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Multidrug resistance proteins type 4 (MRP4) and 5 (MRP5) play pivotal roles in the transport of cyclic nucleotides in various tissues. However, their specific functions within the lower urinary tract remain relatively unexplored. This study aimed to investigate the effect of pharmacological inhibition of MRPs on cyclic nucleotide signaling in isolated pig bladder. The relaxation responses of the bladder were assessed in the presence of the MRP inhibitor, MK571. The temporal changes in intra- and extracellular levels of cAMP and cGMP in stimulated tissues were determined by mass spectrometry. The gene (ABCC4) and protein (MRP4) expression were also determined. MK571 administration resulted in a modest relaxation effect of approximately 26% in carbachol-precontracted bladders. The relaxation induced by phosphodiesterase inhibitors such as cilostazol, tadalafil, and sildenafil was significantly potentiated in the presence of MK571. In contrast, no significant potentiation was observed in the relaxation induced by substances elevating cAMP levels or stimulators of soluble guanylate cyclase. Following forskolin stimulation, both intracellular and extracellular cAMP concentrations increased by approximately 15.8-fold and 12-fold, respectively. Similarly, stimulation with tadalafil + BAY 41-2272 resulted in roughly 8.2-fold and 3.4-fold increases in intracellular and extracellular cGMP concentrations, respectively. The presence of MK571 reduced only the extracellular levels of cGMP. This study reveals the presence and function of MRP4 transporters within the porcine bladder and paves the way for future research exploring the role of this transporter in both underactive and overactive bladder disorders.NEW & NOTEWORTHY This study investigates the impact of pharmacological inhibition of MRP4 and MRP5 transporters on cyclic nucleotide signaling in isolated pig bladders. MK571 administration led to modest relaxation, with enhanced effects observed in the presence of phosphodiesterase inhibitors. However, substances elevating cAMP levels remained unaffected. MK571 selectively reduced extracellular cGMP levels. These findings shed light on the role of MRP4 transporters in the porcine bladder, opening avenues for further research into bladder disorders.

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ß2-adrenoceptors agonists and phosphodiesterase (PDE) inhibitors are effective bronchodilators, due to their ability to increase intracellular cyclic AMP (cAMP) levels and induce airway smooth muscle (ASM) relaxation. We have shown that increment of intracellular cAMP induced by ß2-adrenoceptors agonist fenoterol is followed by efflux of cAMP, which is converted by ecto-PDE and ecto-5'-nucleotidases (ecto-5'NT) to adenosine, leading to ASM contraction. Here we evaluate whether other classical bronchodilators used to treat asthma and chronic obstructive pulmonary disease (COPD) could induce cAMP efflux and, as consequence, influence the ASM contractility. Our results showed that ß2-adrenoceptor agonists formoterol and PDE inhibitors IBMX, aminophylline and roflumilast induced cAMP efflux and a concentration-dependent relaxation of rat trachea precontracted with carbachol. Pretreatment of tracheas with MK-571 (MRP transporter inhibitor), AMP-CP (ecto-5'NT inhibitor) or CGS-15943 (nonselective adenosine receptor antagonist) potentiated the relaxation induced by ß2-adrenoceptor agonists but did not change the relaxation induced by PDE inhibitors. These data showed that all bronchodilators tested were able to induce cAMP efflux. However, only ß2-adrenoceptor-induced relaxation of tracheal smooth muscle was affected by cAMP efflux and extracellular cAMP-adenosine pathway.

