Aging-associated prostate smooth muscle hypercontractility in rats

Abstract Benign prostatic hyperplasia (BPH) is a multifactorial disease, highly associated with aging and characterized by increased prostate smooth muscle (PSM) contractility. Animal models have been employed to explore the aging-associated PSM hypercontractility; however, studies have focused in old animals, neglecting the initial alterations in early ages. The determination of prostatic dysfunctions onset is crucial to understand the BPH pathophysiology and to propose new BPH treatments. Considering that PSM contractility in 10-month-old rats has already been explored, the aim of the present study was to characterize the PSM contractility in younger rats. Male Wistar control (3.5-month-old), 6- and 8-month-old rats were used. Concentration-response curves to phenylephrine and electrical-field stimulation (EFS) were conducted in prostate from all groups. For the first time, we showed that 6- and 8-month-old rats exhibit PSM hypercontractility. The increased prostate contractility to phenylephrine starts around at 6-month-old, worsening during the aging. The 8-month-old rats exhibited hypercontractility to phenylephrine and EFS compared to the control and 6-month-old groups. Reduced phenylephrine potency was observed in 8-month-old rats, indicating an increased age-dependent prostate sensibility to this agonist. Collectively, our findings support the use of 6- and 8-month-old aged rats as new models to explore prostate hypercontractility in BPH.

Trends of vasopressor use in intensive care units in Colombia / Tendencias de consumo de vasopresores en unidades de cuidados intensivos de Colombia

Abstract Introduction Vasopressors are essential in the management of various types of shock. Objective To establish the trend of vasopressors use in the intensive care units (ICU) in a population of patients affiliated with the Colombian Health System, 2010-2017. Methods Observational trial using a population database of patients hospitalized in eleven ICUs in various cities in Colombia. The drugs dispensed to hospitalized patients over 18 years old, from January 2010 until December 2017 were considered. A review and analysis of the vasopressors dispensed per month was conducted, taking into account sociodemographic and pharmacological variables (vasopressor used and daily doses defined per 100/beds/day (DBD). Results 81,348 dispensations of vasopressors, equivalent to 26,414 treatments in 19,186 patients receiving care in 11 hospitals from 7 cities were reviewed. The mean age of patients was 66.3±18.1 years and 52.6 % were males. Of the total number of treatments recorded, 17,658 (66.8 %) were with just one vasopressor. Norepinephrine was the most frequently prescribed drug (75.9 % of the prescriptions dispensed; 60.5 DBD), followed by adrenaline (26.6 %; 41.6 DBD), dopamine (19.4%), dobutamine (16.0 %), vasopressin (8.5 %) and phenylephrine (0.9 %). The use of norepinephrine increased from 2010 to 2017 (+6.19 DBD), whilst the use of other drugs decreased, particularly the use of adrenaline (-60.6 DBD) and dopamine (-10.8 DBD). Conclusions Norepinephrine is the most widely used vasopressor showing a growing trend in terms of its use during the study period, which is supported by evidence in favor of its effectiveness and safety in patients with shock.

Resumen Introducción Los fármacos vasopresores son fundamentales en el manejo de los diferentes tipos de choque. Objetivo Determinar la tendencia de utilización de fármacos vasopresores en unidades de cuidados intensivos (UCI) en una población de pacientes afiliados al Sistema de Salud de Colombia, 2010-2017. Métodos Estudio observacional, a partir de una base de datos poblacional con pacientes hospitalizados en once UCI de diferentes ciudades de Colombia. Se obtuvieron las dispensaciones de pacientes mayores de 18 años hospitalizados desde enero de 2010 hasta diciembre de 2017. Se hizo revisión y análisis de la dispensación mensual de vasopresores. Se consideraron variables sociodemográficas y farmacológicas (medicamento vasopresor usado y dosis diarias definidas por 100 camas/día [DCD]). Resultados Se revisaron 81.348 dispensaciones de vasopresores, equivalentes a 26.414 terapias en 19.186 pacientes atendidos en 11 hospitales de 7 ciudades, cuya edad promedio fue 66,3±18,1 años y el 52,6 % eran hombres. Del total de terapias registradas, 17.658 (66,8 %) fueron con un solo vasopresor. La norepinefrina fue el más comúnmente prescrito (75,9 % de las dispensaciones; 60,5 DCD), seguido por adrenalina (26,6 %; 41,6 DCD), dopamina (19,4 %), dobutamina (16,0 %), vasopresina (8,5 %) y fenilefrina (0,9 %). El uso de norepinefrina se incrementó de 2010 a 2017 (+6,19 DCD), mientras que el de otros fármacos disminuyó, especialmente adrenalina (-60,6 DCD) y dopamina (-10,8 DCD). Conclusiones La norepinefrina es el fármaco vasopresor más utilizado y el que ha demostrado una tendencia de uso incremental durante el periodo de estudio, lo cual está respaldado por evidencia a favor de su efectividad y seguridad en pacientes con choque.

Seguridad del uso combinado de lidocaína y fenilefrina como midriáticos intracamerales en la cirugía de catarata / Safety of the combined use of lidocaine and phenylephrine as intracameral mydriatics in cataract surgery

Objetivo: Evaluar la seguridad ocular y sistémica de una combinación de lidocaína 2 por ciento y fenilefrina 1 por ciento administrada por vía intracameral para provocar midriasis intraoperatoria en la cirugía de catarata. Métodos: Se realizó un estudio prospectivo de serie de casos en 70 ojos de igual número de pacientes sometidos a facoemulsificación con implante de lente intraocular. El grupo midriasis intraoperatoria en la cirugía lo conformaron 35 pacientes dilatados con una inyección intracameral de lidocaína y fenilefrina antes de la cirugía, mientras otros 35 ojos se dilataron de manera tradicional, con un colirio midriático previo. Para la seguridad ocular se evaluaron múltiples parámetros del examen oftalmológico pre- y posoperatorio. Resultados: La presión intraocular, el espesor corneal central, la densidad celular del endotelio corneal y el edema corneal posoperatorio como hallazgo del segmento anterior se comportaron de manera similar en ambos grupos de estudio. Se reportó una complicación transoperatoria en el grupo de manera tradicional y un caso con edema quístico macular posoperatorio en el grupo midriasis intraoperatoria en la cirugía que no representaron diferencias significativas. Conclusión: La inyección de lidocaína más fenilefrina intracameral es una opción segura tanto ocular como sistémica para provocar midriasis durante la facoemulsificación(AU)

