RESUMEN
OBJECTIVE: To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. PATIENTS AND METHODS: This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. RESULTS: Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3-34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1-30.2), UTUC (n = 128) 1.14% (95% CI 0.77-1.52), renal cancer (n = 107) 1.05% (95% CI 0.80-1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32-2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03-1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90-4.15; P < 0.001), male sex 1.30 (95% CI 1.14-1.50; P < 0.001), and smoking 2.70 (95% CI 2.30-3.18; P < 0.001). CONCLUSIONS: A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer.
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Neoplasias Renales/diagnóstico , Neoplasias Ureterales/diagnóstico , Neoplasias de la Vejiga Urinaria/diagnóstico , Adulto , Anciano , Femenino , Hematuria/etiología , Humanos , Neoplasias Renales/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Derivación y Consulta , Neoplasias Ureterales/complicaciones , Neoplasias de la Vejiga Urinaria/complicacionesRESUMEN
INTRODUCTION: We investigated the effect angiotensin II (Ang II), a corpus cavernosal smooth muscle (CCSM) constrictor peptide, has on tissue taken from rabbits following chronic partial bladder outlet obstruction (PBOO), as this model is characterized by an increase in corpus cavernosal collagen deposition and a marked reduction and impaired relaxation of CCSM cells. AIM: To determine the interaction between Ang II and nitric oxide (NO) and the development of oxidative stress (OS) in a rabbit model of chronic PBOO. METHODS: Corpus cavernosal tissue was obtained from 12 sham-operated and 20 PBOO rabbits. Organ bath studies determined Ang II/NO interaction on CCSM function using losartan (AT1 receptor antagonist), sodium nitroprusside (SNP, NO donor), electrical field stimulation (EFS), and vardenafil (phosphodiesterase type 5 inhibitor). The role of OS in the Ang II response was also determined using diphenylene iodonium chloride (DPI), the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, which inhibits superoxide production and superoxide dismutase (SOD, the enzyme that accelerates the breakdown of superoxide). MAIN OUTCOME MEASURE: Action of Ang II and AT1 receptor antagonist, as well as SOD and DPI on CCSM function. RESULTS: Ang II caused a dose-dependent contraction of CCSM strips that was enhanced in PBOO rabbits and inhibited by losartan, DPI, and SOD. CCSM relaxation induced by SNP/EFS was impaired in this model and improved by vardenafil and losartan. CONCLUSIONS: These findings imply that the increased Ang II contractile response is a pathological consequence of PBOO and that AT1 receptor inhibition may be a therapeutic approach to treat ED associated with PBOO.
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Angiotensina II/fisiología , Disfunción Eréctil/fisiopatología , Músculo Liso/fisiología , Estrés Oxidativo , Pene/fisiología , Angiotensina II/farmacología , Animales , Modelos Animales de Enfermedad , Estimulación Eléctrica , Disfunción Eréctil/metabolismo , Imidazoles/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Nitroprusiato/farmacología , Pene/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/farmacología , Piperazinas/farmacología , Conejos , Sulfonas/farmacología , Triazinas/farmacología , Obstrucción del Cuello de la Vejiga Urinaria/fisiopatología , Diclorhidrato de VardenafilRESUMEN
BACKGROUND: Left ventricular pacing (LVP) in canine heart alters ventricular activation, leading to reduced transient outward potassium current (I(to)), loss of the epicardial action potential notch, and T-wave vector displacement. These repolarization changes, referred to as cardiac memory, are initiated by locally increased angiotensin II (AngII) levels. In HEK293 cells in which Kv4.3 and KChIP2, the channel subunits contributing to I(to), are overexpressed with the AngII receptor 1 (AT1R), AngII induces a decrease in I(to) as the result of internalization of a Kv4.3/KChIP2/AT1R macromolecular complex. OBJECTIVE: To test the hypothesis that in canine heart in situ, 2h LVP-induced decreases in membrane KChIP2, AT1R, and I(to) are prevented by blocking subunit trafficking. METHODS: We used standard electrophysiological, biophysical, and biochemical methods to study 4 groups of dogs: (1) Sham, (2) 2h LVP, (3) LVP + colchicine (microtubule-disrupting agent), and (4) LVP + losartan (AT1R blocker). RESULTS: The T-wave vector displacement was significantly greater in LVP than in Sham and was inhibited by colchicine or losartan. Epicardial biopsies showed significant decreases in KChIP2 and AT1R proteins in the membrane fraction after LVP but not after sham treatment, and these decreases were prevented by colchicine or losartan. Colchicine but not losartan significantly reduced microtubular polymerization. In isolated ventricular myocytes, AngII-induced I(to) reduction and loss of action potential notch were blocked by colchicine. CONCLUSIONS: LVP-induced reduction of KChIP2 in plasma light membranes depends on an AngII-mediated pathway and intact microtubular status. Loss of I(to) and the action potential notch appear to derive from AngII-initiated trafficking of channel subunits.