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In the present study, we investigated whether magnesium sulphate activates the L-arginine/NO/cGMP pathway and elicits peripheral antinociception. The male Swiss mice paw pressure test was performed with hyperalgesia induced by intraplantar injection of prostaglandin E2. All drugs were administered locally into the right hind paw of animals. Magnesium sulphate (20, 40, 80 and 160 µg/paw) induced an antinociceptive effect. The dose of 80 µg/paw elicited a local antinociceptive effect that was antagonized by the non-selective NOS inhibitor, L-NOArg, and by the selective neuronal NOS inhibitor, L-NPA. The inhibitors, L-NIO and L-NIL, selectively inhibited endothelial and inducible NOS, respectively, but were ineffective regarding peripheral magnesium sulphate injection. The soluble guanylyl cyclase inhibitor, ODQ, blocked the action of magnesium sulphate, and the cGMP-phosphodiesterase inhibitor, zaprinast, enhanced the antinociceptive effects of intermediate dose of magnesium sulphate. Our results suggest that magnesium sulphate stimulates the NO/cGMP pathway via neuronal NO synthase to induce peripheral antinociceptive effects.

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En el presente trabajo se realiza la estandarización del procedimiento espectrofotométrico de determinación de polisacárido capsular e intermedios de Neisseria meningitidis serogrupo X, mediante la determinación de los grupos fosfodiéster presentes en su estructura, por el método de Chen. Se realizó un análisis de los siguientes criterios para la estandarización: linealidad, precisión (repetibilidad y precisión intermedia) y exactitud. Se demostró mediante el diseño experimental y los procedimientos estadísticos empleados que el método es lineal (r > 0,99), el coeficiente de variación del factor respuesta < 5 por ciento, la desviación estándar relativa de la pendiente < 2 por ciento, no existiendo diferencia estadísticamente significativa entre el intercepto de la ecuación con respecto a cero; exacto, porque no existe diferencia estadísticamente significativa entre la concentración determinada en un material de trabajo y su concentración nominal; también demostró ser repetible, pues el coeficiente de variación de las concentraciones de la muestra evaluada (2,44; 2,43; 0,88 por ciento para las concentraciones bajas, medias y altas, respectivamente) es inferior al 3 por ciento y no existen diferencias estadísticamente significativas entre las medias de los resultados obtenidos por dos analistas, evaluados durante cuatro días a tres niveles de concentración. La precisión intermedia es satisfactoria(AU)

The present work comprises the standardization a spectrophotometric procedure for assessing Neisseria meningitidis, serogroup X capsular polysaccharide and their intermediates of modification, the phosphodiesters groups present in its structure, based on Chen method. An analysis of the following standardization criteria was performed: linearity, precision (repeatability and intermediate precision) and accuracy. It was demonstrated through the experimental design and the statistical procedures used that the method is linear (r > 0.99), the coefficient of variation of the response factor < 5 percent, the relative standard deviation of the slope < 2 percent, with no statistically significant difference between the intercept of the equation with respect to zero; exact, because there is no statistically significant difference between the concentration determined in a work material and its nominal concentration; it also proved to be repeatable, because the coefficient of variation of the concentrations of the sample (2.44; 2.43; 0.88 percent for low, medium and high concentrations respectively) is less than 3 percent and there is no statistically significant difference between the means of the results obtained by two analysts, evaluated for four days at three concentration levels. Its intermediate precision was satisfactory(AU)

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A previous work indicates that the red LASER (660 nm) induces vascular relaxation by nitric oxide (NO)-dependent mechanism. NO activates soluble guanylate cyclase (sGC) which produces cGMP, the main effector in the vasodilation pathway. An interesting pharmacological strategy is to control the levels of intracellular cGMP, preventing its efflux (with multidrug-resistant protein blockers, such as MK-571), or preventing its degradation (such as sildenafil, which inhibits the enzyme responsible for cGMP degradation, the phosphodiesterase-5 PDE5). This study aimed to look for pharmacological strategies to improve vasodilation LASER effect in normotensive and hypertensive rats (L-NAME model). The vascular reactivity study was performed in isolated aortic rings from normotensive and hypertensive rats, with a single LASER application and sodium nitroprusside (SNP) treatment. In aortic rings from normotensive rats, MK-571 and sildenafil potentiated the relaxation induced by LASER, compared to control. The vasodilation induced by SNP was potentiated by MK-571 and sildenafil, compared to control. In aortic rings from hypertensive rats, vasodilation effect induced by LASER and by SNP was potentiated just by MK-571, compared to control, with no potentiation by sildenafil. In addition, it was seen that the withdrawal of nitric oxide stocks carried out by L-cysteine is capable of being reversed with the use of the SNP. The results support the evidence that the vasodilation induced by red LASER is potentiated by MK-571 and sildenafil in aortic rings from normotensive rats. However, in aortic rings from L-NAME hypertensive rats, the potentiation in vasodilation was induced just by MK-571.