Objective: Evaluate the ocular and systemic safety of a combination of 2 percent lidocaine and 1 percent phenylephrine administered intracamerally to achieve intraoperative mydriasis in cataract surgery. Methods: A prospective study was conducted of a case series of 70 patients (70 eyes) who underwent phacoemulsification with intraocular lens implantation. The intraoperative mydriasis group was composed of 35 patients dilated with an intracameral injection of lidocaine and phenylephrine before surgery, whereas another 35 eyes were dilated by the conventional method, with mydriatic eye drops. Ocular safety evaluation was based on the analysis of a wide variety of pre- and postoperative ophthalmological examination parameters. Results: Intraocular pressure, central corneal thickness, corneal endothelial cell density and postoperative corneal edema as an anterior segment finding, behaved in a similar manner in both study groups. An intraoperative complication was reported in the conventional method group and a case with postoperative cystoid macular edema in the intraoperative mydriasis group group, neither of them exhibiting significant differences. Conclusion: Intracameral lidocaine plus phenylephrine injection is a safe ocular and systemic option to achieve mydriasis during phacoemulsification(AU)

Cardioprotective solutions exposure for 1 hour in hypoxia and low temperatures affects vascular reactivity differently

Abstract Introduction: Heart preservation benefits cardiac performance after operations decreasing morbidity but the contribution of the vascular reactivity has been neglected. Objective: We evaluated whether cardioprotective solutions, Krebs-Henseleit (KH), Bretschneider-HTK (BHTK), St. Thomas No. 1 (STH-1), and Celsior (CEL), affect vascular reactivity. Methods: Aortic rings from Wistar rats were used in two protocols. First, the rings were exposed to BHTK, STH-1 or CEL for 1 hour of hypoxia at 37 °C. Second, the rings were exposed to 10 °C or 20 °C for 1 hour under hypoxia. After treatment, the rings were immersed in KH at 37 °C, endothelial integrity was tested and concentration-response curves to phenylephrine were performed. Results: In the first protocol, the solutions did not damage the endothelium; CEL and BHTK reduced KCl-induced contractions but not STH-1; only CEL and BHTK reduced vascular reactivity; there was a positive correlation between Rmax and KCl concentration. At 20 °C, 1 hour under hypoxia, the solutions produced similar KCl-induced contractions without endothelial damage. CEL, BHTK and STH-1 decreased vascular reactivity. At 10 °C, STH-1 increased reactivity but CEL and BHTK decreased. After 1 hour under hypoxia in CEL or BHTK solutions, reactivity was similar at different temperatures. At 20 °C, endothelial damage after exposure to STH-1 produced more vasoconstriction than CEL and BHTK. However, at 10 °C, endothelial damage after CEL and BHTK exposure elicited more vasoconstriction while STH-1 showed a small vasoconstrictor response, suggesting endothelial damage. Conclusion: STH-1 decreased reactivity at 20 °C and increased at 10 °C. CEL promoted greater endothelial modulation at 10 °C than at 20 °C, while STH-1 promoted higher modulation at 20 °C than at 10 °C. Vascular tone was reduced by CEL and BHTK exposure, also depending on the KCl concentration.

The effect of epinephrine for the treatment of spinal-hypotension: comparison with norepinephrine and phenylephrine, clinical trial / O efeito de epinefrina, norepinefrina e fenilefrina no tratamento da hipotensão pós-raquianestesia: estudo clínico comparativo

Abstract Background and objectives: Limited data are present on safety and efficiency of epinephrine for the prophylaxis and treatment of spinal-hypotension. This study was conducted to compare the effect of epinephrine with norepinephrine and phenylephrine on the treatment of spinal-hypotension and ephedrine requirement during cesarean delivery. Methods: One hundred and sixty parturients with uncomplicated pregnancies undergoing elective cesarean delivery under spinal anesthesia were recruited. They were allocated randomly to receive norepinephrine 5 µg.mL−1 (n = 40), epinephrine 5 µg.mL−1 (n = 40), phenylephrine 100 µg.mL−1 (n = 40) or 0.9% saline infusions (n = 40) immediately after induction of spinal anesthesia. Whenever systolic blood pressure drops to less than 80% of baseline, 5 mg of intravenous ephedrine was administered as rescue vasopressor. The incidence of hypotension, total number of hypotension episodes, the number of patients requiring ephedrine, the mean amount of ephedrine consumption and side effects were recorded. Results: There was no statistically significant difference in incidence of maternal hypotension between groups. The number of patients requiring ephedrine was significantly greater in group saline than in group phenylephrine (p< 0.001). However, it was similar between phenylephrine, norepinephrine, and epinephrine groups. The mean ephedrine consumption was significantly higher in group saline than in norepinephrine, epinephrine, phenylephrine groups (p= 0.001). Conclusion: There is no statistically significant difference in incidence of hypotension and ephedrine consumption during spinal anesthesia for cesarean delivery with the use of epinephrine when compared to norepinephrine or phenylephrine. Epinephrine can be considered an alternative agent for management of spinal hypotension.

Resumo Justificativa e objetivos: Existem dados limitados sobre segurança e eficiência da epinefrina na profilaxia e tratamento da hipotensão arterial associada à raquianestesia. O presente estudo foi realizado para comparar o efeito da epinefrina com norepinefrina e fenilefrina no tratamento da hipotensão após raquianestesia e necessidade de efedrina durante o parto cesáreo. Método: Foram recrutadas 160 parturientes com gestações não complicadas, submetidas a cesariana eletiva sob raquianestesia. Elas foram alocadas aleatoriamente para receber norepinefrina 5 µg.mL-1 (n = 40), epinefrina 5 µg.mL-1 (n = 40), fenilefrina 100 µg.mL-1 (n = 40) ou infusão de solução fisiológica NaCl a 0,9% (n = 40) imediatamente após a indução da raquianestesia. Sempre que houvesse redução da pressão arterial sistólica para valor inferior a 80% da linha de base, 5 mg de efedrina iv eram administrados como vasopressor de resgate. A incidência de hipotensão, o número total de episódios de hipotensão, o número de pacientes que necessitaram de efedrina, o consumo médio de efedrina e os efeitos colaterais foram registrados. Resultados: Não houve diferença estatisticamente significante na incidência de hipotensão materna entre os grupos. O número de pacientes que necessitaram de efedrina foi significantemente maior no grupo solução fisiológica do que no grupo fenilefrina (p< 0,001). No entanto, foi semelhante entre os grupos fenilefrina, norepinefrina e epinefrina. O consumo médio de efedrina foi significantemente maior no grupo solução fisiológica do que nos grupos norepinefrina, epinefrina e fenilefrina (p = 0,001). Conclusão: Não houve diferença estatisticamente significante na incidência de hipotensão e consumo de efedrina durante raquianestesia para parto cesáreo com uso de epinefrina quando comparada à norepinefrina ou fenilefrina. A epinefrina pode ser considerada como agente alternativo para o tratamento da hipotensão após raquianestesia.