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Estimulación Cardíaca Artificial , Sistema de Conducción Cardíaco/fisiología , Losartán/farmacología , Microtúbulos/metabolismo , Canales de Potasio/fisiología , Receptores de Angiotensina/metabolismo , Adaptación Fisiológica/fisiología , Análisis de Varianza , Animales , Biopsia , Western Blotting , Colchicina/farmacología , Perros , Sistema de Conducción Cardíaco/efectos de los fármacos , Proteínas de Interacción con los Canales Kv/metabolismo , Masculino , Técnicas de Placa-Clamp , Canales de Potasio/efectos de los fármacosRESUMEN
BACKGROUND: In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel is largely inactivated, contributing to slow conduction and reentry. We have demonstrated that adenoviral delivery of the skeletal muscle Na(+) channel (SkM1) to epicardial border zones normalizes conduction and reduces induction of ventricular tachycardia/ventricular fibrillation. We now studied the impact of canine mesenchymal stem cells (cMSCs) in delivering SkM1. METHODS AND RESULTS: cMSCs were isolated and transfected with SkM1. Coculture experiments showed cMSC/SkM1 but not cMSC alone and maintained fast conduction at depolarized potentials. We studied 3 groups in the canine 7d infarct: sham, cMSC, and cMSC/SkM1. In vivo epicardial border zones electrograms were broad and fragmented in sham, narrower in cMSCs, and narrow and unfragmented in cMSC/SkM1 (P<0.05). During programmed electrical stimulation of epicardial border zones, QRS duration in cMSC/SkM1 was shorter than in cMSC and sham (P<0.05). Programmed electrical stimulation-induced ventricular tachycardia/ventricular fibrillation was equivalent in all groups (P>0.05). CONCLUSION: cMSCs provide efficient delivery of SkM1 current. The interventions performed (cMSCs or cMSC/SkM1) were neither antiarrhythmic nor proarrhythmic. Comparing outcomes with cMSC/SkM1 and viral gene delivery highlights the criticality of the delivery platform to SkM1 antiarrhythmic efficacy.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Proteínas Musculares/metabolismo , Infarto del Miocardio/cirugía , Miocitos Cardíacos/metabolismo , Canales de Sodio/metabolismo , Sodio/metabolismo , Taquicardia Ventricular/prevención & control , Fibrilación Ventricular/prevención & control , Potenciales de Acción , Animales , Animales Recién Nacidos , Estimulación Cardíaca Artificial , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Perros , Técnicas Electrofisiológicas Cardíacas , Humanos , Proteínas Musculares/genética , Infarto del Miocardio/complicaciones , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.5 , Ratas , Ratas Sprague-Dawley , Canales de Sodio/genética , Taquicardia Ventricular/etiología , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatología , Factores de Tiempo , Transfección , Fibrilación Ventricular/etiología , Fibrilación Ventricular/genética , Fibrilación Ventricular/metabolismo , Fibrilación Ventricular/fisiopatologíaRESUMEN
AIMS: Reentry accounts for most life-threatening arrhythmias, complicating myocardial infarction, and therapies that consistently prevent reentry from occurring are lacking. In this study, we compare antiarrhythmic effects of gene transfer of green fluorescent protein (GFP; sham), the skeletal muscle sodium channel (SkM1), the liver-specific connexin (Cx32), and SkM1/Cx32 in the subacute canine infarct. METHODS AND RESULTS: Immediately after ligation of the left anterior descending artery, viral constructs were implanted in the epicardial border zone (EBZ). Five to 7 days later, efficient restoration of impulse propagation (narrow QRS and local electrogram duration) occurred in SkM1, Cx32, and SkM1/Cx32 groups (P< 0.05 vs. GFP). Programmed electrical stimulation from the EBZ induced sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) in 15/22 GFP dogs vs. 2/12 SkM1, 6/14 Cx32, and 8/10 SkM1/Cx32 (P< 0.05 SkM1 vs. GFP). GFP, SkM1, and SkM1/Cx32 had predominantly polymorphic VT/VF, whereas in Cx32 dogs, monomorphic VT predominated (P< 0.05 for Cx32 vs. GFP). Tetrazolium red staining showed significantly larger infarcts in Cx32- vs. GFP-treated animals (P< 0.05). CONCLUSION: Whereas SkM1 gene transfer reduces the incidence of inducible VT/VF, Cx32 therapy to improve gap junctional conductance results in larger infarct size, a different VT morphology, and no antiarrhythmic efficacy.
