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As standard therapy for prostate cancer, radical prostatectomy causes cavernous nerve (CN) injury and increases fibrosis and hypoxia-induced penile structural alterations. This study aimed to determine the potential beneficial effects of adipose-derived stem cells (ADSCs) and l-arginine alone or in combination on the penile erection in a rat model of erectile dysfunction caused by bilateral cavernous nerve transection (CNT). Male rats (n = 35) were randomized into five groups: Sham-operated; CNT (4-weeks); CNT plus ADSCs (1 × 106 cells by intracavernosal injection); CNT plus l-arginine (4 weeks, 10 mg/kg/day, oral); and ADSCs combined with l-arginine in CNT. In vivo erectile responses and in vitro relaxant responses were measured. Western blot and immunohistochemistry analyses were used to determine the expression and localization of endothelial nitric oxide synthase, neuronal nitric oxide synthase, transforming growth factor-beta 1, hypoxia-inducible factor-1 alpha (HIF-1α), and apoptosis markers (Bax and Bcl-2). The ratio of smooth muscle to collagen and nerve regeneration were calculated using Masson's trichrome and nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining. The combined treatment restored diminished erectile responses, endothelium-dependent acetylcholine, and electrical field stimulation-induced relaxation of the corpus cavernosum in rats with CNT, whereas either monotherapy produced only partial improvements. All treatment regimens restored increases in the protein expression of HIF-1 and Bax in rats with CNT. The decrease in smooth muscle mass and NADPH-diaphorase-positive nerve fibers was partially ameliorated by monotherapy, whereas combined therapy led to recovery. These findings indicate that combined treatment with ADSCs and l-arginine may restore erectile function in rats with CNT by inhibiting hypoxia-induced neurotoxicity and preserving endothelium function and smooth muscle content.
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Disfunção Erétil , Humanos , Ratos , Masculino , Animais , Ratos Sprague-Dawley , NADP , Proteína X Associada a bcl-2 , Disfunção Erétil/etiologia , Disfunção Erétil/terapia , Pênis , Prostatectomia/efeitos adversos , Células-Tronco , Hipóxia , Modelos Animais de DoençasRESUMO
ABSTRACT Purpose: This study aimed to assess the possible healing effect of combination treatment with a hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS) plus tadalafil on partial bladder outlet obstruction (PBOO)-induced bladder dysfunction. Materials and Methods: A total of 75 male Sprague-Dawley rats aged 10-wk and 300-350g were divided into five groups; control; PBOO; PBOO+NaHS (5.6mg/kg/day, i.p., 6-wk); PBOO+tadalafil (2mg/kg/day, oral, 6-wk) and PBOO+NaHS+tadalafil. PBOO was created by partial urethral ligation. 6 weeks after obstruction, the in vitro contractile responses of the detrusor muscle and Western blotting, H2S and malondialdehyde assay were performed in bladder tissues. Results: There was an increase in bladder weight(p<0.001) and a decrease in contractile responses to KCl (p<0.001), carbachol (p<0.01), electrical field stimulation (p<0.05) and ATP (p<0.001) in the detrusor smooth muscle of obstructed rats which was normalized after the combination treatment. Cystathionine γ-lyase and cystathionine β-synthase, and nuclear factor kappa B protein levels did not significantly differ among groups. The obstruction induced decrement in 3-mercaptopyruvate sulfur transferase protein expression(p<0.001) and H2S levels(p<0.01) as well as increment in protein expressions of neuronal nitric oxide synthase (NO, p<0.001), endothelial NOS (p<0.05), inducible NOS(p<0.001), hypoxia-inducible factor 1-alpha (p<0.01), and malondialdehyde levels (p<0.01), when combined treatment entirely normalized. Conclusions: Combination therapy has beneficial effects on bladder dysfunction via regulating both H2S and nitric oxide pathways as well as downregulation of oxidative stress and hypoxia. The synergistic effect of H2S and nitric oxide is likely to modulate bladder function, which supports the combined therapy for enhancing clinical outcomes in men with BPH/LUTS.
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PURPOSE: This study aimed to assess the possible healing effect of combination treatment with a hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS) plus tadalafil on partial bladder outlet obstruction (PBOO)-induced bladder dysfunction. MATERIALS AND METHODS: A total of 75 male Sprague-Dawley rats aged 10-wk and 300-350g were divided into five groups; control; PBOO; PBOO+NaHS (5.6mg/kg/day, i.p., 6-wk); PBOO+tadalafil (2mg/kg/day, oral, 6-wk) and PBOO+NaHS+tadalafil. PBOO was created by partial urethral ligation. 6 weeks after obstruction, the in vitro contractile responses of the detrusor muscle and Western blotting, H2S and malondialdehyde assay were performed in bladder tissues. RESULTS: There was an increase in bladder weight(p<0.001) and a decrease in contractile responses to KCL(p<0.001), carbachol(p<0.01), electrical field stimulation(p<0.05) and ATP (p<0.001) in the detrusor smooth muscle of obstructed rats which was normalized after the combination treatment. Cystathionine γ-lyase and cystathionine ß-synthase, and nuclear factor kappa B protein levels did not significantly differ among groups. The obstruction induced decrement in 3-mercaptopyruvate sulfur transferase protein expression(p<0.001) and H2S levels(p<0.01) as well as increment in protein expressions of neuronal nitric oxide synthase (NO, p<0.001), endothelial NOS (p<0.05), inducible NOS(p<0.001), hypoxia-inducible factor 1-alpha (p<0.01), and malondialdehyde levels (p<0.01), when combined treatment entirely normalized. CONCLUSIONS: Combination therapy has beneficial effects on bladder dysfunction via regulating both H2S and nitric oxide pathways as well as downregulation of oxidative stress and hypoxia. The synergistic effect of H2S and nitric oxide is likely to modulate bladder function, which supports the combined therapy for enhancing clinical outcomes in men with BPH/LUTS.
