Sildenafil in endotoxin-induced pulmonary hypertension: an experimental study

Abstract Background Sepsis and septic shock still represent great challenges in critical care medicine. Sildenafil has been largely used in the treatment of pulmonary arterial hypertension, but its effects in sepsis are unknown. The aim of this study was to investigate the hypothesis that sildenafil can attenuate endotoxin-induced pulmonary hypertension in a porcine model of endotoxemia. Methods Twenty pigs were randomly assigned to Control group (n = 10), which received saline solution; or to Sildenafil group (n = 10), which received sildenafil orally (100 mg). After 30 minutes, both groups were submitted to endotoxemia with intravenous bacterial lipopolysaccharide endotoxin (LPS) infusion (4 µg.kg-1.h-1) for 180 minutes. We evaluated hemodynamic and oxygenation functions, and also lung histology and plasma cytokine (TNFα, IL-1β, IL6, and IL10) and troponin I response. Results Significant hemodynamic alterations were observed after 30 minutes of LPS continuous infusion, mainly in pulmonary arterial pressure (from Baseline 19 ± 2 mmHg to LPS30 52 ± 4 mmHg, p< 0.05). There was also a significant decrease in PaO2/FiO2 (from Baseline 411 ± 29 to LPS180 334 ± 49, p< 0.05). Pulmonary arterial pressure was significantly lower in the Sildenafil group (35 ± 4 mmHg at LPS30, p< 0.05). The Sildenafil group also presented lower values of systemic arterial pressure. Sildenafil maintained oxygenation with higher PaO2/FiO2 and lower oxygen extraction rate than Control group but had no effect on intrapulmonary shunt. All cytokines and troponin increased after LPS infusion in both groups similarly. Conclusion Sildenafil attenuated endotoxin-induced pulmonary hypertension preserving the correct heart function without improving lung lesions or inflammation.

Tratamiento con sildenafilo en disfunción ventricular izquierda e hipertensión pulmonar asociada / Treatment with sildenafil in left ventricular dysfunction and associated pulmonary hypertension

RESUMEN Introducción: la hipertensión pulmonar es un hallazgo frecuente en la insuficiencia cardíaca. El uso del sildenafilo en estos casos es una práctica habitual, pero aún controversial por lo limitado de los estudios realizados. Objetivo: comparar las variables ecocardiográficas de hemodinamia pulmonar, en pacientes con disfunción sistólica ventricular izquierda e hipertensión pulmonar secundaria severa, antes y después del uso del sildenafilo. Materiales y métodos: se realizó un estudio de cohorte, donde se incluyeron 19 pacientes; se realizó un seguimiento de dos años. Se analizaron variables clínicas, de laboratorio y ecocardiográficas. Se evaluaron las principales variables de hemodinamia pulmonar antes del uso del sildenafilo y a las doce semanas de su indicación. Se realizó una curva de supervivencia al concluir el seguimiento. El nivel de significación estadístico empleado fue de p < 0,05. Resultados: la edad promedio fue de 56,16 ± 15,77 años y predominó el sexo masculino, con un 73,7 %. La supervivencia al término del seguimiento fue de 78,9 %. Las principales variables ecocardiográficas de hemodinamia pulmonar mostraron una reducción significativa a las doce semanas del tratamiento con sildenafilo. La supervivencia de los pacientes con una reducción del 25 % de las presiones pulmonares en el ecocardiograma realizado a las doce semanas del tratamiento, fue mayor al terminar el estudio (100 % vs 33 %, log-rank test p = 0,001). Conclusiones: posterior al uso del sildenafilo se encontró una reducción significativa de las variables de hemodinamia pulmonar en el ecocardiograma evolutivo. La sobrevida fue mayor en los pacientes que presentaron dicha reducción (AU).

ABSTRACT Introduction: pulmonary hypertension is a common finding in heart failure. The use of sildenafil in these cases is a common practice, but still controversial due to the limited number of studies carried out. Objective: to compare echocardiographic variables of pulmonary hemodynamics, in patients with left ventricular systolic dysfunction and severe secondary pulmonary hypertension, before and after the use of sildenafil. Materials and methods: a cohort study was led, including 19 patients; a two-year follow-up was carried out. Clinical, laboratory and echocardiographic variables were analyzed. The main pulmonary hemodynamics variables were evaluated before the use of sildenafil and 12 weeks after its indication. A survival curve was performed at the end of the follow-up. The statistical significance level used was p < 0.05. Results: the average age was 56.16 ± 15.77 years, and male sex predominated with 73.3 %. Survival at the end of the follow up was 78.9 %. The main echocardiographic variables of pulmonary hemodinamics showed a significant reduction at 12 weeks of treatment with sildenafil. The survival of patients with a 25 % reduction in pulmonary pressures in the echocardiogram performed at 12 weeks of treatment was greater at the end of the study (100 % vs 33 %, log-rank test p = 0.001). Conclusions: after using sildenafil, a significant reduction of pulmonary hemodynamics variables was found in the evolutionary echocardiogram. Survival was higher in patients who had this reduction (AU).