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Arritmias Cardíacas/tratamiento farmacológico , Conexinas/metabolismo , Uniones Comunicantes/efectos de los fármacos , Proteínas Musculares/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/fisiopatología , Canales de Sodio/metabolismo , Fibrilación Ventricular/tratamiento farmacológico , Animales , Antiarrítmicos/uso terapéutico , Conexinas/genética , Perros , Estimulación Eléctrica , Electrocardiografía , Masculino , Ratones , Proteínas Musculares/genética , Ratas , Canales de Sodio/genética , Fibrilación Ventricular/fisiopatología , Proteína beta1 de Unión ComunicanteRESUMEN
Biological pacing has been proposed as a physiologic counterpart to electronic pacing, and the sinoatrial node (SAN) is the general standard for biological pacemakers. We tested the expression of SAN pacemaker cell activity when implanted autologously in the right ventricle (RV). We induced complete heart block and implanted electronic pacemakers in the RV of adult mongrel dogs. Autologous SAN cells isolated enzymatically were studied by patch clamp to confirm SAN identity. SAN cells (400,000) were injected into the RV subepicardial free wall and dogs were monitored for 2 weeks. Pacemaker function was assessed by overdrive pacing and IV epinephrine challenge. SAN cells expressed a time-dependent inward current (I(f)) activating on hyperpolarization: density = 4.3 ± 0.6 pA/pF at -105 mV. Four of the six dogs demonstrated >50% of beats originating from the implant site at 24 h. Biological pacemaker rates on days 7-14 = 45-55 bpm and post-overdrive escape times = 1.5-2.5 s. Brisk catecholamine responsiveness occurred. Dogs implanted with autologous SAN cells manifest biological pacing properties dissimilar from those of the anatomic SAN. This highlights the importance of cell and substrate interaction in generating biological pacemaker function.
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Relojes Biológicos/fisiología , Nodo Sinoatrial/trasplante , Potenciales de Acción/efectos de los fármacos , Animales , Relojes Biológicos/efectos de los fármacos , Células Cultivadas , Perros , Electrocardiografía , Epinefrina/farmacología , Bloqueo Cardíaco/fisiopatología , Ventrículos Cardíacos/fisiopatología , Masculino , Técnicas de Placa-Clamp , Nodo Sinoatrial/citología , Trasplante AutólogoRESUMEN
BACKGROUND: Biological pacemakers based on the HCN2 channel isoform respond to beta-adrenergic and muscarinic stimulation, suggesting a capacity to respond to autonomic input. OBJECTIVE: The purpose of this study was to investigate autonomic response to emotional arousal in canines implanted with murine HCN2-based biological pacemakers using gene therapy. METHODS: An electronic pacemaker was implanted with its lead in the right ventricular apical endocardium (VVI 35 bpm). An adenoviral HCN2/GFP construct (Ad-HCN2, n = 7) or saline (control, n = 5) was injected into the left bundle branch on day 2 after radiofrequency ablation of the atrioventricular node to induce complete atrioventricular block. Emotional arousal was achieved by presenting food following an overnight fast. Autonomic control was evaluated with Poincaré plots of R-R(N) against R-R(N+1) intervals to characterize heart rate variability (HRV) and with continuous RR interval assessment via 24-hour ambulatory ECG. The 24-hour ECG and Poincaré plot shape were analyzed. RESULTS: During day 1 after biological pacemaker implantation, Poincaré HRV parameters and RR intervals were unchanged with food presentation. However, on day 7, food presentation was accompanied by an increase in HRV (SD1, p < 0.07, and SD2, p < 0.05) and shortening of RR interval (P < .05) in dogs with Ad-HCN2 but not in controls. CONCLUSION: This is the first demonstration that biological pacemakers are capable of responding to natural arousal stimuli to elicit appropriate chronotropic responses, a potential advantage over electronic pacemakers.
