endothelin-1 and Prostatic-Hyperplasia

Benign prostatic hyperplasia (BPH) is a common disease in older men that can lead to lower urinary tract symptoms (LUTS). Male sexual dysfunction is also an age-related condition. Epidemiological studies have confirmed an association between BPH/LUTS and sexual dysfunction in ageing men that is independent of the effects of age, other co-morbidities and lifestyle factors. Proposed pathophysiological mechanisms for BPH/LUTS-associated sexual dysfunction include the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway, rho-kinase and endothelin-1 activity, autonomic nervous system overactivity and the metabolic syndrome, and pelvic organ atherosclerosis. Both BPH/LUTS and sexual dysfunction can have a substantial negative impact on a man's quality of life. However, urologists and primary care physicians appear to under-recognise sexual dysfunction in men with BPH/LUTS. Current guidelines recommend alpha-blockers and 5-alpha reductase inhibitors, either alone or in combination, among appropriate medical treatment options for BPH/LUTS. Randomised, controlled trials demonstrate that these therapies can be associated with sexual adverse effects (AEs) such as loss of libido, erectile dysfunction and ejaculatory disorders. Sexual dysfunction should be fully evaluated in men requiring treatment for BPH/LUTS using validated questionnaires. Management of sexual dysfunction in men treated for BPH/LUTS should involve assessment of co-morbidities and concomitant medications, consideration of lifestyle interventions such as weight loss and increased physical activity to improve risk factors and, if necessary, introduction of pharmacotherapies. In addition, physicians should provide patients with proper counselling on the possible sexual AEs of medical therapies for BPH/LUTS and their impact on sexual satisfaction, while being aware of the possibility that counselling in itself is likely to influence reported rates of sexual dysfunction.

Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Adult; Aged; Atherosclerosis; Autonomic Nervous System Diseases; Cyclic GMP; Drug Combinations; Endothelin-1; Humans; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide; Prostatic Hyperplasia; Prostatism; rho-Associated Kinases; Sexual Dysfunction, Physiological

alpha-Agonists and endothelins (ETs) are the only agents that have been proved to induce significant contraction of the prostate. Although the response to phenylephrine (PE) is dependent on the quality of smooth muscle (SM) within the prostate, it is not clear whether the response to ET-1 is also influenced by SM density. We evaluate the relationship between contractile responsiveness to ET-1 and the area density of SM of the human prostate.. Specimens were obtained from 17 patients with prostatic hyperplasia that underwent transurethral resection of the prostate. Specimens were used for isometric tension study (PE, KCl and ET) and also for quantitative morphometric analysis.. PE and ET-1 induced dose-dependent contractile responses. There were no significant differences in the average maximum response (E(max)) to these two agents. E(max) to KCl and PE showed direct positive correlations with the area density of SM. E(max) to ET-1 also showed a positive correlation with the SM density, although this relationship was weaker than those for the other two agents. Moreover, there was a strong positive relationship between E(max) to PE, KCl and that to ET-1.. The area density of SM appeared to significantly influence the contractile response to ET-1 as well as the response to PE and KCl.

Topics: Aged; Cells, Cultured; Dose-Response Relationship, Drug; Endothelin-1; Humans; In Vitro Techniques; Isometric Contraction; Male; Middle Aged; Muscle, Smooth; Phenylephrine; Potassium Chloride; Probability; Prostate; Prostatic Hyperplasia; Sensitivity and Specificity; Transurethral Resection of Prostate

Recently, the European Association of Urology recommended hexane-extracted fruit of Serenoa repens (HESr) in their guidelines on management of non-neurogenic male lower urinary tracts symptoms (LUTS). Despite previously lacking recommendations, Permixon® is the most investigated HESr in clinical trials, where it proved effective for male LUTS. In contrast, underlying mechanisms were rarely addressed and are only marginally understood. We therefore investigated effects of Permixon® on human prostate and detrusor smooth muscle contraction and on growth-related functions in prostate stromal cells.. Permixon® capsules were dissolved using n-hexane. Contractions of human prostate and detrusor tissues were induced in organ bath. Proliferation (EdU assay), growth (colony formation), apoptosis and cell death (flow cytometry), viability (CCK-8) and actin organization (phalloidin staining) were studied in cultured human prostate stromal cells (WPMY-1).. Permixon® inhibited α. Our results provide a novel basis that allows, for the first time, to fully explain the ubiquitous beneficial effects of HESr in clinical trials. HESr may inhibit at least neurogenic, α

Topics: Actins; Adrenergic Agents; Endothelin-1; Hexanes; Humans; Male; Methacholine Chloride; Muscle Contraction; Muscle, Smooth; Phalloidine; Plant Extracts; Prostate; Prostatic Hyperplasia; Serenoa; Sincalide; Stromal Cells; Thromboxanes; Urinary Bladder

Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients' adherence is particularly low to combination therapies of 5α-reductase inhibitors and α1-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1-10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.