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The COVID-19 pandemic has established an unparalleled necessity to rapidly find effective treatments for the illness; unfortunately, no specific treatment has been found yet. As this is a new emerging chaotic situation, already existing drugs have been suggested to ameliorate the infection of SARS-CoV-2. The consumption of caffeine has been suggested primarily because it improves exercise performance, reduces fatigue, and increases wakefulness and awareness. Caffeine has been proven to be an effective anti-inflammatory and immunomodulator. In airway smooth muscle, it has bronchodilator effects mainly due to its activity as a phosphodiesterase inhibitor and adenosine receptor antagonist. In addition, a recent published document has suggested the potential antiviral activity of this drug using in silico molecular dynamics and molecular docking; in this regard, caffeine might block the viral entrance into host cells by inhibiting the formation of a receptor-binding domain and the angiotensin-converting enzyme complex and, additionally, might reduce viral replication by the inhibition of the activity of 3-chymotrypsin-like proteases. Here, we discuss how caffeine through certain mechanisms of action could be beneficial in SARS-CoV-2. Nevertheless, further studies are required for validation through in vitro and in vivo models.

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Resumen: Los tumores cardíacos pueden ser primarios o, más frecuentemente secundarios o metastásicos. Entre los tumores primarios es más frecuente el mixoma, cuya ubicación más común es en la aurícula izquierda. Las manifestaciones clínicas son diversas, producidas principalmente por obstrucción mecánica, embolizaciones, y manifestaciones constitucionales. Se comunica el caso de un paciente de 32 años, con cuadro clínico de insuficiencia cardíaca, hipertensión pulmonar severa y tromboembolismo pulmonar bilateral. Se hizo el diagnóstico de mixoma auricular izquierdo. Se resecó el tumor y se manejó la hipertensión pulmonar desde el ingreso al hospital con inhibidores de la fosfodiesterasa asociado a anticoagulación. Se discute el tema dando énfasis a aspectos fisiopatológicos involucrados tanto en la hipertensión pulmonar como en la presencia de tromboembolia pulmonar.

Abstract: Cardiac tumors may be primary or, more frequently secondary or associated to metastasis. Atril myxoma es the most frequent primary tumor, usually located in the left atrium. Clinical manifestations include those due to mitral valve occlusión, emboli and general non spedific symptoms and signs. Herein we report the clinical case of a 32 year old patient with severe pulmonary hypertension and bilateral pulmonary embolism. The tumor was extirpated, and he received phosphoro-diesterase inhiborts and anticoagulants. Subsequent clinical course was satisfactory. A brief discussion of this condicion is included.