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Nivel de Alerta/fisiología , Relojes Biológicos/fisiología , Emociones/fisiología , Adenoviridae/genética , Animales , Bloqueo Atrioventricular/fisiopatología , Bloqueo Atrioventricular/terapia , Perros , Electrocardiografía , Terapia Genética , Proteínas Fluorescentes Verdes , Frecuencia Cardíaca/fisiología , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Canales Iónicos/fisiología , Sustancias Luminiscentes , Marcapaso ArtificialRESUMEN
BACKGROUND: Skeletal muscle sodium channel (Nav1.4) expression in border zone myocardium increases action potential upstroke velocity in depolarized isolated tissue. Because resting membrane potential in the 1-week canine infarct is reduced, we hypothesized that conduction velocity (CV) is greater in Nav1.4 dogs compared with in control dogs. OBJECTIVE: The purpose of this study was to measure CV in the infarct border zone border in dogs with and without Nav1.4 expression. METHODS: Adenovirus was injected in the infarct border zone in 34 dogs. The adenovirus incorporated the Nav1.4- and a green fluorescent protein (GFP) gene (Nav1.4 group, n = 16) or only GFP (n = 18). After 1 week, upstroke velocity and CV were measured by sequential microelectrode recordings at 4 and 7 mM [K(+)] in superfused epicardial slabs. High-density in vivo epicardial activation mapping was performed in a subgroup (8 Nav1.4, 6 GFP) at three to four locations in the border zone. Microscopy and antibody staining confirmed GFP or Nav1.4 expression. RESULTS: Infarct sizes were similar between groups (30.6% +/- 3% of left ventricle mass, mean +/- standard error of the mean). Longitudinal CV was greater in Nav1.4 than in GFP sites (58.5 +/- 1.8 vs. 53.3 +/- 1.2 cm/s, 20 and 15 sites, respectively; P <.05). Transverse CV was not different between the groups. In tissue slabs, dV/dt(max) was higher and CV was greater in Nav1.4 than in control at 7 mM [K(+)] (P <.05). Immunohistochemical Nav1.4 staining was seen at the longitudinal ends of the myocytes. CONCLUSION: Nav1.4 channels in myocardium surviving 1 week infarction increases longitudinal but not transverse CV, consistent with the increased dV/dt(max) and with the cellular localization of Nav1.4.