Eficacia del uso combinado de lidocaína y fenilefrina como midriáticos intracamerales en la cirugía de catarata / Efficacy of the combined use of lidocaine and phenylephrine as intracameral mydriatics in cataract surgery

RESUMEN Objetivo: Evaluar la eficacia de una combinación de lidocaína 2 por ciento y fenilefrina 1 por ciento administrada intracameralmente para provocar midriasis intraoperatoria en la cirugía de catarata. Métodos: Realizamos un estudio prospectivo, comparativo, de serie de casos en 70 ojos de igual número de pacientes quienes fueron sometidos a cirugía de catarata mediante facoemulsificación con implante de lente intraocular, en el Instituto Cubano de Oftalmología "Ramón Pando Ferrer" entre septiembre del año 2017 y febrero de 2018. 35 pacientes fueron dilatados con una combinación de fenilefrina y lidocaína inyectada en la cámara anterior justo antes de la cirugía (grupo midriáticos intracamerales) y otros 35 ojos se dilataron con un colirio midriático como se realiza cotidianamente y de manera tradicional (grupo midriáticos tópicos). La eficacia se evaluó mediante la medición del diámetro pupilar (pupilometría) realizada con un compás quirúrgico en diferentes momentos de la cirugía en ambos grupos de estudio. Los resultados de ambos grupos se compararon entre sí. Resultados: En ambos grupos de pacientes se lograron diámetros pupilares superiores a los 7 mm justo antes de la capsulorrexis, aunque fueron ligeramente mayor en el grupo midriáticos tópicos (8,17 vs. 7,55 mm). En las mediciones posteriores todas las pupilometrías del grupo midriáticos intracamerales fueron superiores y se mantuvieron por encima de los 7 mm, mientras las del grupo midriáticos tópicos sufrieron una reducción paulatina hasta el final de la cirugía (5,68 mm). Conclusiones: La combinación de lidocaína más fenilefrina aplicada de manera intracameral es efectiva para provocar una midriasis adecuada y mantenida durante la cirugía de catarata(AU)

ABSTRACT Objective: Evaluate the efficacy of the combination 2 percent lidocaine / 1 percent phenylephrine administered intracamerally to achieve intraoperative mydriasis in cataract surgery. Methods: A prospective comparative study was conducted of a case series of 70 patients (70 eyes) who underwent cataract surgery by phacoemulsification with intraocular lens implantation at Ramón Pando Ferrer Cuban Institute of Ophthalmology from September 2017 to February 2018. Of the total eyes, 35 were dilated with a combination of phenylephrine and lidocaine injected into the anterior chamber just before surgery (MIC group), whereas the remaining 35 were dilated with mydriatic eye drops in the habitual traditional manner (MT group). Efficacy was evaluated in the two study groups measuring the pupil diameter (pupilometry) with a surgical compass at several moments during the surgery. The results for each group were compared. Results: In both groups patients achieved pupil diameters above 7 mm just before capsulorhexis, though values were slightly higher in the MT group (8.17 vs. 7.55 mm). Later measurement showed that in the MIC group all pupilometries were higher, remaining above 7 mm, whereas in the MT group they underwent gradual reduction until the end of surgery (5.68 mm). Conclusions: The combination of lidocaine and phenylephrine administered intracamerally is effective to achieve appropriate, sustained mydriasis during cataract surgery(AU)

Evaluation of the bioequivalence of two formulations containing the combination of 400 mg of acetaminophen (paracetamol), 4 mg of phenylephrine and 4 mg of chlorpheniramine in capsules: open-label, three-way crossover study, partially replicated in healthy volunteers of both sexes

This study was carried out in order to compare the relative bioavailability of two different formulations containing 400 mg of acetaminophen + 4 mg of phenylephrine hydrochloride + 4 mg of chlorpheniramine maleate, Test formulation (Cimegripe®) and Reference formulation (Resfenol®) in 84 healthy volunteers of both sexes under fasting conditions. The study was conducted in a single dose, randomized, open-label, crossover 3-way and partially replicated. The tolerability was evaluated by the monitoring of adverse events and vital signs, results of clinical and laboratory tests. Plasma concentrations were quantified by validated bioanalytical methods using the ultra-performance liquid chromatography coupled to tandem mass spectrometry. The Cmax, Tmax, AUC0-t, AUC0-inf, T1/2 and Kel pharmacokinetic parameters were calculated from these obtained concentrations. The 90% confidence intervals were constructed for the ratio reference/test from the geometric average of the Cmax and AUC parameters which were comprised between 80% and 125%. Only the Cmax parameter of the phenylephrine was applied the scaled average bioequivalence due to the intraindividual coefficient of variation > 30% obtained, thus extending the acceptance limits of the interval. It can be concluded that the two formulations were bioequivalent in terms of rate and absorption extent and thus interchangeable

A via Nrf2 participa da maior modulação endotelial induzida pela prenhez sobre reatividade de aortas à fenilefrina / The Nrf2 pathway participates in the greater endothelial modulation induced by pregnancy on reactivity of aortas to phenylephrine

