Tadalafil enhances the inhibitory effects of tamsulosin on neurogenic contractions of human prostate and bladder neck.

INTRODUCTION: Lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTSs) may be associated with erectile dysfunction (ED). Phosphodiesterase type 5 (PDE5) inhibitors used for treating ED have shown clinical benefit in patients with LUTS but their actions in human LUT tissues are not well defined. AIM: To determine the effects of the long-acting PDE5 inhibitor, tadalafil, on smooth muscle tone in human prostate and bladder neck as well as to evaluate the influence of tadalafil on the efficacy of the α-adrenergic receptor antagonist, tamsulosin, in inhibiting contractile responses in these tissues. METHODS: Strips of human peripheral prostate (HPP), human internal prostate (HIP), and human bladder neck (HBN) were obtained from organ donors and patients with BPH. The strips were then disposed in organ baths to evaluate nitric oxide/cyclic guanosine monophosphate (cGMP)-mediated relaxation and cGMP kinetics in HPP and HIP, and electrical field stimulation (EFS)-induced neurogenic contractions in HPP and HBN. MAIN OUTCOME MEASURES: Tadalafil-induced effects on sodium nitroprusside (SNP)-induced relaxation and cGMP accumulation in HPP and HIP and influence of tadalafil and tamsulosin on EFS-induced contractions of HPP and HBN. RESULTS: SNP-induced relaxation of HPP and HIP was significantly potentiated by tadalafil (30-60 nM). SNP-induced cGMP accumulation in HPP and HIP was enhanced by tadalafil (30-60 nM), but significant difference was only obtained in HPP. EFS-induced contractions sensitive to tetrodotoxin in HPP were significantly inhibited by tadalafil (30 nM) but not by tamsulosin (0.01-100 nM) or vehicle. Further inhibition of neurogenic responses in HPP was achieved by combining tadalafil and tamsulosin treatments. Tamsulosin, but not tadalafil, significantly reduced EFS-induced contractions in HBN, but the coadministration of both therapies resulted in additional inhibition of contractions. CONCLUSIONS: While tadalafil enhances cGMP accumulation and potentiates prostate relaxation, tadalafil combined with tamsulosin results in enhanced inhibition of neurogenic contractions of HPP and HBN.

Diabetes exacerbates the functional deficiency of NO/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries.

INTRODUCTION: Diabetic men with erectile dysfunction (ED) are less responsive to therapy with type 5 phosphodiesterase (PDE5) inhibitors. Although an impairment of the nitric oxide (NO)/cyclic guanosin-monophosphate (cGMP) pathway has been shown in diabetic ED vs. non-diabetic ED, the functionality of NO/cGMP pathway in non-diabetic and diabetic ED patients with respect to non-ED patients has not been established. AIM: The aim of this study is to evaluate the function of NO/cGMP signalling in human erectile tissues from ED patients exploring the added impact of diabetes. METHODS: Corpus cavernosum strips (human corpus cavernosum [HCC]) and penile resistance arteries (HPRA) were collected from penile specimens from organ donors (OD) and from diabetic and non-diabetic men with ED undergoing penile prosthesis implantation. MAIN OUTCOME MEASURES: Relaxations to acetylcholine, electrical field stimulation, sodium nitroprusside, and sildenafil were evaluated in phenylephrine-contracted HCC and norepinephrine-contracted HPRA. cGMP content in HCC was also determined. RESULTS: The impairment of endothelium-dependent relaxation in HCC and HPRA from ED patients was exacerbated by diabetes (E(max) 76.1, 62.9, and 49.3% in HCC and 73.1, 59.8, and 46.0% in HPRA from OD, non-diabetic and diabetic ED, respectively). Hypertension, hypercholesterolemia, or aging did not exert a further impairment of endothelial relaxation among ED patients. Diabetes also causes a further impairment of neurogenic relaxation in HCC and HPRA. The basal and stimulated content of cGMP in HCC was significantly decreased in patients with ED, but specially reduced in diabetic patients. Diabetes clearly impaired PDE5 inhibitor-induced vasodilation of HPRA from ED patients. CONCLUSIONS: ED is related to impaired vasodilation, reduced relaxant capacity, and diminished cGMP content in penile tissue. These alterations are more severe in diabetes and accompany reduced relaxant efficacy of PDE5 inhibition. Thus, an exacerbated reduction of nitric oxide/cGMP signaling could be responsible for ED in diabetic men and would explain their reduced response to treatment.

