors mediate relaxation of smooth muscle in the bladder, urethra and prostate. The available tools have limited the unequivocal identification of receptor subtypes at the protein and functional levels, but it appears that the beta(3)- and beta(2)-subtypes are important in the human bladder and urethra, respectively. Beta(3)-adrenoceptor agonists are promising drug candidates for the treatment of the overactive bladder. 5 We propose that the overall function of adrenoceptors in the lower urinary tract is to promote urinary continence. Further elucidation of the functional roles of their subtypes will help a better understanding of voiding dysfunction and its treatment.