Alterações em diferentes vias de sinalização levam a disfunção vascular e endotelial e consequentemente a hipertensão. A hipertensão está relacionada diretamente com o aumento da produção de espécies reativas de oxigênio (ROS) e diminuição da biodisponibilidade de óxido nítrico (NO) nos vasos sanguíneos. A via do Nrf2 (fator nuclear eritróide 2) está envolvida nos mecanismos que levam ao aumento da biodisponibilidade vascular de NO, pois controla a expressão de enzimas antioxidantes. A ativação do Nrf2 é modulada por sua ligação com a Keap-1 (Kelch-like ECH-associated protein 1) e sua atividade é modulada pelo fator de transcrição Bach-1, que compete pelo mesmo sitio ativo no DNA com o Nrf2. Em ratas normotensas e em ratas espontaneamente hipertensas (SHR) é observada uma redução da pressão arterial ao final da prenhez, que tem sido associada à redução do estresse oxidativo e maior biodisponibilidade de NO. Com o aumento da biodisponibilidade de NO, é aumentada a modulação do endotélio sobre a reatividade vascular à agonistas vasoconstritores, como à fenilefrina (PE). Levantamos a hipótese que a prenhez altera a expressão e ou a atividade do Nrf2 e de seus inibidores Keap-1 e Bach-1 e que estas possíveis alterações estariam associadas à maior modulação endotelial sobre contração de aortas à PE. Para testarmos esta hipótese, a expressão de Nrf2, Keap-1 e Bach-1 e também das enzimas antioxidantes transcritas pelo Nrf2, como a NADP(H) quinona oxirredutase-1 (NQO1), SOD-1 e SOD-2 foram avaliadas em aortas de ratas prenhes e comparadas as aortas de ratas não-prenhes. A fim de identificarmos outros possíveis mecanismos alterados pela prenhez em ratas Wistar e SHR, avaliamos a expressão de NOXO-1, subunidade regulatória da NOX1 e de p47phox, subunidade regulatória de NOX2. A participação do Nrf2 na produção de NO endotelial em aortas de ratas prenhes, foi avaliada pela utilização de Brusatol, uma droga inibidora do Nrf2. Avaliamos também a participação do Nrf2 na reatividade de aortas de ratas prenhes à fenilefrina e à acetilcolina, utilizando o Brusatol. Todos os resultados foram comparados entre ratas não-prenhes normotensas (Wistar) e hipertensas (SHR) e entre ratas não-prenhes e prenhes nos grupos (análise de multivariância, post-test Tukey, p< 0,05). Os resultados mostraram que a expressão de Nrf2 está aumentada em aortas de ratas prenhes Wistar, apesar da expressão de Keap-1 e de Bach1 não estar alterada. Associado a expressão aumentada de Nrf2 observamos maior expressão de SOD-2, mas não de SOD-1 ou NQO1, em aortas de ratas prenhes. Em aortas de ratas SHR não prenhes, observamos entre todas as proteínas avaliadas, menor expressão de Bach-1 e de NQO1 quando comparadas às aortas de ratas normotensas. A prenhez reduziu ainda mais a expressão apenas de NQO1 em aortas de SHR. A prenhez reduziu a expressão de NOXO-1 e de p47phox em aortas de SHR, enquanto que em aortas de ratas Wistar reduziu apenas a expressão de NOXO-1. Os resultados obtidos neste estudo mostraram também que a incubação de HUVEC com Brusatol aumentou as concentrações intracelulares de ERO, mas não alterou as concentrações de NO, no entanto, reduziu significativamente a concentração de NOx estimulada pela ACh em aortas de ratas prenhes, Wistar ou SHR. Além disto, o Brusatol aumentou a reatividade à PE em aortas de ratas normotensas não prenhes e prenhes, igualando a reatividade de aortas de ratas prenhes as aortas de ratas não prenhes. No entanto, o Brusatol não alterou a reatividade de aortas de SHR, prenhes ou não-prenhes. Nenhum efeito significativo do Brusatol foi observado na reatividade à Acetilcolina em aortas de ratas Wistar ou SHR, prenhes ou não prenhes. Em conclusão, nossos resultados sugerem que a atividade da via de sinalização do Nrf2 está aumentada, favorecendo a maior atividade de enzimas antioxidantes como a SOD-2, que contribuiria para maior biodisponibilidade de NO e maior modulação endotélio-dependente da contração vascular à PE em aortas de ratas normotensas prenhes. No entanto, em aortas de SHR prenhes, este mecanismo parecer não ser mais importante que a redução da atividade de isoformas NOX e de suas subunidades regulatórias que contribuiria para menor geração de O2•- e consequentemente, maior biodisponibilidade de NO(AU)

Modifications in different signaling pathways lead to vascular and endothelial dysfunction and, consequently, hypertension. Hypertension is directly related to an increase in the production of reactive oxygen species (ROS) and a decrease in the bioavailability of nitric oxide (NO) in blood vessels. The Nrf2 (erythroid nuclear factor 2) pathway is involved in the mechanisms that lead to the increased vascular bioavailability of NO, as it controls the expression of antioxidant enzymes. The activation of Nrf2 is modulated by Keap-1 (Kelch-like ECH-associated protein 1) and its activity is modulated by the transcription factor Bach-1, which competes for the same active site in DNA with Nrf2. In normotensive rats and spontaneously hypertensive rats (SHR), a reduction in blood pressure at the end of pregnancy is observed, which has been associated with a reduction in oxidative stress and greater bioavailability of NO. This increased NO bioavailability has been associated with the higher endothelium modulation over blood vessel reactivity to vasoconstrictor agonists, such as phenylephrine (PE), observed in pregnant rats. We hypothesized that pregnancy alters the expression and/or activity of Nrf2 and its inhibitors Keap-1 and Bach-1 and that these changes are associated with greater endothelial modulation on the contraction of aortas to PE. To test this hypothesis, the expression of Nrf2, Keap-1 and Bach-1 and the antioxidant enzymes transcribed by Nrf2, such as NADP (H) quinone oxidoreductase-1 (NQO1), SOD-1 and SOD-2 were evaluated in aortas of pregnant rats and compared to aortas of non-pregnant rats. In order to identify other possible mechanisms altered by pregnancy in Wistar rats and SHR, we evaluated the expression of NOXO-1, NOX1 regulatory subunit and p47phox, NOX2 regulatory subunit. The role of Nrf2 in the production of endothelial NO in aortas of pregnant rats was evaluated by use of Brusatol, an inhibitor of Nrf2. We also evaluated the role of Nrf2 in the reactivity of aortas of pregnant rats to phenylephrine and acetylcholine, using Brusatol. All results were compared between normotensive (Wistar) and hypertensive (SHR) non-pregnant rats and between pregnant and non-pregnant rats in the groups (multivariate analysis, Tukey post-test, p< 0.05). The results showed that the expression of Nrf2 is increased in aortas of pregnant Wistar rats, although the expression of Keap-1 and Bach-1 is not altered. The increased expression of Nrf2 was associated with the greater expression of SOD-2, but not of SOD-1 or NQO1, in aortas of pregnant rats. In aortas of non-pregnant SHR rats, we observed among all evaluated proteins, lower expression of Bach-1 and NQO1 when compared to the aortas of normotensive rats. Pregnancy reduced even more the expression of NQO1 in SHR aortas. Pregnancy reduced the expression of NOXO-1 and p47phox in SHR aortas, whereas in aorta of Wistar rats it reduced only the expression of NOXO-1. The results obtained in this study also showed that the incubation of HUVEC with Brusatol increased the intracellular concentrations of ROS, but did not alter the concentrations of NO, however, Brusatol significantly reduced the concentration of NOx stimulated by ACh in aortas of pregnant rats, Wistar or SHR. Moreover, Brusatol increased the reactivity to PE in aortas of pregnant normotensive rats and pregnant, matching the reactivity of aortas of pregnant rats to aortas of non-pregnant rats. However, Brusatol did not alter the reactivity of pregnant or non-pregnant SHR aortas. No significant effect of Brusatol was observed in the reactivity to Acetylcholine in aortas of Wistar rats or SHR, pregnant or non-pregnant rats. In conclusion, our results suggest that the activity of the Nrf2 signaling pathway is increased, favoring the greater activity of antioxidant enzymes such as SOD-2, which would contribute to greater bioavailability of NO and greater endothelium-dependent modulation of vascular contraction to PE in aortas of pregnant normotensive rats. However, in pregnant SHR aortas, this mechanism appears to be no more important than the lower the activity of NOX isoforms and their regulatory subunits that would contribute to lower O2•- generation and, consequently, greater NO bioavailability(AU)

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.