[Robotic and laparosocpic urological surgery during COVID-19 pandemia.] / Situación de la cirugía laparoscópica y robótica urológica durante la pandemia COVID-19.

OBJECTIVE: SARS-CoV-2 pandemic hashigh repercussion on urologic minimally invasive surgery (MIS). Controversy about safety of MIS procedures during COVID-19 pandemic has been published. Nowadays, our priority should be create agreement in order to restart and organize MIS with safety conditions for patients and healthcare workers. METHODS: Pubmed and web search was conducted with following terms: "SARS-CoV-2", "COVID19", "COVID19 Urology", COVID19 Surgery", "COVID19 transmission", "SARS-CoV-2 transmission", "COVID19 nd minimally invasive surgery", "SARS-CoV-2 and CO 2insuflation". A narrative review of available literature and scientific evidence summary was done. A modify nominal group technique was used to achieve an expert consensus. First draft was circulated amongst authors. Definitive document was approved in May 26th. RESULTS: Non evidence supports higher risk of SARSCoV-2 healthcare workers infection with MIS compared to open surgery. MIS is associated with shorter hospital stay than open surgery. Modify MIS indications to open surgery, with no scientific evidence, could spend valuable resources in detriment to COVID-19 patients. MIS indications should be prioritized attending to available resources and pandemic intensity. SARS-CoV-2screening 72 hours prior to surgery by clinical and epidemiological questionnaire and nasopharyngeal PCRis recommended, in order to prevent nosocomial transmission, professional infections and to minimize postoperative complications. Intraoperative steps should be established to reduce professional exposure to surgical aerosols, including: surgical room reorganization, adequate personal protective equipment, surgical technique optimization and management of CO2 and surgical smoke. CONCLUSIONS: In COVID-19 pandemic de-escalation, MIS carried out with optimal safety measurements, could contribute to reduce hospital resources utilization. With current evidence, MIS should not be limited or reconverted to open surgery during COVID-19 pandemic.

OBJETIVO: La pandemia provocada por el nuevo coronavirus SARS-CoV-2 ha tenido una elevada repercusión sobre la cirugía mínimamente invasiva (CMI). Ha surgido una importante controversia sobre la realización de CMI durante la pandemia COVID-19. Es prioritario, establecer un consenso sobre la organización y realización con seguridad de la CMI durante la pandemia. MATERIAL Y MÉTODOS: Se realizó una búsqueda web y en PubMed con los términos: "SARS-CoV-2", "COVID19", "COVID19 Urology", "COVID19 Surgery", "COVID19 transmission", "SARS-CoV-2 transmission", "COVID19 and minimally invasive surgery", "SARSCoV-2 and CO2 insuflation". Se realizó una revisión narrativa de la literatura y una síntesis de la evidencia disponible. Se ha utilizado una técnica de grupo nominal modificada, circulando un primer borrador a todos los autores y aprobándose la versión definitiva el día 26 de Mayo de 2020. RESULTADOS: No existe evidencia sobre una mayor exposición a SARS-CoV-2 en CMI respecto a cirugía abierta. La CMI se asocia a una menor estancia hospitalaria por lo que cambiar, sin justificación, la indicaciónde CMI puede retrotraer recursos que podrían ser utilizados para la pandemia COVID-19. Se debe priorizar la CMI según los recursos disponibles y la intensidad de la pandemia en cada momento. Se recomienda realizar despistaje de SARS-CoV-2 mediante cuestionario clínico-epidemiológico y PCR nasofaríngea 72 horas antes de la CMI electiva, para minimizar las complicaciones postoperatorias, evitar la transmisión cruzada entre pacientes y la posible exposición de los profesionales sanitarios. Se recomienda establecer medidas de organización en quirófano, de protección personal, técnica quirúrgica y manejo del CO2 y aerosoles generados para reducir la exposición y riesgos del personal sanitario. CONCLUSIONES: La CMI realizada con las medidasd e seguridad adecuadas para el paciente y profesionales, puede contribuir durante la desescalada a una menor utilización de recursos sanitarios y por tanto, no debe limitarse su utilización o cambiar sus indicaciones.

Activation and potentiation of the NO/cGMP pathway by NG-hydroxyl-L-arginine in rabbit corpus cavernosum under normoxic and hypoxic conditions and ageing.