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Introducción El deseo sexual hipoactivo describe el bajo interés hacia la actividad sexual en general, caracterizando la escasa o nula motivación para tener relaciones eróticas, con disminución o ausencia de pensamientos o fantasías sexuales. Objetivo Evaluar la prevalencia y factores asociados, al deseo sexual hipoactivo en hombres del Quindío, así como estimar las demás disfunciones sexuales. Métodos Estudio observacional. La población estuvo constituida por 171 hombres que asistieron a consulta externa en una clínica universitaria de la ciudad de Armenia, Colombia, en el 2019. Se excluyeron los hombres menores de 18 años, residentes fuera del Quindío, situación psicopatológica o social que dificultara la comprensión del instrumento y los que no consintieron participar en el estudio. Se aplicó como instrumento el "Massachusetts General Hospital-Sexual Functioning Questionnaire (MGH-SFQ)". Se evaluaron las características socio-demográficas, estilos de vida, salud sexual y reproductiva, antecedentes y comportamiento sexual. Se hizo análisis descriptivo. Resultados La edad promedio fue de 41,79 ± 11,46 años (rango 18­81). La prevalencia de disfunciones sexuales en el grupo estudiado fue de 21,63%. La puntuación del MGH-SFQ fue de 14,61 ± 4,23 puntos (variación: 7,26 - 19,26). Se presentaron dificultades con el interés sexual (15,78%), excitación sexual (6,43%), orgasmo (8,77%), erección (21,63%) y satisfacción sexual global (12,28%). La mediana de disfunciones sexuales por hombre fue de 2, que se hizo presente en el 27,48% %. El análisis multivariado (regresión logística) mostró que los factores asociados al deseo sexual hipoactivo fueron testosterona baja (OR: 5,59; IC95% 1,82­18,37), ansiedad / depresión (OR: 5,53; IC95% 1,72­18,43), convivencia en pareja mayor a 10 años (OR: 5,19; IC95%: 2,71­11,71), ansiedad de desempeño (OR: 4,62; IC95% 1,95­10,56), incremento de la edad (OR: 3,42; IC95%: 1,26­9,36), cansancio / estrés (OR: 2,58; IC95%: 1,08­3,28), trastornos del sueño (OR: 1,89; IC95%: 1,35­2,58), conflictos de pareja (OR: 1,53; IC95%: 1,02­2,37) y antecedente de disfunciones sexuales (OR: 1,47; IC95%: 0,99­2,22); mientras que, el uso de juguetes sexuales (OR: 0,78; IC95%: 0,72­0,96; p = 0,021), consumo de vitamina D (2000 UI / diarias) (OR: 0,64; IC95%: 0,42­0,96) o de Inhibidores de fosfodiesterasa-5 (OR: 0,78; IC95%: 0,63­0,93) constituyeron factores protectores. Conclusiones En el presente estudio, el 21,63% de los hombres presentaron disfunciones sexuales. Los trastornos de la erección (21,63%) y el interés sexual (15,78%), fueron los más afectados. La testosterona baja, ansiedad / depresión y convivencia en pareja mayor a 10 años, encabezan los principales factores asociados al deseo sexual hipoactivo. El hacer actividades juntos (OR: 0,44; IC95%: 0,34­0,68), el respeto a ser personas diferentes (OR: 0,53; IC95%: 0,41­0,71), mantener la armonía en la pareja (OR: 0,61; IC95%: 0,47­0,79) y la expresión de sentimientos a la pareja (OR: 0,68; IC95%: 0,46­0,95) constituyen una línea de protección para mejorar las estrategias de prevención de los trastornos sexuales en esa población