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Sulfeto de Hidrogênio , Obstrução do Colo da Bexiga Urinária , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/uso terapêutico , Animais , Carbacol/metabolismo , Carbacol/farmacologia , Carbacol/uso terapêutico , Cistationina beta-Sintase/metabolismo , Cistationina beta-Sintase/farmacologia , Cistationina beta-Sintase/uso terapêutico , Cistationina gama-Liase/metabolismo , Cistationina gama-Liase/farmacologia , Cistationina gama-Liase/uso terapêutico , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia/farmacologia , Fator 1 Induzível por Hipóxia/uso terapêutico , Masculino , Malondialdeído , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Sulfetos , Enxofre/metabolismo , Enxofre/farmacologia , Enxofre/uso terapêutico , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Transferases/metabolismo , Transferases/farmacologia , Transferases/uso terapêutico , Bexiga Urinária , Obstrução do Colo da Bexiga Urinária/tratamento farmacológicoRESUMO
Objectives: Colorectal cancer (CRC) remains a crucial health problem due to the toxicity of 5-Fluorouracil (5-FU) as first-line chemotherapy agent for treating CRC. The anticancer effects of boron and its compounds have been shown in various cell lines. This study aimed to examine the cytotoxic and apoptotic effects of borax (sodium tetraborate) alone or along with 5-FU on human CRC cells, DLD-1. Materials and Methods: Cytotoxicity and apoptosis were determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, 4',6-diamidino-2-phenylindole and annexin V/propidium iodide staining. Results: The results showed that combined treatment revealed a significant time- and concentration-dependent cytotoxic effect on DLD-1 cells compared with borax or 5-FU treatment alone. The combination of borax and 5-FU induced a clear increase in the early apoptotic cell percentage, compared to the cells treated with monotherapies. Additionally, a significant increase in condensed and fragmented nuclei was detected in DLD-1 cells treated with the combination treatment compared with borax or 5-FU alone. Conclusion: Our current findings suggest that the combination of borax with 5-FU has a strong cytotoxic and apoptotic effect on the human CRC DLD-1 cells.
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BACKGROUND: In different animal models, a histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu) reduced inflammation, oxidative stress and fibrosis which were involved in the pathogenesis of erectile dysfunction (ED), but whether NaBu could improve ED in an experimental animal model of benign prostate hyperplasia (BPH) was not known. OBJECTIVE: To investigate the preventive effect of NaBu on ED in a partial bladder outlet obstruction (PBOO) rat model. MATERIALS AND METHODS: PBOO was induced by partial urethral obstruction. NaBu (20 mg/kg/day) was administered orally to rats for 6 weeks after creation of PBOO. In vivo erectile responses, in vitro relaxation and contraction responses in cavernosal tissue were measured. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to determine the gene and protein expression. Inflammation, fibrosis, and localization of proteins were evaluated using histological techniques. HDAC activity and tumor necrosis factor (TNF)-α levels were measured in penile tissues. RESULTS: NaBu improved decreased intracavernosal pressure/mean arterial pressure, nitrergic and endothelium-dependent relaxation responses, and contractile responses to phenylephrine and electrical field stimulation in the PBOO group without affecting increased bladder weight. Increased endothelial nitric oxide synthase (eNOS), transforming growth factor (TGF)-ß1, and nuclear factor kappa B (NF-κB) gene levels in PBOO group were ameliorated by NaBu treatment. The administration of NaBu to PBOO rats significantly increased neuronal NOS (nNOS) and decreased TGF-ß1 protein expression. The nuclear/cytosolic ratio of NF-κB demonstrated a decrease in PBOO and all treatment groups compared to control. A significant increase in the nuclear-to-cytoplasmic ratio of nuclear factor erythroid 2-related factor 2 (Nrf2) after PBOO was reduced by the treatment. Both eNOS and inducible NOS (iNOS) protein expression, together with TNF-α levels did not differ in the penile tissue of all groups. In histological analysis, increased TGF-ß1 protein expression and fibrosis, as well as decreased nNOS protein in PBOO, were reversed by the treatment. NaBu did not normalize moderate inflammation in obstructed rats. An increase in the HDAC activity in PBOO was significantly suppressed by NaBu. DISCUSSION: Inhibition of the HDAC activity by NaBu in penile tissue could ameliorate fibrosis-associated changes induced by PBOO. CONCLUSION: NaBu promotes recovery of erectile function, and also significantly prevents penile fibrosis and normalizes TGF-ß1 and nNOS protein expression in a rat model of PBOO. The HDAC pathway may present a promising target to prevent ED in patients with BPH.