Curcuma Longa Abolishes Phenylephrine-Induced Contractions in Isolated Aortic Artery of Rats

Curcuma longa has biological effects. Its cardiovascular activities are yet to be scientifically studied. Objectives: To investigate the vasorelaxant effects of the aqueous extract of Curcuma longa (AECL). Methods: Aortic annuli of normotensive rats, with or without endothelium, were set up in a data storage system with nutrient solution in recipients, with scientifically recommended temperature, aeration and tension. Over contraction by Phenylephrine, the AECL (1, 3, 10, 30, 100, 300 and 1000 µg/mL) was incubated before and after incubation with atropine or L-name or indomethacin. An AECL concentration-response curve was also built over contractions caused by elevation of extracellular K+. Data were significant when p < 0.05, with GraphPad Prism 6.0 software resolutions. Results: The AECL induced 100% vasorelaxation also in the endothelium-free annuli. The part of the endothelium-dependent effect had EC50 = 4.32 ± 0.05 µg/mL. With inhibition of NO production, the EC50 increased to 126.50 ± 2.35 µg/mL; after inhibition of prostacyclin production, to 124.6 ± 0.05 µg/mL; and after muscarinic blockade, to 437.10 ± 0.2 µg/mL. Opening of K+ channels (relaxation of 56.98%) and VOCC blockade (relaxation of 31.56%) were evident. Conclusion: AECL induced significant vasorelaxation, being more significant in the presence of endothelium. The muscarinic pathway seems to be the main one involved in this effect, followed by the NO production and prostacyclin pathways. The activity in K+ channels by AECL was more significant than its VOCC blockade. The use of other models and tools to study action mechanisms will be important and elucidating

Midriáticos intracamerales en la cirugía de catarata / Intracameral mydriatics in cataract surgery

RESUMEN Durante la cirugía de catarata, la inducción de la dilatación de la pupila (midriasis) y el mantenimiento de un grado adecuado de esta a lo largo de toda la operación son elementos críticos para la eliminación y el reemplazo exitoso del cristalino. Una pupila pequeña o un cierre pupilar durante la cirugía hacen que esta sea un desafío desde el punto de vista técnico y aumente el riesgo de complicaciones transquirúrgicas, por lo que una midriasis adecuada y mantenida ha permanecido hasta nuestros días como un pilar fundamental para maximizar la seguridad y los resultados refractivos de la cirugía de catarata moderna. Esta midriasis se consigue habitualmente con la aplicación previa de colirios anticolinérgicos y simpaticomiméticos, con los cuales el tiempo de espera para la dilatación pupilar es frecuentemente más largo que el procedimiento quirúrgico; tienen una significativa absorción sistémica que pueden aumentar el riesgo de efectos secundarios cardiovasculares, y el efecto midriático tiende a desaparecer durante la cirugía. Con el objetivo de acceder a la información actualizada sobre los fármacos midriáticos más usados de modo intracameral, sus dosis y formas de aplicación durante la cirugía de catarata, se realiza el presente trabajo de revisión(AU)

ABSTRACT In cataract surgery, induction and maintenance of an adequate degree of pupil dilation (mydriasis) throughout the operation are critical elements for the successful removal and replacement of the crystalline lens. A small pupil or pupil closure during surgery pose a technical challenge and increase the risk of intraoperative complications. This is the reason why adequate, maintained mydriasis has remained to this day a fundamental pillar to maximize both safety and satisfactory refractive results in modern cataract surgery. Mydriasis is normally achieved with the previous application of anticholinergic and sympathomimetic eye drops, for which the waiting time for pupil dilation is often longer than the surgical procedure, they have significant systemic absorption which may increase the risk of cardiovascular side effects, and the mydriatic effect tends to vanish during surgery. A bibliographic review was conducted with the purpose of accessing updated information about the most commonly used intracameral mydriatic drugs, their doses and modes of application during cataract surgery(AU)

Efficacy of preoperative nonsteroidal anti-inflammatory drug and the re-dilation technique in minimizing miosis after femtosecond laser in cataract surgery / Eficácia do AINE pré-operatório e da técnica de re-dilatação em minimizar a miose na cirurgia de catarata com laser de femtosegundo

ABSTRACT Purpose: To assess the efficacy of using a nonste­roidal anti-inflammatory drug preoperatively and of applying the re-dilation technique when necessary to minimize pupil size variation when comparing the degree of mydriasis before femtosecond laser pretreatment with that at the beginning of phacoemulsification. Methods: This retrospective study included patients who underwent cataract surgery using the LenSx (Alcon Laboratories, Inc., Fort Worth, TX). Our routine dilating regimen with flurbiprofen, tropicamide, and phenylephrine was used. The re-dilation technique was applied on eyes that manifested with a pupillary diameter that was smaller than the programmed capsulotomy diameter after laser pretreatment. The technique consists of overcoming pupillary contraction by instilling tropicamide and phenylephrine before phacoemulsification. Pupil size was assessed before femtosecond laser application and at the beginning of phacoemulsification. Results: Seventy-five eyes (70 patients) were included. Nine (12%) eyes underwent the re-dilation technique. There was no significant difference in mean pupillary diameter and mean pupillary area between the two studied surgical time points (p=0.412 and 0.437, respectively). The overall pupillary area constriction was 2.4 mm2. Immediately before opening the wounds for phacoemulsification, none of the eyes presented with a pupillary diameter <5 mm, and 61 (85.3%) eyes had a pupillary diameter >6 mm. Conclusion: Preoperative administration of nonsteroidal anti-inflammatory drug and the re-dilation technique resulted in no significant pupil size variation in eyes that were pretreated with the femtosecond laser, when comparing the measurements made before the laser application and at the beginning of phacoemulsification. This approach can avoid the need to proceed with cataract extraction with a constricted pupil.