Introduction Hypoactive sexual desire describes the low interest in sexual activity in general, characterizing the little or no motivation to have erotic relationships, with a decrease or absence of sexual thoughts or fantasies. Objective To determine the sexual dysfunctions and to evaluate the prevalence and associated factors, to the hypoactive sexual desire in men of Quindío. Methods Observational study. The population consisted of 171 men who attended an outpatient clinic at a university clinic in the city of Armenia, Colombia, in 2019. Men under 18 years of age, residents outside of Quindío, psychopathological or social situation that made understanding difficult, were excluded of the instrument and those who did not consent to participate in the study. The "Massachusetts General Hospital-Sexual Functioning Questionnaire (MGH-SFQ)" was applied as an instrument. Socio-demographic characteristics, lifestyles, sexual and reproductive health, background and sexual behavior were evaluated. Descriptive analysis was done. Results The average age was 41.79 ± 11.46 years (variation: - 81). The prevalence of sexual dysfunctions in the study group was 21.63%. The MGH-SFQ score was 14.61 ± 4.23 points (range between 7.26 - 19.26). There were difficulties with sexual interest (15.78%), sexual arousal (6.43%), orgasm (8.77%), erection (21.63%) and overall sexual satisfaction (12.28%). The median sexual dysfunction per man was 2, which was present in 27.48%%. The multivariate analysis (logistic regression) showed that the factors associated with hypoactive sexual desire were low testosterone (OR: 5.59; 95% CI 1.82­18.37), anxiety / depression (OR: 5.53 ; 95% CI 1.72­18.43), cohabitation in a couple older than 10 years (OR: 5.19; 95% CI: 2.71­11.71), performance anxiety (OR: 4.62; 95% CI 1.95­10.56), increase in age (OR: 3.42; 95% CI: 1.26­9.36), fatigue / stress (OR: 2.58; 95% CI: 1.08­3, 28), sleep disorders (OR: 1.89; 95% CI: 1.35­2.58), couple conflicts (OR: 1.53; 95% CI: 1.02­2.37) and a history of sexual dysfunctions (OR: 1.47; 95% CI: 0.99­2.22); while, the use of sex toys (OR: 0.78; 95% CI: 0.72­0.96; p = 0.021), vitamin D consumption (2000 IU / daily) (OR: 0.64; 95% CI: 0.42­0.96) or of phosphodiesterase-5 inhibitors (OR: 0.78; 95% CI: 0.63­0.93) constituted protective factors. Conclusions In the present study, 21.63% of men had sexual dysfunction. Disorders of erection (21.63%) and sexual interest (15.78%) were the most affected. Low testosterone, anxiety / depression and coexistence in a couple older than 10 years, lead the main factors associated with hypoactive sexual desire. Low testosterone, anxiety / depression and coexistence in couples older than 10 years, are the main factors associated with hypoactive sexual desire. Doing activities together (OR: 0.44, 95% CI: 0.34­0.68), respect for being different people (OR: 0.53, 95% CI: 0.41­0.71), maintaining harmony in the couple (OR: 0.61; 95% CI: 0.47­0.79) and the expression of feelings toward the couple (OR: 0.68; 95% CI: 0.46­0.95) constitute a protection line to improve prevention strategies for sexual disorders in this population.

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Pyrazolones are heterocyclic compounds with interesting biological properties. Some derivatives inhibit phosphodiesterases (PDEs) and thereby increase the cellular concentration of cyclic AMP (cAMP), which plays a vital role in the control of metabolism in eukaryotic cells, including the protozoan Trypanosoma cruzi, the etiological agent of Chagas disease (CD), a major neglected tropical disease. In vitro phenotypic screening identified a 4-bromophenyl-dihydropyrazole dimer as an anti-T. cruzi hit and 17 novel pyrazolone analogues with variations on the phenyl ring were investigated in a panel of phenotypic laboratory models. Potent activity against the intracellular forms (Tulahuen and Y strains) was obtained with 50% effective concentration (EC50) values within the 0.17 to 3.3 µM range. Although most were not active against bloodstream trypomastigotes, an altered morphology and loss of infectivity were observed. Pretreatment of the mammalian host cells with pyrazolones did not interfere with infection and proliferation, showing that the drug activity was not the result of changes to host cell metabolism. The pyrazolone NPD-227 increased the intracellular cAMP levels and was able to sterilize T. cruzi-infected cell cultures. Thus, due to its high potency and selectivity in vitro, and its additive interaction with benznidazole (Bz), NPD-227 was next assessed in the acute mouse model. Oral dosing for 5 days of NPD-227 at 10 mg/kg + Bz at 10 mg/kg not only reduced parasitemia (>87%) but also protected against mortality (>83% survival), hence demonstrating superiority to the monotherapy schemes. These data support these pyrazolone molecules as potential novel therapeutic alternatives for Chagas disease.

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