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Disfunção Erétil , Hiperplasia Prostática , Obstrução do Colo da Bexiga Urinária , Animais , Ácido Butírico/metabolismo , Ácido Butírico/farmacologia , Ácido Butírico/uso terapêutico , Modelos Animais de Doenças , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Disfunção Erétil/metabolismo , Fibrose , Histona Desacetilases/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pênis , Fenilefrina/metabolismo , Fenilefrina/farmacologia , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fatores de Crescimento Transformadores/metabolismo , Fatores de Crescimento Transformadores/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Obstrução do Colo da Bexiga Urinária/complicações , Obstrução do Colo da Bexiga Urinária/tratamento farmacológicoRESUMO
Objectives: This study aimed to investigate the role of new adipocytokines (omentin, vaspin, irisin and visfatin) in the development of endometriosis and the relationship of these adipocytokines with the inflammatory marker, C-reactive protein (CRP) levels in serum. Materials and Methods: In this study, endometriosis (n=16) and control groups (n=14) were determined via ultrasound. Serum omentin, vaspin and irisin levels were measured by ELISA method. CRP levels in serum and the gene expression of visfatin and vaspin in whole blood samples were determined by clinical analyzer and the real-time polymerase chain reaction, respectively. Results: Serum irisin and CRP levels in the endometriosis group were significantly higher than in the control group. Irisin protein levels demonstrated a positive correlation with body mass index and CRP in women diagnosed with endometriosis. No statistically significant difference was found in serum omentin and vaspin levels between groups. The visfatin and vaspin gene expression in whole blood samples from the endometriosis group was found to be significantly lower than the control group. Conclusion: Increased levels of serum irisin and decreased visfatin and vaspin gene expressions in blood may be considered as a potential biomarker in endometriosis. The identification of new adipocytokines, which demonstrate an alteration in the presence of endometriosis and the relationship between these adipocytokines and inflammation will facilitate the detection of mechanisms involved in endometriosis and will lead to the development of targeted therapy.
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Benign prostatic hyperplasia (BPH) is one of the most prevalent conditions among aged men. The use of 5α-reductase inhibitors (5-ARIs) to treat BPH was linked to erectile dysfunction (ED). Many medicinal plants and secondary metabolites are used in the management of ED. Onion (Allium cepa L.) is an economically affordable vegetable with vital phytochemicals and biological functions. The study aimed to identify the beneficial effects of onion juice on dutasteride (a 5-ARI)-induced ED. Rats were divided into two groups (n = 5 per group): control and dutasteride-treated rats (0.5 mg/kg/day). Dutasteride was administered in drinking water for 12 weeks. Experiments were performed at the end of the 12th week. In vivo erectile responses were measured before and after intracavernosal injection of onion. Relaxant responses to onion juice were examined in the corpus cavernosum (CC). Acetylcholine (ACh)-, electrical field stimulation (EFS)-, sodium nitroprusside (SNP)-induced relaxation responses in CC tissues were evaluated in the absence and presence of onion juice. Total intracavernosal pressure (ICP) and ICP/ mean arterial pressure were significantly reduced in dutasteride-treated rats (1881.14 ± 249.72 mmHg, P < 0.001;0.26 ± 0.03, P < 0.01) as compared to control rats (4542.60 ± 429.19 mmHg, 0.51 ± 0.05), which was normalized after the intracavernous administration of onion (3288.60 ± 185.45 mmHg, 0.58 ± 0.04). Onion markedly induced relaxant responses in control (72.5 ± 4.7) and dutasteride-treated (66.5 ± 2.7) groups after precontraction with phenylephrine. Relaxation responses to onion were partially inhibited after precontraction with KCl (32.5 ± 3.1, P < 0.001). The relaxant responses to ACh (14.9 ± 4.2, P < 0.01) were diminished in dutasteride-treated CC) compared to control CC (59.8 ± 3.4), which was enhanced after the incubation with onion (36.6 ± 4.8). There were no differences in relaxation response to SNP among all groups. However, relaxation response to SNP was reduced in dutasteride-treated CC at 1 µM (P < 0.05) and 10 µM dosages (P < 0.001), which was partially increased after the incubation with onion at 10 µM dosage (P < 0.01). The presence of onion did not change the reduction in EFS-caused relaxation in the dutasteride-treated group. The current data suggest that red onion juice has a restorative effect on erectile function and endothelium-dependent relaxation response following the treatment of dutasteride.