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Sistema de Conducción Cardíaco/fisiopatología , Músculo Esquelético/fisiología , Infarto del Miocardio/fisiopatología , Canales de Sodio/biosíntesis , Potenciales de Acción , Animales , Modelos Animales de Enfermedad , PerrosRESUMEN
BACKGROUND: Left ventricular pacing (LVP) to induce cardiac memory (CM) in dogs results in a decreased transient outward K current (I(to)) and reduced mRNA and protein of the I(to) channel accessory subunit, KChIP2. The KChIP2 decrease is attributed to a decrease in its transcription factor, cyclic adenosine monophosphate response element binding protein (CREB). OBJECTIVE: This study sought to determine the mechanisms responsible for the CREB decrease that is initiated by LVP. METHODS: CM was quantified as T-wave vector displacement in 18 LVP dogs. In 5 dogs, angiotensin II receptor blocker, saralasin, was infused before and during pacing. In 3 dogs, proteasomal inhibitor, lactacystin, was injected into the left anterior descending artery before LVP. Epicardial biopsy samples were taken before and after LVP. Neonatal rat cardiomyocytes (NRCM) were incubated with H(2)O(2) (50 micromol/l) for 1 hour with or without lactacystin. RESULTS: LVP significantly displaced the T-wave vector and was associated with increased lipid peroxidation and increased tissue angiotensin II levels. Saralasin prevented T-vector displacement and lipid peroxidation. CREB was significantly decreased after 2 hours of LVP and was comparably decreased in H(2)O(2)-treated NRCM. Lactacystin inhibited the CREB decrease in LVP dogs and H(2)O(2)-treated NRCM. LVP and H(2)O(2) both induced CREB ubiquitination, and the H(2)O(2)-induced CREB decrease was prevented by knocking down ubiquitin. CONCLUSION: LVP initiates myocardial angiotensin II production and reactive oxygen species synthesis, leading to CREB ubiquitination and its proteasomal degradation. This sequence of events would explain the pacing-induced reduction in KChIP2, and contribute to altered repolarization and the T-wave changes of cardiac memory.
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Estimulación Cardíaca Artificial , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Sistema de Conducción Cardíaco/metabolismo , Proteínas de Interacción con los Canales Kv/análisis , Función Ventricular Izquierda/fisiología , Potenciales de Acción/fisiología , Angiotensina II/fisiología , Animales , Arritmias Cardíacas/metabolismo , Western Blotting , Células Cultivadas , Perros , Canales Iónicos/fisiología , Peroxidación de Lípido , Masculino , Modelos Animales , Modelos Cardiovasculares , Miocardio/metabolismo , Miocitos Cardíacos/citología , Estrés Oxidativo/fisiología , Complejo de la Endopetidasa Proteasomal/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ubiquitina/fisiología , Ubiquitinación , Remodelación Ventricular/fisiologíaRESUMEN
BACKGROUND: In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (V(max)), slow conduction, and reentry. We hypothesized that a fast inward current such as the skeletal muscle sodium channel (SkM1) operating more effectively at depolarized membrane potentials might restore fast conduction in epicardial border zones and be antiarrhythmic. METHODS AND RESULTS: Computer simulations were done with a modified Hund-Rudy model. Canine myocardial infarcts were created by coronary ligation. Adenovirus expressing SkM1 and green fluorescent protein or green fluorescent protein alone (sham) was injected into epicardial border zones. After 5 to 7 days, dogs were studied with epicardial mapping, programmed premature stimulation in vivo, and cellular electrophysiology in vitro. Infarct size was determined, and tissues were immunostained for SkM1 and green fluorescent protein. In the computational model, modest SkM1 expression preserved fast conduction at potentials as positive as -60 mV; overexpression of SCN5A did not. In vivo epicardial border zone electrograms were broad and fragmented in shams (31.5 +/- 2.3 ms) and narrower in SkM1 (22.6 +/- 2.8 ms; P=0.03). Premature stimulation induced ventricular tachyarrhythmia/fibrillation >60 seconds in 6 of 8 shams versus 2 of 12 SkM1 (P=0.02). Microelectrode studies of epicardial border zones from SkM1 showed membrane potentials equal to that of shams and V(max) greater than that of shams as membrane potential depolarized (P<0.01). Infarct sizes were similar (sham, 30 +/- 2.8%; SkM1, 30 +/- 2.6%; P=0.86). SkM1 expression in injected epicardium was confirmed immunohistochemically. CONCLUSIONS: SkM1 increases V(max) of depolarized myocardium and reduces the incidence of inducible sustained ventricular tachyarrhythmia/fibrillation in canine infarcts. Gene therapy to normalize activation by increasing V(max) at depolarized potentials may be a promising antiarrhythmic strategy.