RESUMO Objetivo: Avaliar a eficácia do uso de anti-inflamatório não-esteróide no pré-operatório e aplicação da técnica de re-dilatação quando necessária para minimizar a variação do tamanho pupilar ao comparar o grau de midríase antes do tra­tamento com laser de femtosegundo no início da facoemulsificação. Métodos: Esse estudo retrospectivo incluiu pacientes que foram submetidos à cirurgia de catarata usando o LenSx (Alcon Laboratories, Inc., Fort Worth, TX). Nosso regime de di­latação de rotina com flurbiprofeno, tropicamida e fenilefrina foi usado. A técnica de re-dilatação doi aplicada em olhos que se manifestaram com um diâmetro pupilar menor do que o diâmetro da capsulotomia programado após o pré-tratamento a laser. A técnica consiste em superar a contração pupilar pela instilação de tropicamida e fenilefrina antes da facoemulsificação. O tamanho pupilar foi avaliado antes da aplicação do laser de femtosegundo e no inicio da facoemulsificação. Resultados: Setenta e cinco olhos (70 pacientes) foram incluídos. Nove (12%) olhos foram submetidos à técnica de re-dilatação. Não houve diferença significativa no diâmetro pupilar médio e na área pupilar média entre os dois tempos cirúrgicos estudados (p=0,412 e 0,437, respectivamente). A constrição global da área pupilar foi de 2,4 mm2. Imediatamente antes de abrir as incisões para a facoemulsificação, nenhum dos olhos apresentava diâmetro pupilar <5 mm e 61 (85,3%) olhos apresentavam um diâmetro pupilar >6 mm. Conclusões: O administração pré-operatória de anti-inflamatório não-esteróide e da técnica de re-dilatação resultaram em uma variação significativa do tamanho pupilar em olhos que foram pré-tratados com laser de femtosegundo, comparando as medidas realizadas antes da aplicação do laser e no inicio da facoemulsificação. Essa abordagem pode evitar a necessidade de prosseguir com a extração da catarata com uma pupila contraída.

Late cardiac perconditioning by phenylephrine in an isolated rat heart model is mediated by mitochondrial potassium channels

The present study was designed to investigate the effect of early and late administration of phenylephrine during ischemia against regional ischemia-reperfusion injuries in an isolated rat heart model. All animals were randomly divided into experimental groups: (I) IR (Ischemic/ reperfusion): the hearts underwent 35 min of regional ischemia followed by 60 min of reperfusion; (II) 5HD-IR-0: the hearts were perfused for 5 min with 5HD (5-hydroxydecanoate, specific mKATP channel blocker, 100 µM) at the onset of regional ischemia; (III) 5HD-IR-20: the hearts were perfused for 5 min with 5HD 20 min after regional ischemia; (IV) PE-IR-10: the hearts were perfused for 5 min with phenylephrine 10 min after regional ischemia; (V) PE-IR-30: the hearts were perfused for 5 min with phenylephrine (100 µM) 30 min after regional ischemia; (VI) PE-5HD-IR-10 group: the hearts were perfused for 5 min with 5HD at the onset of regional ischemia after which phenylephrine was administrated as in group IV; and (VII) PE-5HD-IR-30: the hearts were perfused for 5 min with 5HD 20 min after the ischemia and then phenylephrine was administrated as in group V. The hemodynamic parameters were recorded throughout the experiment. Ischemia-induced arrhythmias, myocardial infarct size (IS), creatin kinase-MB isoenzyme (CK-MB), plasma lactate dehydrogenase (LDH) activities, and coronary blood flow (CBF) were measured in all animals. Perfusion of phenylephrine 30 min after the regional ischemia curtailed the myocardial infarct size, reduced CK-MB, and improved cardiac function and CBF. Administration of 5HD 30 min after the ischemia abolished cardioprotective effects of phenylephrine in the late phase. These results suggest the involvement of mKATP in the mechanism of phenylephrine-induced late preconditioning.

Eficacia de fenilefrina en la prevención de hipotensión en cesárea bajo anestesia subaracnoidea / Effectiveness of phenylefrine in prevention of hypotension during spinal anesthesia for cesarean delivery

Resumen Introducción: la hipotensión es el evento adverso más incidente cuando se administra anestesia subaracnoidea para cesárea; múltiples estrategias para su prevención y manejo se han propuesto, entre ellas el uso de vasopresores profilácticos con resultados no concluyentes. Objetivo: evaluar la eficacia preventiva del uso de Fenilefrina en la hipotensión arterial inducida por la anestesia subaracnoidea en gestantes llevadas a cesárea. Materiales y Métodos: ensayo clínico controlado, doble ciego, en gestantes, mayores de 18 años, ASA 1 y 2, quienes recibieron anestesia subaracnoidea para cesárea, fueron aleatorizadas a recibir placebo o infusión profiláctica de fenilefrina 40 mcg/min, durante 5 minutos. Resultados: se incluyeron 140 pacientes en el análisis de datos. La incidencia de hipotensión fue mayor en el grupo control que en el intervenido (RA 45,71% vs 32,85%). Sin presentarse diferencias significativas entre ambos grupos (p=0,119). RR de hipotensión en el grupo intervenido fueron menores, independiente del criterio de hipotensión (tensión arterial sistólica, RR 0,72 (IC95% 0,47-1,09); tensión arterial media, RR 0.93 (IC95% 0,64-1,37); TAS o TAM RR 0.86 (IC95% 0,62-1,21)), pero sin diferencias significativas p>0,05. El uso de vasopresores en los pacientes que presentaron este evento se dio en 75.4% (n=52), con RR mayor en el grupo control y diferencias significativas al evaluar los dos grupos. (RR: 1,4 p=0,032). Conclusiones: fenilefrina profiláctica no demostró ser eficaz en disminuir la incidencia de hipotensión; sin embargo, sí se asocia con una disminución significativa en los requerimientos de vasopresores, así como en la incidencia de náuseas y vómito. MÉD.UIS. 2018;31(2):33-9.