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Disfunção Erétil , Hiperplasia Prostática , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/uso terapêutico , Assistência ao Convalescente , Idoso , Animais , Dutasterida/farmacologia , Dutasterida/uso terapêutico , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Humanos , Masculino , Cebolas , Oxirredutases/farmacologia , Pênis , Hiperplasia Prostática/complicações , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Effects of human umbilical cord blood (HUCB) as a valuable source for stem cell-based therapies have not been studied in persistent post-5-alpha reductase inhibitors (5ARI) erectile dysfunction (PPED). AIM: To determine the effect of intracavernosal injection of HUCB mononuclear cells (MNCs) on ED associated with dutasteride treatment. METHODS: Twenty five adult male Sprague-Dawley rats were divided into 5 groups (n = 5 per group): (i) control, (ii) 8-week dutasteride (0.5 mg/kg/day, in drinking water), (iii) 12-week dutasteride, (iv) 8-week dutasteride+HUCB-MNCs (1 × 106) and (v) 12-week dutasteride+HUCB-MNCs. HUCB-MNCs were administered intracavernosally after eight weeks of dutasteride treatment. Experiments were performed at 4 weeks following the injection of HUCB-MNCs. Erectile responses and isometric tension of corpus cavernosum (CC) were measured. The protein expressions of phosphodiesterase type 5 (PDE5), endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), hypoxia-inducible factor (HIF)-1α and smooth muscle/collagen contents in penile tissue were evaluated by Western blotting, immunohistochemistry, and Masson's trichrome staining, respectively. MAIN OUTCOME: In vivo erectile function, in vitro relaxant and contractile responses of CC, protein expression and localization of PDE5, eNOS, nNOS, HIF-1α, and smooth muscle content in penile tissue. RESULTS: Erectile responses in the dutasteride-treated groups were significantly decreased compared with controls (P < .001), persisting after 4-wk of washout. HUCB-MNCs restored diminished intracavernosal pressure responses, acetylcholine-, sodium nitroprusside-, sildenafil-induced relaxations, and increased phenylephrine and electrical field stimulation (EFS)-induced contractions. Decreased EFS-induced relaxations in dutasteride-treated groups were not restored by HUCB-MNCs. Increased PDE5 and reduced nNOS expressions in dutasteride groups were restored by HUCB-MNCs in the 12-week dutasteride group. eNOS and HIF-1α protein expression and serum total and free testosterone levels were similar among groups. HUCB-MNCs reversed the decreased smooth muscle/collagen ratio in dutasteride-treated tissues. There was a significant increase in PDE5 and HIF-1α staining in 8-week dutasteride animals. CLINICAL TRANSLATION: This study demonstrates the corrective potential of HUCB-MNCs on some persistent structural and functional deterioration caused by 5ARI treatment in rats, which may encourage further evaluation of HUCB-MNCs in men with PPED. STRENGTHS AND LIMITATIONS: Therapeutic application of intracavernosal HUCB-MNCs is a novel approach for the rat model of post-5ARI ED. Lack of serum and tissue dihydrotestosterone measurements, vehicle injections and characterization of the cells remain limitations of our study. CONCLUSION: The persistent ED after prolonged administration of dutasteride in rats is reversed by HUCB-MNC treatment, which holds promise as a realistic therapeutic modality for this type of ED. Oztekin CV, Yilmaz-Oral D, Kaya-Sezginer E, et al. Beneficial Effects of Human Umbilical Cord Blood Mononuclear Cells on Persistent Erectile Dysfunction After Treatment of 5-Alpha Reductase Inhibitor in Rats. J Sex Med 2021;18:889-899.
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Disfunção Erétil , Inibidores de 5-alfa Redutase/farmacologia , Animais , Disfunção Erétil/tratamento farmacológico , Sangue Fetal , Humanos , Masculino , Ereção Peniana , Pênis , Ratos , Ratos Sprague-DawleyRESUMO
AIM: To investigate the possible beneficial effect of mirabegron [a selective ß3-adrenoceptor (AR) agonist] treatment on erectile dysfunction (ED) in streptozotocin-induced diabetic rats. METHODS: Sprague-Dawley rats (n=20) were divided into two groups: control group and streptozotocin-induced diabetic group. In vivo erectile responses were evaluated after intracavernosal injection of mirabegron (0.4 mg/kg) in rats. The relaxation responses to electrical field stimulation (EFS, 10 Hz), sodium nitroprusside (SNP, 10 nM) and sildenafil (1 µM) of corpus cavernosum (CC) strips were examined after the incubation with mirabegron (10 µM). ß3-ARs expression and localization were determined by Western blot and immunohistochemical analyses in CC tissue. RESULTS: In vivo erectile responses of diabetic rats [intracavernasal pressure (ICP)â/âmean arterial pressure, 0.17±0.01] were decreased, which were restored after administration of mirabegron (0.75±0.01, P<0.001). The basal ICP (7.1±0.6 mmHg) in diabetic rats was markedly increased after mirabegron (36.1 ±5.4 mmHg, P<0.01). Mirabegron caused markedly relaxation in diabetic rat CC after phenylephrine precontraction. The relaxation responses to EFS and sildenafil were reduced in diabetic CC, which were increased in the presence of mirabegron. Mirabegron enhanced SNP-induced relaxation response in both groups. The expression and immunoreactivity of ß3-ARs localized to CC smooth muscle were observed in control and diabetic rats. CONCLUSIONS: This is the first study to show that intracavernosal administration of mirabegron improved erectile function and neurogenic relaxation of CC in diabetic rats. These results may be supported by further studies using combinations of mirabegron and phosphodiesterase type 5 (PDE5) inhibitors for the treatment of diabetic ED, especially in patients who do not respond to PDE5 inhibitor therapy.