Effect of creatine and sildenafil citrate on the physical performance of mice / Efecto de la creatina y del citrato de sildenafil sobre el desempeño físico de ratones / Efeito da creatina e do citrato de sildenafila sobre o desempenho físico de camundongos

ABSTRACT Introduction: The use of substances to enhance sports performance among professional and amateur athletes is increasing. Such substances may either be included in the group of dietary supplements or fall into pharmacological classes. Every substance used for this purpose is called an ergogenic agent. The number of ergogenic options available increases every day, favoring overuse and use without proper guidance. Among the dietary supplements, we highlight the use of creatine, a substance widespread in sports. Among the pharmacological groups, many drugs are used. Recently the use of sildenafil citrate by professional athletes from various predominantly aerobic sports modalities was reported in the media. Objective: To compare and demonstrate the responses caused by physical training associated with the use of creatine and sildenafil citrate in mice. Methods: A swim training protocol was applied and then an electrophysiograph was used in order to obtain parameters related to contraction intensity, the area under the curve and the percentage drop. Results: The responses obtained demonstrated the ergogenic action of creatine because it altered the parameters used for measurement. The use of sildenafil citrate did not yield satisfactory results to frame the drug as an ergogenic agent. Conclusion: Creatine has an ergogenic effect, reducing the percentage drop after 10 seconds, while sildenafil demonstrated no ergogenic potential and, interestingly, resulted in weaker responses when compared to the exercise groups. Evidence level II; Comparative prospective study .

RESUMEN Introducción: El uso de sustancias con el objetivo de aumentar el rendimiento deportivo entre atletas profesionales y amateurs es creciente. Tales sustancias pueden formar parte del grupo de suplementos alimentarios o integrar clases farmacológicas. Toda sustancia empleada para ese fin es denominada agente ergogénico. El número de opciones entre los agentes ergogénicos aumenta cada día, favoreciendo así su uso excesivo y sin la debida orientación. Entre los suplementos alimentarios, se destaca el uso de creatina, sustancia muy difundida en el medio deportivo. Ya entre los grupos farmacológicos, muchas sustancias son usadas. Recientemente, fue divulgado entre los medios de comunicación el uso de citrato de sildenafil por atletas profesionales, de varias modalidades deportivas, predominantemente las aeróbicas. Objetivos: Comparar y demostrar las respuestas ocasionadas por el entrenamiento físico, asociadas al uso de creatina y citrato de sildenafil en ratones. Métodos: Se aplicó un protocolo de entrenamiento de natación y, a continuación, se usó un electrofisiógrafo con el objetivo de obtener parámetros referentes a la intensidad de contracción, al área bajo la curva y a la caída porcentual. Resultados: Las respuestas obtenidas demuestran acción ergogénica de la creatina, visto que alteraron los parámetros empleados para la medición. Ya el uso de citrato de sildenafil no presentó resultados satisfactorios para encuadrar al fármaco como agente ergogénico. Conclusión: La creatina presenta efecto ergogénico porque reduce la caída porcentual después de 10 segundos, mientras que el sildenafil no presentó potencial ergogénico y, curiosamente, demostró respuestas inferiores cuando comparado a los grupos de ejercicio. Nivel de evidencia II; Estudio prospectivo comparativo .