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Terapia Genética/métodos , Sistema de Conducción Cardíaco/fisiología , Modelos Cardiovasculares , Canales de Sodio/genética , Taquicardia Ventricular/fisiopatología , Taquicardia Ventricular/terapia , Potenciales de Acción/fisiología , Adenoviridae/genética , Animales , Línea Celular , Simulación por Computador , Modelos Animales de Enfermedad , Perros , Expresión Génica , Proteínas Fluorescentes Verdes/genética , Humanos , Técnicas In Vitro , Riñón/citología , Masculino , Músculo Esquelético/fisiología , Contracción Miocárdica/fisiología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Canal de Sodio Activado por Voltaje NAV1.5 , Penicilina G/metabolismo , Pericardio/fisiología , Canales de Sodio/metabolismo , Canales de Sodio/fisiología , Taquicardia Ventricular/patologíaAsunto(s)
Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/fisiopatología , Inhibidores de Fosfodiesterasa/uso terapéutico , Receptores de Serotonina/metabolismo , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/uso terapéutico , Disfunción Eréctil/sangre , Predicción , Humanos , Masculino , Receptores de Serotonina/efectos de los fármacos , Sensibilidad y Especificidad , Transducción de SeñalRESUMEN
BACKGROUND: Diabetic nephropathy is a common cause of impaired renal function. We investigated the effect vardenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, has on renal function in the diabetic rabbit. MATERIALS AND METHODS: Blood was taken at 4 and 6 months from control and alloxan-induced diabetic animals (n=8, in each group) and biochemical variables pertaining to renal function determined. A 7-month sample was also analysed after giving control and diabetic animals (n=4 in each group) either vardenafil (3 mg/kg) or vehicle to drink for 4 weeks. Spot urine total protein/ creatinine ratio (TP/C) was determined at 4 and 6 months. At 7 months a 24 h-urine sample was collected to measure TP/C and creatinine clearance (CrCl). RESULTS: There was a significant increase in serum creatinine concentration after 6 months diabetes, which was significantly reduced by vardenafil. TP/C from diabetic rabbit spot urine samples at 6 months were significantly elevated compared to control animals, indicating the presence of proteinuria. Vardenafil treatment caused a normalisation of TP/C. Diabetic animals receiving vardenafil showed a significant improvement in CrCl when compared with diabetic animals given vehicle. CONCLUSION: These findings highlight a potential role for vardenafil in the treatment of diabetic nephropathy.
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Diabetes Mellitus/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Imidazoles/uso terapéutico , Riñón/efectos de los fármacos , Riñón/fisiología , Inhibidores de Fosfodiesterasa 5 , Piperazinas/uso terapéutico , Administración Oral , Aloxano/farmacología , Animales , Creatina/sangre , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Diabetes Mellitus/inducido químicamente , Imidazoles/administración & dosificación , Riñón/ultraestructura , Masculino , Microscopía Electrónica de Transmisión , Proyectos Piloto , Piperazinas/administración & dosificación , Conejos , Sulfonas/administración & dosificación , Sulfonas/uso terapéutico , Factores de Tiempo , Triazinas/administración & dosificación , Triazinas/uso terapéutico , Diclorhidrato de VardenafilRESUMEN
INTRODUCTION: Serotonin (5-hydroxytryptamine; 5-HT) can cause contraction in cavernosal smooth muscle. We further evaluated this effect of 5-HT. METHODS: Organ bath studies were used. RESULTS: 5-HT induced a sustained contraction occasionally accompanied by a transient relaxation (in 30% of rabbit cavernosal tissues) that preceded the contraction. Ondansetron and Y-25130 (both 5-HT3 receptor antagonists) but not SB-269970 (a 5-HT7 receptor antagonist) significantly inhibited or abolished this transient relaxation. Doxazosin (dox, an alpha1-receptor antagonist) and ketanserin (ketan, a 5-HT2A receptor antagonist) significantly inhibited or abolished the sustained contraction. The effects of dox on 5-HT-mediated contraction were concentration-dependent. CONCLUSIONS: Our findings further confirm that the peripheral serotonergic pathway may play a part in the erectile process via 5-HT2A receptor-mediated contractile and 5-HT3 receptor-mediated relaxant activities. Our results also support the findings of human studies, which suggest that both ketan and dox may exert beneficial effects on the erectile process.