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Acetanilidas/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Disfunção Erétil/tratamento farmacológico , Tiazóis/farmacologia , Acetanilidas/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Animais , Complicações do Diabetes/etiologia , Disfunção Erétil/etiologia , Masculino , Ratos , Ratos Sprague-Dawley , Tiazóis/administração & dosagemRESUMO
BACKGROUND: Testosterone (T) deficiency is associated with erectile dysfunction (ED). The relaxant response of T on the corporal smooth muscle through a non-genomic pathway has been reported; however, the in vitro modulating effects of T on human corpus cavernosum (HCC) have not been studied. OBJECTIVES: To compare the effects of various concentrations of T on nitric oxide (NO)-dependent and nitric oxide-independent relaxation in organ bath studies and elucidate its mode of action, specifically targeting the cavernous NO/cyclic guanosine monophosphate (cGMP) pathway. MATERIALS AND METHODS: Human corpus cavernosum (HCC) samples were obtained from men undergoing penile prosthesis implantation (n = 9). After phenylephrine (Phe) precontraction, the effects of various relaxant drugs of HCC strips were performed using organ bath at low (150 ng/dL), eugonadal (400 ng/dL), and hypergonadal (600 ng/dL) T concentrations. The penile tissue measurements of endothelial nitric oxide synthase (eNOS), neuronal (n)NOS, and phosphodiesterase type 5 (PDE5) were evaluated via immunostaining, Western blot, cGMP and nitrite/nitrate (NOx) assays. RESULTS: Relaxation responses to ACh and EFS in isolated HCC strips were significantly increased at all T levels compared with untreated tissues. The sildenafil-induced relaxant response was significantly increased at both eugonadal and hypergonadal T levels. Normal and high levels of T are accompanied by increased eNOS, nNOS, cGMP, and NOx levels, along with reduced PDE5 protein expression. CONCLUSION: This study reveals an important role of short-term and modulatory effects of different concentrations of T in HCC. T positively regulates functional activities, inhibition of PDE5 expression, and formation of cGMP and NOx in HCC. These results demonstrate that T indirectly contributes to HCC relaxation via downstream effects on nNOS, eNOS, and cGMP and by inhibiting PDE5. This action provides a rationale for normalizing T levels in hypogonadal men with ED, especially when PDE5 inhibitors are ineffective. T replacement therapy may improve erectile function by modulating endothelial function in hypogonadal men.
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GMP Cíclico/metabolismo , Óxido Nítrico/biossíntese , Pênis/metabolismo , Testosterona/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/análise , Disfunção Erétil/sangue , Terapia de Reposição Hormonal , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/análise , Óxido Nítrico Sintase Tipo III/análise , Induração Peniana/sangue , Citrato de Sildenafila/farmacologia , Testosterona/sangueRESUMO
Diabetic men are at a higher risk of erectile dysfunction (ED). A tropical plant, clove (Syn. Eugenia caryophyllata, Caryophyllus aromaticus L., Syzygium aromaticum (L.) Merr. & L.M. Perry) from the Myrtaceae family has displayed aphrodisiac activity. The present research aimed to investigate the impacts of clove essential oil (CEO) and the ingredient of CEO, eugenol (E) on ED in diabetic rats. We divided Sprague-Dawley rats into control and diabetic groups. Erectile function was evaluated before and after CEO and E intracavernosal injection. CEO- and E-induced relaxation responses were investigated in isolated corpus cavernosum (CC) using various inhibitors. The intracavernous administration of CEO and E restored erectile responses in diabetic rats. CEO and E induced remarkable relaxation in all groups. CEO- and E-induced relaxation responses were partially inhibited after pre-contraction with KCl. Tetraethylammonium and glibenclamide inhibited the relaxation response to CEO. Glibenclamide inhibited maximum relaxation to E. The inhibitors of nitric oxide synthase (NOS), soluble guanylyl cyclase and nifedipine did not change CEO- and E-induced relaxation responses. The current results suggest that CEO and the major compound of the essential oil, E improved diabetes-induced ED in rats, and CEO caused CC relaxation via K+ channels independently NO signalling pathway.
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Óleo de Cravo/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Disfunção Erétil/fisiopatologia , Eugenol/farmacologia , Ereção Peniana/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Disfunção Erétil/etiologia , Disfunção Erétil/metabolismo , Glibureto/farmacologia , Técnicas In Vitro , Injeções , Masculino , Nifedipino/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óleos Voláteis/farmacologia , Pênis/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Guanilil Ciclase Solúvel/antagonistas & inibidores , Tetraetilamônio/farmacologiaRESUMO
BACKGROUND: Erectile dysfunction (ED) is an evolving health problem in the aging male population. Chronic low-grade inflammation is a critical component of ED pathogenesis and a probable intermediate stage of endothelial dysfunction, especially in metabolic diseases, with the inclusion of obesity, metabolic syndrome, and diabetes. OBJECTIVE: This review will present an overview of preclinical and clinical data regarding common inflammatory mechanisms involved in the pathogenesis of ED associated with metabolic diseases and the effect of antiinflammatory drugs on ED. METHODS: A literature search of existing pre-clinical and clinical studies was performed on databases [Pubmed (MEDLINE), Scopus, and Embase] from January 2000 to October 2019. RESULTS: Low-grade inflammation is a possible pathological role in endothelial dysfunction as a consequence of ED and other related metabolic diseases. Increased inflammation and endothelial/prothrombotic markers can be associated with the presence and degree of ED. Pharmacological therapy and modification of lifestyle and risk factors may have a significant role in the recovery of erectile response through reduction of inflammatory marker levels. CONCLUSION: Inflammation is the least common denominator in the pathology of ED and metabolic disorders. The inflammatory process of ED includes a shift in the complex interactions of cytokines, chemokines, and adhesion molecules. These data have established that anti-inflammatory agents could be used as a therapeutic opportunity in the prevention and treatment of ED. Further research on inflammation-related mechanisms underlying ED and the effect of therapeutic strategies aimed at reducing inflammation is required for a better understanding of the pathogenesis and successful management of ED.