Topics: Adrenergic alpha-1 Receptor Antagonists; Cell Proliferation; Disulfides; Electric Stimulation; Endothelin-1; Humans; Male; Muscle Contraction; Muscle, Smooth; Naphthols; Norepinephrine; p21-Activated Kinases; Phenylephrine; Phosphorylation; Prostate; Prostatic Hyperplasia; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Receptors, Adrenergic, alpha-1; Signal Transduction; Stromal Cells

To investigate the expressions of VEGF in prostate cancer (PCa) and benign prostatic hyperplasia (BPH), their clinical significance and their relationship with that of ET-1.. A total of 44 specimens of PCa and 36 of BPH tissues were examined by the immunohistochemical Elivision plus method for the expressions of VEGF and ET-1. The intensity of staining for VEGF and ET-1 was assessed by light microscopy on a scale from "-" to "+ + +".. The rates of positive expression of VEGF were 69.4% in BPH and 80.9% in PCa, positive staining mostly in the cytoplasm of glandular epithelia and cancer cells, and strongly positive in all the stroma vascular endothelial cells. The staining intensity of VEGF was significantly higher in the PCa than in the BPH group (P < 0.05) , in the bone metastasis (BM) than in the non-BM group (P < 0.01), and in the lowly than in the highly and moderately differentiated PCa tissues (P < 0.01). The expression of VEGF was positively correlated with that of ET-1 ( r(s) = 0.780, P < 0.01).. VEGF is involved in the development, progression and metastasis of PCa. VEGF and ET-1 may play a joint role in its development and progression.

Topics: Aged; Aged, 80 and over; Endothelin-1; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prostatic Hyperplasia; Prostatic Neoplasms; Vascular Endothelial Growth Factor Receptor-1

Topics: Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelin-1; Humans; Isometric Contraction; Male; Muscle Tonus; Muscle, Smooth; Nitric Oxide Donors; Organ Culture Techniques; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Prostate; Prostatic Hyperplasia

To investigate the different expressions of endothelin-1 ET-1) in prostate cancer (PCa) and benign prostatic hyperplasia (BPH) tissues and their clinical significance.. A total of 36 BPH and 44 PCa specimens were examined for the expression of ET-1 by immunohistochemical technique (Elivision plus method). The staining intensity for ET-1 was assessed by light microscopy on a scale from "-" to "+ + +".. Positive immunoreactivity was found in BPH and PCa, with a positive rate of 100%. Positive staining was located mostly in the cytoplasm of glandular epithelia and smooth muscle cells of both BPH and PCa and was noted in all stroma vascular endothelial cells. These were no significant differences in the intensity of positive staining for ET-1 between the groups of BPH and PCa (P > 0.05), bone metastasis (BM) and non-BM (P > 0.05), and highly and moderately differentiated PCa (P > 0.05), but the staining intensity for ET-1 was significantly higher in the poorly than in the highly and moderately differentiated PCa (P < 0.01).. ET-1 has a high expression and the localization is the same in both BPH and PCa. It is involved in the development and progression of BPH and PCa.

Topics: Aged; Aged, 80 and over; Endothelin-1; Humans; Immunohistochemistry; Lymphatic Metastasis; Male; Middle Aged; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms

To investigate plasma endothelin-1 (ET-1) level in patients with prostate cancers and its clinical significance.. Plasma ET-1 level was measured by radioimmunoassay in 31 patients of prostate cancer (23 with non-HRPC, 8 with HRPC) and 26 patients of BPH.. Compared with each other of the ET-1 level, there were no significant difference among the BPH group,non-HRPC group and HRPC group. No significant difference was found either between bone metastasis (BM) and non- BM, between high and middling differentiation prostate cancer group, as well as in different PSA level groups (P >0.05). But the ET-1 level in low differentiation prostate cancer was notably lower than those of the high and middle respectively (P < 0.05).. To detect plasma endothelin-1 (ET-1) level is not a useful method to evaluate the development and the prognosis of prostate cancer.