RESUMO Introdução: O uso de substâncias com o objetivo de aumentar o rendimento esportivo entre atletas profissionais e amadores é crescente. Tais substâncias podem fazer parte do grupo de suplementos alimentares ou integrar classes farmacológicas. Toda substância empregada para esse fim é denominada de agente ergogênico. O número de opções entre os agentes ergogênicos aumenta a cada dia, favorecendo assim o uso em demasia e sem a devida orientação. Entre os suplementos alimentares, salientamos a utilização de creatina, substância muito difundida no meio esportivo. Já entre os grupos farmacológicos, muitas substâncias são utilizadas. Recentemente, foi divulgado entre os meios de comunicação o uso de citrato de sildenafila por atletas profissionais de várias modalidades esportivas, predominantemente as aeróbicas. Objetivos: Comparar e demonstrar as repostas ocasionadas pelo treinamento físico, associadas ao uso de creatina e citrato de sildenafila em camundongos. Métodos: Aplicou-se um protocolo de treinamento de natação e, a seguir, empregou-se um eletrofisiógrafo com objetivo de obter parâmetros referentes à intensidade de contração, à área sob a curva e à queda percentual. Resultados: As respostas obtidas demonstram ação ergogênica da creatina, visto que alteraram os parâmetros empregados para a mensuração. Já a utilização de citrato de sildenafila não apresentou resultados satisfatórios para enquadrar o fármaco como agente ergogênico. Conclusão: A creatina apresenta efeito ergogênico porque reduz a queda percentual após 10 segundos, já a sildenafila não apresentou potencial ergogênico e, curiosamente, demonstrou respostas inferiores quando comparado aos grupos de exercício. Nível de evidência II; Estudo prospectivo comparativo .

Evaluation of relaxant responses properties of cinnamon essential oil and its major component, cinnamaldehyde on human and rat corpus cavernosum

ABSTRACT Cinnamomum cassia (Cinnamon) is a well-known traditional medicine with therapeutic benefits for centuries. We evaluated the effects of cinnamon essential oil (CEO) and its main component cinnamaldehyde (CA) on human corpus cavernosum (HCC) and rat CC. The essential oil of cinnamon was analyzed for the confirmation of the oil profile. HCC specimens from patients undergoing penile prosthesis surgery (age 48-69 years) were utilized for functional studies. In addition, erectile responses in anesthetized control and diabetic rats were evaluated in vivo after intracavernosal injection of CEO and CA, and rat CC strips were placed in organ baths. After precontraction with phenylephrine (10µM), relaxant responses to CEO and CA were investigated. CA (96.9%) was found as the major component. The maximum relaxation responses to CEO and CA were 96.4±3.5% and 96.0±5.0% in HCC and 97.5±5.5% and 96.8±4.8% in rat CC, respectively. There was no difference between control and diabetic rats in relaxation responses to CEO and CA. The relaxant responses obtained with essential oil and CA were not attenuated in the presence of nitric oxide synthase (NOS) inhibitor, and soluble guanylate cyclase inhibitor (sGS) in CC. In vivo, erectile responses in diabetic rats were lower than in control rats, which was restored after intracavernosal injection of CEO and CA. CEO and CA improved erectile function and relaxation of isolated strips of rat CC and HCC by a NO/cGMP-independent mechanism. Further investigations are warranted to fully elucidate the restorative effects of CEO and CA on diabetic erectile dysfunction.

Evaluation of prophylactic and therapeutic effects of sildenafil on acute radiation proctitis in rats

Abstract Purpose: To investigate the prophylactic and therapeutical effects of sildenafil in a model of acute radiation proctitis (ARP). Methods: All experimental procedures of this study was examined by histopathological, immunohistochemical and transmission electron microscopic analysis. Results: Our histopathological evaluations indicated significant increases in lesion severity, cryptic apsis, cryptitis, cryptic distortion, reactive atypia and infiltration depth of the control (proctitis) group. While the prophylaxis group and the treatment group had significantly lower scores. High-dose group showed similar results as prophylaxis group. Histopathological findings of the prophylaxis group was more significant than the treatment group. Immunoreactivities of IL-1β, FGF-2, TNF- α and HIF-1α increased in the control group especially in the epithelial and cryptic regions. On the contrary, sildenafil application caused significant decreases of inflammatory markers in all treatment groups, specifically better results in the prophylaxis group. Conclusion: The sildenafil has anti-inflammatory effects on ARP, as well as protective effects against ARP and the protective effect of sildenafil surpasses its therapeutic effect histopathologically.

Preoperative subcutaneous sildenafil injection increases random flap survival in rats

Abstract Purpose: To investigate the effect of subcutaneous sildenafil on random flap survival. Methods: Fourteen Wistar rats, which were divided in to two groups, were used for this experimental study. Rats in the sildenafil group received subcutaneous sildenafil injections daily for seven days before flap elevation. At the end of the treatment period, 9x3 cm dorsal skin flaps were elevated and reinserted back into their place in all of the animals. Necrotic and whole flaps areas were recorded on graph papers. Seven days after the flap elevation samples for histological examination were taken and angiographies were performed to visualize the flap vascularization. Results: The calculated average percentage of necrotic flap areas were 18.29% and 42.26% in the sildenafil and control group respectively.(p=0.0233). In selected angiography images, vessels were found to be more prominent in the sildenafil group. The average number of capillary formations under light microscopy was higher in the sildenafil group (p= 0.0286). Conclusion: The subdermal high dose sildenafil has a positive effect on flap survival.