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Contracción Muscular , Relajación Muscular , Músculo Liso/metabolismo , Erección Peniana , Pene/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Serotonina/metabolismo , Antagonistas Adrenérgicos alfa/farmacología , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Erección Peniana/efectos de los fármacos , Pene/efectos de los fármacos , Pene/enzimología , Conejos , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos alfa/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2 , Antagonistas del Receptor de Serotonina 5-HT3 , Antagonistas de la Serotonina/farmacologíaRESUMEN
Current available treatment options for erectile dysfunction (ED) are effective but not without failure and/or side effects. Although the development of phosphodiesterase type 5 (PDE5) inhibitors (i.e. sildenafil, tadalafil and vardenafil) has revolutionized the treatment of ED, these oral medications require on-demand access and are not as effective in treating ED related to diabetic, post-prostatectomy and severe veno-occlusive disease states. Improvement in the treatment of ED is dependent on understanding the regulation of human corporal smooth muscle tone and on the identification of relevant molecular targets. Future ED therapies might consider the application of molecular technologies such as gene therapy. As a potential therapeutic tool, gene therapy might provide an effective and specific means for altering intracavernous pressure "on demand" without affecting resting penile function. However, the safety of gene therapy remains a major hurdle to overcome before being accepted as a mainstream treatment for ED. Gene therapy aims to cure the underlying conditions in ED, including fibrosis. Furthermore, gene therapy might help prolong the efficacy of the PDE5 inhibitors by improving penile nitric oxide bioactivity. It is feasible to apply gene therapy to the penis because of its location and accessibility, low penile circulatory flow in the flaccid state and the presence of endothelial lined (lacunar) spaces. This review provides a brief insight of the current role of gene therapy in the management of ED.
Asunto(s)
Disfunción Eréctil/genética , Disfunción Eréctil/terapia , Terapia Genética , 3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Disfunción Eréctil/tratamiento farmacológico , Técnicas de Transferencia de Gen , Terapia Genética/efectos adversos , Humanos , Masculino , Inhibidores de Fosfodiesterasa/uso terapéutico , Vasodilatadores/uso terapéuticoRESUMEN
Penile erection results from the balance between relaxation and contractile mechanisms of the corpus cavernosum. Only a few studies suggest a role for endogenous contractile agents such as 5-hydroxytryptamine (5-HT). Our aim was to confirm the possible role of 5-HT in human erection. The effect of 5-HT on human cavernosal tissues, as well as those of doxazosin (shown previously to have 5-HT inhibitory action), ketanserin (5-HT (2A) receptor antagonist), NAN-190 (5-HT (1A) receptor antagonist), and SB 203186 (5-HT (4) receptor antagonist) on 5-HT-mediated effects, were assessed using the organ bath technique, including electrical field stimulation study (EFS). Results are presented as median (mg/mg = mg contraction/mg of tissue). Consistent 5-HT-mediated (10(-3) M) contractions were demonstrated (n = 18; 63 mg/mg). These contractions were inhibited with ketanserin by 90% (n = 8), NAN-190 by 68% (n = 12), and SB 203186 by 55% (n = 12). Doxazosin showed a similar 5-HT inhibitory action in a concentration-dependent manner (10(-4) M; 94% reduction; n = 8, 10(-6) M; 68.3% reduction; n = 8). Our EFS studies indicated the presence of neuronally derived 5-HT and that a majority of the nonnoradrenogenic contraction (54%) was mediated via 5-HT(2A) receptors. These findings suggest that 5-HT may play a role in the human detumescence process via 5-HT(1A), 5-HT(2A), and 5-HT(4) receptors. Neuronally released 5-HT is probably an important contractile neurotransmitter in the erectile process. Doxazosin, ketanserin, and 5-HT(1A) and 5-HT(4) receptor antagonists may be useful as part of combination therapy used to treat erectile dysfunction.