Topics: Aged; Aged, 80 and over; Endothelin-1; Humans; Male; Prognosis; Prostatic Hyperplasia; Prostatic Neoplasms; Radioimmunoassay

Prostate growth seems to be influenced by paracrine factors like endothelin-1 (ET-1), originating from the microvascular endothelium. Recently, we reported on the first isolation and primary culture of microvascular endothelial cells (HPEC) derived from tissue of human benign prostatic hyperplasia (BPH). Therefore, direct investigation of growth factor secretion by HPEC is now possible. BPH tissue was cut into small cubes and gently squeezed after incubation with dispase. HPEC were cultured from the resulting cell suspension after a stepwise selection by use of superparamagnetic beads coated with antibodies against endothelial specific antigens. HPEC were characterized by flow cytometry. After the incubation of HPEC either with vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-alpha), or adenosine triphosphate (ATP), the secretion of ET-1 was measured by ELISA. HPEC showed a typical endothelial morphology. They were positive for von Willebrand factor and CD31. The ET-1 secretion of HPEC was inhibited by VEGF, but was unaffected by TNF-alpha or ATP. Furthermore, histochemistry revealed that in vivo microvascular endothelial cells were negative for ET-1. Because of the suppression by the widespread VEGF, it is unlikely that ET-1 from the microvascular endothelium acts as a growth factor in human BPH.

Topics: Adenosine Triphosphate; Aged; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Growth Substances; Humans; Immunohistochemistry; Male; Microcirculation; Microscopy, Electron, Scanning; Microscopy, Fluorescence; Middle Aged; Platelet Endothelial Cell Adhesion Molecule-1; Prostatic Hyperplasia; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Bladder outlet obstruction (BOO) is associated with altered bladder structure and function. Endothelin-1 (ET-1) has mitogenic and potent contractile properties. There are two ET receptors: ET(A) and ET(B). Nitric oxide synthase (NOS) is the enzyme responsible for the synthesis of nitric oxide (NO) which is involved in smooth muscle relaxation. We investigated whether there are any changes in the density of ET-receptors and NOS in the detrusor and bladder neck in a rabbit model of BOO. Partial BOO was induced in adult male New Zealand White rabbits. Sham operated age-matched rabbits acted as controls. After six weeks the urinary bladders were excised and detrusor and bladder neck sections incubated with radioligands for ET-1, ET(A) and ET(B) receptors and with [3H]-1-NOARG (a ligand for NOS). NADPH histochemistry was also performed. BOO bladder weights were significantly increased (P = 0.002). ET-1 binding and ETA receptor binding sites were significantly increased in the BOO detrusor smooth muscle (P = 0.04, P = 0.03 respectively) and urothelium (P = 0.002, P = 0.02 respectively). ET(B) receptor binding sites were also significantly increased in the BOO detrusor smooth muscle (P = 0.04). However, there was no change in the BOO bladder neck. NOS was significantly decreased in the detrusor smooth muscle (P = 0.003) and urothelium (P = 0.0002). In the bladder neck NOS was also significantly reduced in the urothelium (P = 0.003). NADPH staining was decreased in the detrusor and bladder neck. The up-regulation of ET receptors along with the down-regulation of NOS in the detrusor may contribute to the symptoms associated with BOO. Since ET-1 has a mitogenic role, especially via its ETA receptors, the increase in ETA receptors may also be involved in detrusor hyperplasia and hypertrophy in BOO. ET antagonists may therefore have a role in the treatment of patients with BOO.

Topics: Animals; Autoradiography; Binding Sites; Disease Models, Animal; Down-Regulation; Endothelin-1; Humans; Hyperplasia; Hypertrophy; Male; Muscle, Smooth; NADPH Dehydrogenase; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroarginine; Prostatic Hyperplasia; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Up-Regulation; Urinary Bladder Neck Obstruction

Endothelin-1 (ET-1) interacts with specific G-protein-coupled receptors to initiate short-term (contraction) and long-term (mitogenesis) events in target cells. ET-1 is an abundant prostate secretory protein that, in its biologically active form, elicits prostatic smooth muscle contraction. The present study was designed to determine the effects of ET-1 on prostate cell growth and to examine the regulation of endogenous ET-1 activity and bioavailability.. Primary cultures of prostate secretory epithelial (PE) and prostate fibromuscular stromal (PS) cells were established from benign human prostate tissue.. In culture, PE cells secrete immunoreactive ET-1 (38.5 +/- 1.6 pg/ml/10(6) cells/24 hr) into the conditioned medium. Levels of immunoreactive ET-1 produced by PS cells were more than 10-fold lower. Endothelin-converting enzyme-1 (ECE-1) mRNA was detected in PE cells and not in PS cells; however, big ET-1 was the predominant immunoreactive ET-1 secretory product of PE cells. The ET(B) endothelin receptor was the predominant subtype in both PE and PS cells. In PS cells, but not PE cells, ET-1 induced significant inositol phosphate accumulation and [3H]-thymidine uptake. Agonist activity was inhibited by the ET(B) receptor selective antagonist, BQ 788. Intact PE cell monolayers secrete ET-1 through the apical surface, consistent with secretion of ET-1 into the glandular lumen in vivo.. On the basis of these findings, regulation of ET-1 activity and bioavailability appears to be tightly regulated. Such findings have important implications in the pathophysiology of prostate disease.