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Disfunção Erétil , Síndrome Metabólica , Disfunção Erétil/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Estilo de Vida , Masculino , ObesidadeRESUMO
INTRODUCTION: Cardiometabolic syndrome (CMS), as a bunch of metabolic disorders mainly characterized by type 2 diabetes mellitus (T2DM), hypertension, atherosclerosis, central adiposity, and abdominal obesity triggering androgen deficiency, is one of the most critical threats to men. Although many significant preclinical and clinical findings explain CMS, new approaches toward common pathophysiological mechanisms and reasonable therapeutic targets are lacking. AIM: To gain a further understanding of the role of androgen levels in various facets of CMS such as the constellation of cardiometabolic risk factors including central adiposity, dyslipidemia, insulin resistance, diabetes, and arterial hypertension and to define future directions for development of effective therapeutic modalities. METHODS: Clinical and experimental data were searched through scientific literature databases (PubMed) from 2009 to October 2019. MAIN OUTCOME MEASURE: Evidence from basic and clinical research was gathered with regard to the causal impact and therapeutic roles of androgens on CMS. RESULTS: There are important mechanisms implicated in androgen levels and the risk of CMS. Low testosterone levels have many signs and symptoms on cardiometabolic and glycometabolic risks as well as abdominal obesity in men. CLINICAL IMPLICATIONS: The implications of the findings can shed light on future improvements in androgen levels and add potentially predictive risk for CMS, as well as T2DM, abdominal obesity to guide clinical management in the early stage. STRENGTHS & LIMITATIONS: This comprehensive review refers to the association between androgens and cardiovascular health. A limitation of this study is the lack of large, prospective population-based studies that analyze the effects of testosterone treatment on CMS or mortality. CONCLUSION: Low testosterone levels have several common features with metabolic syndrome. Thus, testosterone may have preventive role in the progress of metabolic syndrome and subsequent T2DM, abdominal obesity, and cardiovascular disease and likely affect aging men's health mainly through endocrine and vascular mechanisms. Further studies are necessary to evaluate the therapeutic interventions directed at preventing CMS in men. Kirlangic OF, Yilmaz-Oral D, Kaya-Sezginer E, et al. The Effects of Androgens on Cardiometabolic Syndrome: Current Therapeutic Concepts. Sex Med 2020;8:132-155.
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AIMS: To evaluate the impacts of hydrogen sulfide (H2 S) donor, sodium hydrogen sulfide (NaHS), and phosphodiesterase type-5 inhibitor (PDE5i), tadalafil per se and their combination treatment on partial bladder outlet obstruction (PBOO)-induced erectile dysfunction (ED). METHODS: Sprague-Dawley rats were equally divided into five groups: (a) sham-operated control; (b) PBOO; (c) PBOO-treated with NaHS (5.6 mg/kg/day, ip); (d) PBOO-treated with tadalafil (2 mg/kg/day, oral); and (e) PBOO-treated with combination of NaHS and tadalafil. The obstruction was created by urethral ligation for 6 weeks. In vivo erectile responses, in vitro relaxant and contractile responses in penile tissue as well as protein expression of nitric oxide synthases (NOS), H2 S synthesis enzymes, oxidative stress, hypoxia, fibrosis markers, and the smooth muscle/collagen ratio and apoptosis were analyzed. RESULTS: Combined treatment entirely returned increased bladder mass, reduced erectile responses, relaxation responses to acetylcholine, and electrical field stimulation in obstructed rats, while partial amelioration was observed after mono-treatment. Decreased neuronal NOS and 3-mercaptopiruvate transferase enzyme expressions in penile tissue from obstructed rats were also entirely restored by the combined treatment. Mono-treatment partially improved increased hypoxia, oxidative stress, fibrosis markers, decreased smooth muscle mass, and H2 S levels, while combined therapy completely recovered. CONCLUSIONS: The combination therapy with H2 S donor and PDE5i had positive effects on erectile responses through the improvement of ischemia-induced morphological and functional penile alterations in obstruction. H2 S and NO may likely play a synergistic role in the regulation of erectile function and have constructive effects on clinical outcomes in male patients with ED and benign prostatic hyperplasia/lower urinary tract symptoms.