Asunto(s)
Doxazosina/farmacología , Contracción Muscular/efectos de los fármacos , Pene/fisiología , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT2 , Antagonistas del Receptor de Serotonina 5-HT4 , Antagonistas de la Serotonina/farmacología , Serotonina/fisiología , Adulto , Atropina/farmacología , Estimulación Eléctrica , Guanetidina/farmacología , Humanos , Técnicas In Vitro , Indoles/farmacología , Ketanserina/farmacología , Masculino , Persona de Mediana Edad , NG-Nitroarginina Metil Éster/farmacología , Erección Peniana/efectos de los fármacos , Pene/efectos de los fármacos , Piperazinas/farmacología , Piperidinas/farmacologíaRESUMEN
The oral phosphodiesterase type 5 (PDE5) inhibitors have made a valuable contribution to the treatment of erectile dysfunction (ED). PDE5 inhibitors enhance cavernosal smooth muscle relaxation, vasodilatation and penile erection. However, PDE5 inhibitors are not always effective. Decreased efficacy, cost, incorrect administration, lack of sexual stimulation, vascular risk factors associated with ED and vascular or neurogenic diseases are causes of PDE5 inhibitor failure. Tachyphylaxis may also occur. This is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug. Treatment failure may cause considerable distress. If dose titration, more attempts and continuous dosing of PDE5 inhibitors (taken on a daily basis) fail to resolve the initial PDE5 inhibitor failure, clinicians need to consider alternative treatments. These include sublingual apomorphine, intracavernosal/intraurethral pharmacotherapy, vacuum devices, the insertion of a prosthesis and penile vascular surgery. Combination therapy like prostaglandin E(1) (PGE(1)) with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan; a 5-HT(2) antagonist) as well as other pro-erection agents, like Endothelin-1 antagonists, angiotensin II antagonists (valsartan/losartan), adrenomedullin, Rho kinase inhibitors and nitric oxide (NO) donors may be beneficial in the treatment of ED. However, these combination therapies need to be validated. Adding an androgen to a PDE5 inhibitor may help when circulatory testosterone levels are low. The early use of PDE5 inhibitors in patients with hypertension, hyperlipidaemia or diabetes with concomitant ED and treating these risk factors may improve corporeal blood flow and lead to long-term preservation of cavernosal function. Therefore, the efficacy of PDE5 inhibitors may be maintained. Targeting the risk factors of ED (similar to those for arteriosclerosis) in the early stages of the disease may prevent the development or decrease the severity of ED.
Asunto(s)
Impotencia Vasculogénica/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/fisiología , 3',5'-GMP Cíclico Fosfodiesterasas , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Humanos , Impotencia Vasculogénica/prevención & control , Masculino , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Endothelin (ET-1) may play a role in the regulation of erection but this has not been conclusively demonstrated. Augmented cavernosal smooth muscle (CSM) contraction in the rat occurs following exposure to both ET-1 and phenylephrine (PE; alpha-1 agonist). The aim of this study was to assess the effect of ET-1 and its possible role in the alpha1-adrenergic pathway during the erectile process. MATERIALS AND METHODS: Organ bath studies were performed on CSM strips of penises obtained from 12 age-matched New Zealand White rabbits. The effect of ET-1 and PE alone on CSM tone in the absence and presence of ETA (BQ123) and ETB (BQ788) antagonists was assessed. Tissue responses were measured as tension (newton, N). EC50 values are expressed as mean +/- S.E.M. RESULTS: PE (10(8) - 10(-4) M) and ET-1 (10(-10) - 10(-6) M) produced a concentration-dependent contraction in rabbit CSM strips. The EC50 values were 1.7 x 10(-7) M +/- 1.1 and 3.4 x 10(-9) M +/- 1.5, respectively. BQ123 10(-5) M significantly inhibited ET-1-mediated CSM contractions more than BQ788 10(-5) M (both ANOVA p<0.01). The EC50 were 1.3 x 10(-6) M +/- 2.6 and 2.0 x 10(-7) M +/- 2.1, respectively. Neither the ETA or ETB receptor antagonist had a significant influence on alpha1-adrenergic receptor-mediated CSM contraction. CONCLUSION: ETA receptors may play a greater role than ETB receptors in ET-1-induced rabbit CSM contraction and the detumescence process. The a1-adrenergic-dependent pathway does not involve the ETA or ETB receptors.