Rendimiento deportivo en la altura: Efecto del sildenafil / Sildenafil and exercise performance at altitude

La presión barométrica y la presión parcial de O2 disminuyen con la altura y la hipoxia hipobárica generada es la responsable de las enfermedades relacionadas con la altitud y del deterioro del rendimiento deportivo. Las adaptaciones fisiológicas a la altura son múltiples y contribuyen a la alteración de las diferentes cualidades atléticas. Se ha planteado que el deterioro del VO2 podría estar asociado a incrementos de la resistencia vascular pulmonar, así como a una alteración de la difusión pulmonar de óxido nítrico. La eficacia para el tratamiento de la hipertensión pulmonar demostrada por el sildenafil ha llevado a sugerir que su indicación para competencias en altura podría mejorar el rendimiento. Las investigaciones demuestran resultados diferentes según el nivel de altitud y los tiempos e intensidades del ejercicio. Algunos muestran mejoras del rendimiento, aunque no en todos los participantes. Existen condiciones individuales que podrían resultar en efectos mayores, menores o nulos. En esta presentación se analizan los efectos de la altura sobre la capacidad de esfuerzo, se muestran estudios, efectos colaterales eventuales y repercusiones del empleo de sildenafil para mejorar el rendimiento deportivo en altura. El médico deberá conocer en cada deportista los efectos colaterales individuales que podrían surgir y que influirían negativamente sobre la salud y el rendimiento.

Barometric pressure and partial oxygen pressure decrease with increasing altitude. Hypobaric hypoxia produced is responsible for altitude-related diseases and it can cause severe decrements in exercise performance. The physiological adaptations to the altitude are multiple and they contribute to alter different athletic qualities. The VO2 worsening could be associated to increased pulmonary vascular resistance and nitric oxide diffusion alteration. Performance impairments at altitude can also be accentuated by hypoxia-induced elevations in pulmonary arterial pressure. Clinical studies have demonstrated the beneficial effects of sildenafil on the treatment of pulmonary hypertension. These effects have led to suggest that its indication for competitions at altitude might improve athletic performance. The investigations demonstrate different results depending on the altitude level and times and intensities of exercise. Some studies show performance improvements, although not in all participants. Individual responses vary widely between different athletes. This presentation examines the effects of altitude on exercise capacity and shows studies about the use of sildenafil to improve sport performance. This text also discusses the possible side effects and implications for the use of sildenafil in athletes, indication that is not the basic one of the drug. The physicians must know in each athlete the individual sildenafil side effects that could arise and that would influence negatively on health and performance.

Influence of cyclic guanosine 3', 5' monophosphate modulators on muscle contraction of rat aortas

The study examined the influence of probenecid [Pn], sildenafil [Sd] and oxidiazoloquinoxalin [ODQ] on contraction of phenylephrine [PhE] stimulated rat aortas. The study was performed at Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany, from 1st July to 30th September 2005. Thirty-five isolated rat aortas were stimulated with 10 micro M PhE or preincubated for 30 minutes with 10 micro M Pn, or 10 micro M ODQ, or 50 micro M Sd, and then incubated with 10 micro M PhE in the presence or absence of the substances. The phosphorylated myosin light chain 20 was detected by using an antibody against phosphomyosin light chain 2. The ratio of PhE stimulated phosphorylation of aortas [p<0.05] to the untreated was 16.7:1 at 30 seconds and 20.4:1 at 60 seconds. The stimulation decreased significantly at 120 seconds then during the following 10 minutes. Pre-incubation with 50 micro M Sd [p>0.05] or 10 micro M Pn [p<0.05] reduced the phosphorylation induced by PhE that was added to each for 30 seconds. But pre-incubation with 10 micro M ODQ increased the phosphorylation brought about by addition of PhE for 60 seconds, p>0.05. The washout-effect of these modulators was not significant after stimulation with PhE only. The study demonstrates the involvement of cyclic guanosine 3',5' monophosphate and its modulators on muscle contraction of rat aortas. Sildenafil and Pn reduced while oxidiazoloquinoxalin increased the contraction of rat aortas