Abstract Background: Hypotension is the most common adverse event when subarachnoid anesthesia is administered for cesarean section; multiple strategies for its prevention and management have been proposed, including the use of prophylactic vasopressors with inconclusive results. Objective: To evaluate the preventive efficacy of the use of phenylephrine in hypotension induced by subarachnoid anesthesia in pregnant women taken to caesarean section. Methods: A double-blind, controlled clinical trial in pregnant women, older than 18 years old, ASA 1 and 2, who received a subarachnoid anesthesia for cesarean section, were randomized to receive placebo or prophylactic infusion of phenylephrine 40 mcg / min, for 5 minutes. Results: 140 patients were included in data analysis. Incidence of hypotension was higher in the control group than in the intervention group (AR 45.71% vs 32.85%). There were no significant differences between the two groups (p = 0.119). RR of hypotension in the intervention group were lower, independent of the criterion of hypotension [systolic blood pressure, RR 0.72 (95% CI 0.47-1.09), mean arterial pressure, RR 0.93 (95% CI 0.64-1.37), SBP or MAP 0.86 (RR 0.86) (IC95% 0.62-1.21)], but without significant differences p> 0.05. The use of vasopressors in patients who presented this event occurred in 75.4% (n = 52), with higher RR in the control group and significant differences when evaluating the two groups. (RR 1.4 p = 0.032). Conclusions: Prophylactic phenylephrine did not prove effective in reducing the incidence of hypotension, however, it is associated with a significant decrease in vasopressor requirements, as well as in the incidence of nausea and vomiting. MÉD.UIS. 2018;31(2):33-9.

A Single Resistance Exercise Session Improves Aortic Endothelial Function in Hypertensive Rats / Uma Única Sessão de Exercício Resistido Melhora a Função Endotelial Aórtica em Ratos Hipertensos

Abstract Background: Physical exercise is an important tool for the improvement of endothelial function. Objective: To assess the effects of acute dynamic resistance exercise on the endothelial function of spontaneously hypertensive rats (SHR). Methods: Ten minutes after exercise, the aorta was removed to evaluate the expression of endothelial nitric oxide synthase (eNOS), phosphorylated endothelial nitric oxide synthase (p-eNOS1177) and inducible nitric oxide synthase (iNOS) and to generate concentration-response curves to acetylcholine (ACh) and to phenylephrine (PHE). The PHE protocol was also performed with damaged endothelium and before and after NG-nitro-L-arginine methyl ester (L-NAME) and indomethacin administration. The maximal response (Emax) and the sensitivity (EC50) to these drugs were evaluated. Results: ACh-induced relaxation increased in the aortic rings of exercised (Ex) rats (Emax= -80 ± 4.6%, p < 0.05) when compared to those of controls (Ct) (Emax = -50 ± 6.8%). The Emax to PHE was decreased following exercise conditions (95 ± 7.9%, p < 0.05) when compared to control conditions (120 ± 4.2%). This response was abolished after L-NAME administration or endothelial damage. In the presence of indomethacin, the aortic rings' reactivity to PHE was decreased in both groups (EC50= Ex -5.9 ± 0.14 vs. Ct -6.6 ± 0.33 log µM, p < 0.05 / Emax = Ex 9.5 ± 2.9 vs. Ct 17 ± 6.2%, p < 0.05). Exercise did not alter the expression of eNOS and iNOS, but increased the level of p-eNOS. Conclusion: A single resistance exercise session improves endothelial function in hypertensive rats. This response seems to be mediated by increased NO production through eNOS activation.

Resumo Fundamento: O exercício físico é uma importante ferramenta para o aprimoramento da função endotelial. Objetivo: Avaliar os efeitos do exercício dinâmico resistido agudo na função endotelial de ratos espontaneamente hipertensos (SHR). Métodos: Após 10 minutos de exercício, a aorta foi removida para avaliação da expressão de óxido nítrico sintase endotelial (eNOS), óxido nítrico sintase endotelial fosforilada (p-eNOS1177) e óxido nítrico sintase endotelial induzível (iNOS), e para a construção de curvas concentração-resposta de acetilcolina (ACT) e fenilefrina (FEN). O protocolo FEN foi também realizado com lesão endotelial e antes e depois da administração de N-nitro-L-arginina metil éster (L-NAME) e indometacina. A resposta máxima (Emax) e a sensibilidade (EC50) a esses fármacos foram avaliadas. Resultados: Houve aumento do relaxamento induzido por ACT nos anéis aórticos dos ratos exercitados (Ex) (Emax = -80 ± 4,6%; p < 0,05) quando comparado àquele dos controles (Ct) (Emax = -50 ± 6,8%). A Emax à FEN diminuiu após exercício (95 ± 7,9%; p < 0,05) quando comparada àquela dos controles (120 ± 4,2%). Tal resposta foi abolida após administração de L-NAME ou lesão endotelial. Na presença de indometacina, a reatividade dos anéis aórticos à FEN diminuiu nos dois grupos (EC50= Ex -5,9 ± 0,14 vs. Ct -6,6 ± 0,33 log µM; p < 0,05/ Emax = Ex 9,5 ± 2,9 vs. Ct 17 ± 6,2%; p < 0,05). O exercício não alterou a expressão de eNOS e de iNOS, mas aumentou o nível de p-eNOS. Conclusão: Uma única sessão de exercício resistido melhora a função endotelial em ratos hipertensos. Essa resposta parece ser mediada por elevação da produção de NO através de ativação de eNOS.

Efeito midriático da fenilefrina a 10% na comparação entre a autoinstilação de gota em olhos abertos e a vaporização em olhos fechados / Phenylephrine 10% mydriatic effect: comparison between self instillation of eye drop in open eyes and spray in closed eyes

RESUMO Objetivo: Comparar a eficácia fenilefrina a 10% aplicada pelo próprio paciente por vaporização em olho fechado em relação à instilação de gota em olho aberto em indivíduos que irão realizar exame de fundoscopia e avaliar o nível de dificuldade e a adequação técnica entre os métodos de administração. Métodos: Ensaio clínico controlado, randomizado e pareado realizado em 2014 envolvendo 100 olhos de 50 pacientes na Policlínica Ronaldo Gazolla - RJ, sem doenças oculares ou sistêmicas que comprometiam a dilatação pupilar. Os pacientes foram submetidos à instilação de 1 gota de fenilefrina a 10% e aplicação de vaporizador do mesmo midriático no olho contralateral. O olho em que se instilou o colírio permaneceu aberto, enquanto o olho vaporizado ficou fechado durante as aplicações da medicação. O diâmetro pupilar foi medido antes da aplicação, 10, 20 e 30 minutos após. O processo de instilação ou vaporização foi observado quanto a sua adequação técnica por um dos autores. Após o processo foi perguntado ao paciente questões pré-formuladas sobre a praticidade de ambos os métodos. Resultados: A diferença de midríase média entre os grupos de olhos avaliados em um determinado tempo foi no máximo 0,3 mm , o que não foi clinicamente ou estatisticamente significativo (ANOVA: F = 1,97 e p = 0,163609) . Porém, ao longo do tempo, a diferença entre o diâmetro da pupila no tempo inicial e no tempo de 30 minutos foi 1,15 mm para os olhos vaporizados e 1,58 mm para os olhos instilados com gotas (ANOVA: F = 129,22 e p ≤ 0,0001). Percentual de 60% dos pacientes tocaram a ponta do frasco de colírio nos olhos, enquanto que 12% tocaram o orifício na ponta do vaporizador com os dedos (p < 0,000001). Setenta de dois por cento (72%) consideraram a instilação de gotas fácil ou muito fácil enquanto 62% consideraram a vaporização em olho fechado fácil ou muito fácil (p = 0,238). Conclusão: A instilação de gotas em olhos abertos e a vaporização de olhos fechados da fenilefrina a 10% apresentou eficácia clínica semelhante. A vaporização foi mais segura e apresentou nível de dificuldade um pouco maior do que a instilação, apesar dos pacientes serem experientes para instilar gotas e inexperientes para vaporizar a medicação em olho fechado.