Topics: Apoptosis; Aspartic Acid Endopeptidases; Biological Availability; Endothelin-1; Endothelin-3; Endothelin-Converting Enzymes; Humans; Male; Metalloendopeptidases; Prostate; Prostatic Hyperplasia; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Tumor Cells, Cultured

Endothelin receptors were characterized in rat prostate and potential modification of these receptors was investigated in prostatic hypertrophy induced by testosterone. Both ET(A) and ET(B) endothelin receptor mRNA were detected in rat prostate, whereas binding experiments show the presence of only ET(A) receptors. Testosterone administration produced a 75% increase in prostate weight. Although the density of prostatic endothelin receptors was decreased from 348 +/- 75.0 fmol/mg protein in control rats to 252 +/- 39.9 fmol/mg protein in testosterone-treated animals, the total amount of receptors per prostate was unchanged. The steady-state level of ET(A)- and ET(B)-receptor mRNA was not altered by testosterone treatment. These results suggest that endothelin receptors are not affected in prostatic hypertrophy induced by testosterone.

Topics: Animals; Binding, Competitive; Carcinogens; Endothelin-1; Endothelins; Gene Expression; Iodine Radioisotopes; Male; Organ Size; Peptide Fragments; Peptides, Cyclic; Prostate; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Testosterone

Endothelins (ETs) are 21-amino acid peptides that bind to membrane receptors to initiate pathophysiological effects. This report characterizes ET receptors in benign prostatic hyperplasia-1 (BPH-1) cells, a prostate cell line isolated from a specimen of a 60-yr-old man with benign prostatic hyperplasia. [(125)I]ET-1 or -3 binding was of high affinity, with B(max) and K(d) values of 48 fmol/1 x 10(6) cells and 0.16 nM for ET-1, and 2.9 fmol/1 x 10(6) cells and 0.033 nM for ET-3, respectively. ET-1, ET-3, FR139317, Ro 46-2005, and IRL1620 inhibited [(125)I]ET-1 binding to these cells with IC50 values of 0.22, 186, 0.20, 52.8, and 772.3 nM, respectively. Reverse transcription-polymerase chain reaction confirmed that BPH-1 cells expressed more ET(A) than ET(B) receptors. ET-1 did not have any effect on arachidonic acid release, but caused a modest stimulation of phosphatidylinositol hydrolysis, and induced a prominent, sustained elevation in intracellular Ca2+ concentrations. The functional effects of ET-1 were completely inhibited by the ET(A)-selective antagonists FR139317 and A-127722, suggesting that the effects were mediated by the ET(A) receptor. These results suggest that ET may play functional roles in benign prostatic hyperplasia.

Topics: Arachidonic Acid; Calcium; Endothelin-1; Humans; Hydrolysis; Male; Middle Aged; Phosphatidylinositols; Polymerase Chain Reaction; Prostatic Hyperplasia; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Tumor Cells, Cultured

1. The contractile activity, binding activity and localization of endothelin (ET)-1 were evaluated in human nonhyperplastic (control) and hyperplastic prostates. 2. ET-1 caused contraction of both prostates in a dose-dependent manner. However, this contraction was markedly decreased in hyperplastic prostates. 3. Bmax and Kd values of hyperplastic prostates were greater than those of the control. 4. The muscle and proliferative epithelium of hyperplastic prostates showed strong staining for the anti-ET-1 antibody. However, the glandular epithelium of control prostates was weakly stained. 5. These findings indicate that responsiveness to ET-1 is decreased, though the ET-1 and ET-1 receptors increase in the hyperplastic prostate. Namely, the increase in ET-1 receptors is not effective in regulating the contractile response of the prostate, because its expression is rather dominant in proliferated gland. 6. These suggest that ET-1 may not have an important role in the release of the obstructive symptoms of benign prostatic hypertrophy.

Topics: Aged; Dose-Response Relationship, Drug; Endothelin-1; Humans; In Vitro Techniques; Male; Middle Aged; Muscle Contraction; Phenylephrine; Prostate; Prostatic Hyperplasia