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Disfunção Erétil/tratamento farmacológico , Sulfeto de Hidrogênio/uso terapêutico , Ereção Peniana/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/uso terapêutico , Tadalafila/uso terapêutico , Obstrução do Colo da Bexiga Urinária/complicações , Animais , Modelos Animais de Doenças , Disfunção Erétil/etiologia , Hidrogênio/metabolismo , Hidrogênio/farmacologia , Hidrogênio/uso terapêutico , Sulfeto de Hidrogênio/farmacologia , Masculino , Músculo Liso/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Ratos , Ratos Sprague-Dawley , Tadalafila/farmacologia , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the effect of the If channel inhibitor, ivabradine on human corpus cavernosum (HCC) smooth muscle tone. METHODS: HCC samples were obtained from erectile dysfunction(ED) patients (n = 12) undergoing penile prosthesis surgery. Concentration-response curves for ivabradine were exposed to various inhibitory and stimulatory agents. The relaxant and contractile responses to electrical field stimulation (EFS, 10 Hz and 80 Hz) were examined in the presence or absence of ivabradine (10 µM). HCN3 and HCN4 channel expression and localization were determined by Western blot and immunohistochemical analyses of HCC tissues. RESULTS: Increasing ivabradine concentrations dependently reduced the maximal contractile responses of isolated HCC strips induced by KCl (59.5 ± 2.5%) and phenylephrine (84.0 ± 9.8%), which was not affected by nitric oxide synthase and soluble guanylyl cyclase inhibitors after phenylephrine-induced contraction. Nifedipine and tetraethylammonium inhibited the maximum relaxation to ivabradine by 75% and 39.3%, respectively. Fasudil and sildenafil increased the relaxation response to ivabradine without altering the maximum response. Pre-incubation with ivabradine significantly increased relaxant responses to EFS (p < 0.01) and reduced the contractile tension evoked by EFS (72.3%) (p < 0.001). Ivabradine incubation did not affect the expression and localization of HCN3 and HCN4 channels in the HCC smooth muscle cells. CONCLUSIONS: Ivabradine exhibits a relaxant effect on HCC tissues, which is likely to be attributed to the blocking of L-type Ca2+ channels and the opening of K+ channels, independent of changes in the activation of the nitric oxide/cyclic guanosine monophosphate system. Inhibition of HCN channels localized in cavernosal smooth muscle cells may offer pharmacological benefits for patients with cardiovascular risk factors.
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Disfunção Erétil , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Humanos , Ivabradina/farmacologia , Masculino , Contração Muscular , Óxido Nítrico , Ereção Peniana , PênisRESUMO
OBJECTIVE: This study evaluated the effect of human umbilical cord blood mononuclear cells (HUCB-MNCs) on bladder dysfunction in streptozotocin (STZ; 35 mg/kg, i.v.)-induced diabetic rats. METHODS: Adult male Sprague-Dawley rats (n = 30) were equally divided into three groups: control group, STZ-diabetic group, and HUCB-MNC-treated group (1 × 106 cells). HUCB-MNCs were isolated by density gradient centrifugation from eight healthy donors and injected into the corpus cavenosum in STZ-diabetic rats 4 weeks after the induction of diabetes. Studies were performed 4 weeks after HUCB-MNC or vehicle injection. In vitro organ bath studies were performed on bladder strips, whereas protein expression of hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), and α-smooth muscle actin (SMA) in the bladder and the ratio of smooth muscle cells (SMCs) to collagen were determined using western blotting and Masson trichrome staining. RESULTS: Neurogenic contractions of detrusor smooth muscle strips were 55% smaller in the diabetic group than control group (P < 0.05); these contractions were normalized by HUCB-MNC treatment. In addition, HUCB-MNC treatment restored the impaired maximal carbachol-induced contractile response in detrusor strips in the diabetic group (29%; P < 0.05). HUCB-MNC treatment improved the KCl-induced contractile response in the diabetic bladder (68%; P < 0.05), but had no effect on ATP-induced contractile responses. Increased expression of HIF-1α and VEGF protein and decreased expression of α-SMA protein and the SMC/collagen ratio in diabetic rats were reversed by HUCB-MNC. CONCLUSION: Administration of HUCB-MNCs facilitates bladder function recovery, which is likely related to downregulation of HIF-1α expression and attenuation of fibrosis in STZ-diabetic rats.
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Diabetes Mellitus Experimental/complicações , Sangue Fetal/citologia , Leucócitos Mononucleares/fisiologia , Doenças da Bexiga Urinária/etiologia , Actinas/metabolismo , Animais , Western Blotting , Sangue Fetal/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Contração Muscular/fisiologia , Músculo Liso/fisiopatologia , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiopatologia , Doenças da Bexiga Urinária/fisiopatologia , Doenças da Bexiga Urinária/terapia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Men with hypertension often develop erectile dysfunction (ED). The present study aimed to examine the effects of sodium hydrosulphide (NaHS), a hydrogen (H2 S) donor, treatment on ED in nitric oxide synthase (NOS) inhibitor (L-NAME)-induced hypertensive rats. Forty adult Sprague-Dawley rats were divided into four groups: control, NaHS (0.037 mg kg day-1 )-treated control, L-NAME-induced hypertension (40 mg kg day-1 ) and NaHS-treated L-NAME-induced hypertension. The ratio of intracavernosal pressure to mean arterial pressure and isometric tension of corpus cavernosum (CC) were measured. The penile expression of endothelial and neuronal NOS (eNOS and nNOS), inflammation markers [nuclear factor kappa B (NF-κB) and inhibitor kappa B alpha (IκBα)], H2 S-producing enzymes[cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE)], the smooth muscle/collagen ratio and H2 S concentrations were determined. The blood pressure was significantly increased in the hypertensive group, but not reversed by NaHS. The erectile response in hypertensive rats was partially prevented by NaHS. The relaxation response to electrical field stimulation was increased in CC from NaHS-treated hypertensive rats. NaHS treatment restored decreased protein expression of eNOS, nNOS and CSE as well as smooth muscle/collagen ratio and H2 S levels and increased NF-κB and IκBα protein expression in the penile tissue of hypertensive rats. NaHS promoted the recovery of erectile responses in hypertensive rats by improvement of neuronal function and downregulation of fibrosis and NF-κB signalling.