1 When nitric oxide synthase (NOS) produces NO from N(G)-hydroxy-L-arginine (OH-arginine) instead of L-arginine, the total requirement of molecular oxygen and NADPH to form NO is reduced. The aim of this work was to evaluate the effects of OH-arginine on the contractility of rabbit corpus cavernosum (RCC) and to compare the capacities of L-arginine and OH-arginine to enhance NO-mediated responses under normoxic and hypoxic conditions and in ageing, as models of defective NO production. 2 OH-arginine, but not L-arginine, was able to relax phenylephrine-contracted rabbit trabecular smooth muscle. OH-arginine-induced relaxation was inhibited by the NOS-inhibitor, L-NNA (300 microM), and by the guanylyl cyclase inhibitor, ODQ (20 microM), while it was not affected by the cytochrome P450 oxygenase inhibitor, miconazole (0.1 mM). Administration of OH-arginine, but not L-arginine, produced a significant increment of cGMP accumulation in RCC tissue. 3 Relaxation elicited by OH-arginine (300 microM) was still observed at low oxygen tension. The increase of cGMP levels induced by ACh (30 microM) in RCC was significantly enhanced by addition of OH-arginine (300 microM) in normoxic conditions, as well as under hypoxia, while L-arginine did not alter the effects of ACh on cGMP accumulation. 4 Endothelium-dependent and nitrergic nerve-mediated relaxations were both significantly reduced in RCC from aged animals (>20-months-old) when compared with young adult rabbits (5-months-old). Treatment with OH-arginine (300 microM) significantly potentiated endothelium-dependent and neurogenic relaxation in corpus cavernosum from aged rabbits, while L-arginine (300 microM) did not have significant effects. 5 Results show that OH-arginine promotes NO-mediated relaxation of RCC and potentiates the NO-mediated responses induced by stimulation of endogenous NO generation in hypoxic and aged tissues. We propose that the use of OH-arginine could be of interest in the treatment of erectile dysfunction, at least in those secondary to defective NO production.

Effectiveness of three-dimensional fluoroscopy in percutaneous nephrostomy: an animal model study.

OBJECTIVES: To present, in an experimental study, an assessment of innovative digital fluoroscopy systems with three-dimensional (3D) reconstruction for use in endourologic applications. METHODS: The experiment was performed in a pig model. We used 5 pigs. An obstructive uropathy model was created in the right kidney to dilate the urinary tract for group 1. Group 2 consisted of the nondilated left kidney. After selecting the tract on the 3D image, the lower caliceal group was punctured in the 2 kidneys under fluoroscopic control, to assess the efficiency of the 3D reconstruction when selecting the renal calix to be punctured. RESULTS: The 3D reconstruction system allowed us to obtain reconstruct the pelvis in three dimensions, isolated as the pelvis and renal parenchyma, as well as the adjacent bony relationships. In this study, the success rate was 100% for locating the selected renal calix. CONCLUSIONS: With this 3D reconstruction system, we were able to obtain a series of images that allowed for the study of the volume of the kidney, perfectly determining its renal calix distribution in the operating room. This enabled us to determine the precise delineation of the target calix. We, therefore, consider this new urologic application of fluoroscopy very useful in surgical planning for antegrade access of the upper urinary tract.

Erectile dysfunction in patients in a cardiac rehabilitation program.

INTRODUCTION AND OBJECTIVES: Erectile dysfunction is common in patients with coronary heart disease. The aim of this study was to investigate the incidence of, etiological factors associated with, and treatment results obtained in this condition in patients participating in a cardiac rehabilitation program. METHODS: The study included 420 male patients with heart disease who were taking part in a multicomponent therapeutic program that involved physical exercise, psychological techniques and risk factor reduction. RESULTS: Overall, erectile dysfunction was present in 216 patients (52.6%) and there were clear associations with age (P< .001), diabetes mellitus (P< .001), arterial hypertension (P=.029), cigarette smoking (P=.044) and treatment with angiotensin-converting enzyme inhibitors (P=.003) and diuretics (P< .001). However, there were no links to treatment with beta-blockers, calcium antagonists, statins or antiplatelet agents. There were direct associations with trait anxiety (P=.009) and state anxiety (P=.006) and with depression (P=.003). The final multivariate analysis model included diabetes mellitus, smoking, diuretic use, state anxiety and age as significant variables. Only 59 patients agreed to treatment with a phosphodiesterase-5 inhibitor, with positive results in 45 (76.27%). Treatment was contraindicated in 41 patients because they were taking nitrates for myocardial ischemia. The remaining patients expressed no interest, had relationship problems or were worried about complications. CONCLUSIONS: The incidence of erectile dysfunction was substantial. The condition was directly associated with risk factors for atherosclerosis, treatment, and psychological disorders (i.e., anxiety and depression). Relationship problems and the fear of complications may explain why many patients refused to take phosphodiesterase-5 inhibitors.

Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: role of protein kinase C activity.

We have evaluated the influence of protein kinase C (PKC) activity on penile smooth muscle tone in tissues from diabetic and nondiabetic men with erectile dysfunction. Human corpus cavernosum (HCC) strips were obtained from impotent diabetic and nondiabetic men at the time of penile prosthesis implantation and studied in organ chambers. Contractility responses to a prostanoid precursor, to prostanoids, and to the endothelium-dependent vasodilator acetylcholine were studied. Arachidonic acid (AA; 100 microM) caused cyclooxygenase-dependent relaxation of HCC. This relaxation was impaired in diabetic tissues and normalized by blocking thromboxane (TP) receptors with 20 nM [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ29548). Diabetes did not affect prostaglandin (PG)E(1)-induced relaxation, but it reduced relaxation induced by the PGE(1) metabolite PGE(0). This effect was related to an interaction of PGE(0) with TP receptors. Diabetic tissues had reduced endothelium-dependent relaxation, which was partially improved by SQ29548 and completely normalized by the PKC inhibitor 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X; 1 microM). In HCC from nondiabetic patients, treatment with the PKC activator phorbol-12,13-dibutyrate (0.3 microM) significantly attenuated endothelium-dependent relaxation, an effect prevented by coadministration of GF109203X. Tissues from diabetic patients had enhanced sensitivity to the contractile effects of the TP receptor agonist 9,11-dideoxy-9alpha,11alpha-epoxymethano PGF(2alpha) (U46619) (EC(50) = 0.65 +/- 0.42 and 6.01 +/- 2.28 nM in diabetic and nondiabetic patients, respectively). Inhibition of PKC with 1 microM GF109203X, prevented diabetes-induced hypersensitivity to U46619-induced contractions (EC(50) = 8.55 +/- 3.12 microM). Overactivity of PKC in diabetes is responsible for enhanced contraction and reduced endothelium-dependent relaxation of HCC smooth muscle. Such alterations can result in erectile dysfunction.

Current role of penile implants for erectile dysfunction.

PURPOSE OF REVIEW: The purpose of this review is to appraise new developments and publications in the field of penile prosthetic surgery. Urologists dealing with erectile dysfunction need to recognize the value of penile prosthetic surgery as a very efficacious treatment for this common condition. This type of surgery is needed in a considerable proportion of patients with erectile dysfunction so this review is timely and relevant. RECENT FINDINGS: The main themes in the literature covered include risk factors for infection of penile prostheses, its prevention with the use of hydrophilic and antibiotic-coated prostheses, particularly in re-operations, and its management with the new rescue procedures. Surgical tips for prosthetic surgery are also reviewed as well as clinical outcomes and factors influencing them. SUMMARY: Of all the invasive treatments currently available, placement of a penile prosthesis is one of the most successful, giving high levels of satisfaction. With the aid of new technical advances, the risk of infection--the most feared complication--can be minimized so prosthetic surgery may play a major role in the treatment of erectile dysfunction.

Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF.

Standard treatments for erectile dysfunction (ED) (i.e., PDE5 inhibitors) are less effective in diabetic patients for unknown reasons. Endothelium-dependent relaxation (EDR) of human corpus cavernosum (HCC) depends on nitric oxide (NO), while in human penile resistance arteries (HPRA) endothelium-derived hyperpolarizing factor (EDHF) and NO participate. Here we show that diabetes significantly reduced EDR induced by acetylcholine (ACh) in HCC and HPRA. Relaxation attributed to EDHF was also impaired in HPRA from diabetic patients. The PDE5 inhibitor, sildenafil (10nM), reversed diabetes-induced endothelial dysfunction in HCC, but not in HPRA. Calcium dobesilate (DOBE; 10 microM) fully reversed diabetes-induced endothelial dysfunction in HPRA by specifically potentiating the EDHF-mediated component of EDR. Impairment by diabetes of NO and EDHF-dependent responses precluded the complete recovery of endothelial function in HPRA by sildenafil. This could explain the poor clinical response to PDE5 inhibitors of diabetic men with ED and suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men.