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Disfunção Erétil/tratamento farmacológico , Hipertensão/complicações , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Disfunção Erétil/etiologia , Fibrose/tratamento farmacológico , Fibrose/patologia , Humanos , Sulfeto de Hidrogênio/farmacologia , Hipertensão/induzido quimicamente , Masculino , NG-Nitroarginina Metil Éster/toxicidade , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pênis/metabolismo , Pênis/patologia , Ratos , Ratos Sprague-Dawley , Sulfetos/uso terapêutico , Resultado do TratamentoRESUMO
Transient receptor potential (TRP) channels comprise a family of cation channels implicated in a variety of cellular processes including light, mechanical or chemical stimuli, temperature, pH, or osmolarity. TRP channel proteins are a diverse family of proteins that are expressed in many tissues. We debated our recent knowledge about the expression, function, and regulation of TRP channels in the different parts of the male urogenital system in health and disease. Emerging evidence suggests that dysfunction of TRP channels significantly contributes to the pathophysiology of urogenital diseases. So far, there are many efforts underway to determine if these channels can be used as drug targets to reverse declines in male urogenital function. Furthermore, developing safe and efficacious TRP channel modulators is warranted for male urogenital disorders in a clinical setting.
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Disfunção Erétil/metabolismo , Moduladores de Transporte de Membrana/uso terapêutico , Canais de Cátion TRPV/metabolismo , Bexiga Urinária Hiperativa/metabolismo , Animais , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Moduladores de Transporte de Membrana/farmacologia , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Bexiga Urinária Hiperativa/tratamento farmacológicoRESUMO
BACKGROUND: Colchicine, a tricyclic alkaloid, is commonly used in treatment due to its antiinflammatory and anti-fibrotic effects. Besides its toxicity at high doses, colchicine is reported for its potential anticancer effects at lower concentrations. The present study aimed to evaluate the anticancer effects of colchicine in SW480 cells. METHODS: The effect of colchicine on cell proliferation was determined by MTT assay. The cellular colchicine uptake was measured by HPLC analysis. The apoptotic effects was evaluated by annexin v binding assay and MMP-9 mRNA expression was determined by RT-PCR experiments. RESULTS: Colchicine showed significant cytotoxicity at 10 ng/ml and higher concentrations and caused a cell cycle arrest of SW480 cells at G2/M phase. The results of HPLC analysis showed that colchicine uptake was increased in correlation with treated concentrations. Colchicine concentrations have increased the amount of apoptotic cell population. The elisa and western blot measurements showed that colchicine led to nuclear translocation of NF-κB proteins and increased caspase levels. The real time PCR experiments showed that colchicine has inhibitory effect on MMP-9 mRNA expression in a concentration dependent manner. CONCLUSION: These results illustrated that low dose colchicine efficiently induced cell death and apoptosis of SW480 cells and the inhibition of MMP-9 mRNA levels was significantly correlated with the amount of cellular colchicine uptake, suggesting that colchicine has a potential value in the treatment of human colorectal cancer.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Colchicina/farmacologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação para Baixo/efeitos dos fármacos , Metaloproteinase 9 da Matriz/genética , RNA Mensageiro/biossíntese , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colchicina/síntese química , Colchicina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Perfilação da Expressão Gênica , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Microscopia de Fluorescência , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
BACKGROUND: Erectile dysfunction (ED) affects 30 million men in the US with a decrease in quality of life. Thirty percent of hypertensive men suffer from ED. OBJECTIVE: This review will debate the interplay between hypertension and ED, discovering novel insights concerning hypertension-linked ED, as well as the influence of antihypertensive medications on patients with ED. METHOD: Total number of records screened from PubMed yielded by the search which performed from January 2000 - June 2018. RESULTS: Hypertension can cause ED as a consequence of high blood pressure or antihypertensive treatment. Both hypertension and ED have endothelial dysfunction as a common base mechanism, which can lead to an increase in vascular smooth muscle contraction. Also, some phosphodiesterase (PDE)-5 inhibitors used to treat ED can recover blood pressure. CONCLUSION: Understanding of common mechanisms involved in ED accompanied with hypertension and the research on antihypertensive drugs that impact ED will bring important approaches for identifying novel therapeutic strategies that will improve quality of life in patients with these conditions.