ABSTRACT Objective: To compare the effectiveness of phenylephrine 10% applied by a spray onto the eye closed over drop instillation onto an open eye on patients who will perform ophthalmoscopy and assess the level of difficulty and technical adequacy of the administration methods. Methods: The study was a clinical trial, controlled, randomized and paired, performed in 2014, involving 100 eyes of 50 patients in the Polyclinic Ronaldo Gazolla - RJ, with no ocular or systemic diseases that compromised the pupillary dilation. Patients underwent 10% phenylephrine eye drop instillation onto one open eye and spray application onto the other eye, which was closed. Pupillary diameter was measured before application and 10, 20, 30 minutes after. The process of instillation or vaporization was observed for its technical correctness by one of the authors. A questionnaire was asked to the patient about the difficulty of both methods after topical administration. Results: The average mydriasis difference between the eye groups assessed at a given time was at most 0.3 mm, which was not clinically or statistically significant (ANOVA: F = 1.97 and p = 0.163609). However, over time, the difference between the average pupil diameter before application and after 30 minutes was 1.15 mm to vaporized eyes and to 1.58 mm in eyes instilled with drops (ANOVA: F = 129, 22 and p ≤ 0.0001). Sixty per cent of patients touched the tip of the eye drop bottle onto the eye, while 12% touched the tip of the vaporizer with their fingers (p <0.000001). Seventy two percent (72%) considered the drops instillation easy or very easy, while 62% considered vaporization in a closed eye easy or very easy (p = 0.238). Conclusion: The instillation of drops phenylephrine 10% in open eyes and the vaporization onto closed eyes showed similar clinical efficacy. Vaporization was safer and a little more difficult than instillation, despite the patients being experienced for instilling drops and inexperienced to vaporize the medication in a closed eye.

Alpha antiadrenergic effect of Achyrocline bogotensis extract ("Vira Vira") in isolated rat aortic ring / Efecto antiadrenérgico alfa del extracto de Achyrocline bogotensis ("Vira Vira") en anillos aislados de aorta de rata

The treatment of symptoms of prostatic hyperplasia is among the traditional uses of Achyrocline bogotensis (Kunth) [N.V. "Vira Vira", Compositae] in Colombia. Pharmacological therapy for this disorder depends mainly on alpha-1 antiadrenergic agents, and the mechanism has not been studied previously using A. bogotensis. Objectives: To assess the alpha-1 antiadrenergic effect of the extract obtained from the aerial parts of A. bogotensis in isolated aortic rings from Wistar rats. Methods: The study compared the effects of the ethanol extract of A. bogotensis, prazosin (reference) and DMSO (control) in rings stimulated with phenylephrine (PE) or KCl. The capacity to reduce the PE pressor effect by the ethanol extract (pD2' value) was determined. To quantify the A. bogotensis relaxant potency, increasing concentrations of the ethanol extract (0.1 µg/mL-0.1 mg/mL), were added cumulatively to isolated aortic rings pre-contracted with PE (0.1 µM) or KCl (80 mM). To explore the possible participation of nitric oxide (NO), L-NAME (100 µM) was administered to aortic rings exposed to cumulatively increasing concentrations of PE in isolated aortic rings in the presence of the extract (10 µg/mL). Aqueous, butanol and dichloromethane fractions (10 µg/mL) obtained from the ethanol extract were assayed. Phytochemical screening was also performed. Results: Prazosin and A. bogotensis extract notably reduced the contraction induced by PE whereas their inhibitory effect in rings contracted with KCl were lower. A. bogotensis ethanol extract showed a high capacity for reducing the PE pressor response (pD´2: 5.51) as well as total efficacy for relaxing rings previously precontracted with PE. The relaxant efficacy and potency of A. bogotensis extract against rings previously contracted with KCl were notably lower. L-NAME partly reverted the inhibitory effect of A. bogotensis. Aqueous, butanol and dichloromethane fractions gave inhibitory responses lower than that obtained with the ethanol extract. Phytochemical screening of A. bogotensis extract revealed the significant presence of flavonoid and triterpene metabolites. Conclusions: These results suggest that A. bogotensis elicits a smooth muscle relaxant effect related to the alpha-1 antiadrenergic mechanism. This response is partially NO dependent and seems to be due to interactions among active metabolites likely to be of flavonoid and/or terpenoid nature.

Antecedentes: Uno de los usos tradicionales de la especie Achyrocline bogotensis (Kunth) [N.V. "Vira Vira", Compositae] en Colombia es el tratamiento de los síntomas de la hiperplasia prostática benigna. La terapia farmacológica de este trastorno se basa principalmente en el uso de agentes que ejercen efecto anti-adrenérgico alfa-1, mecanismo no estudiado previamente en esta especie. Objetivos: Evaluar el efecto anti-adrenérgico alfa-1 del extracto de la especie Achyrocline bogotensis (Kunth) en anillos aislados de aorta de ratas Wistar. Métodos: Se comparó el efecto del extracto etanólico de A. bogotensis, prazosin (patrón) y DMSO (control) en anillos aislados de aorta de ratas Wistar estimulados con fenilefrina (PE) o KCl. Se determinó la capacidad del extracto etanólico de A. bogotensis para reducir el efecto contráctil inducido por PE (pD'2 ). Se cuantificó la potencia relajante del extracto etanólico de A. bogotensis (0.1 µg/ mL - 0.1 mg/mL) en anillos de aorta previamente contraídos con PE (0.1 µM) o KCl (80 mM). Se exploró la posible participación del óxido nítrico (NO), administrando L-NAME (100 µM) en anillos de aorta expuestos a concentraciones acumulativas de PE en presencia del extracto etanólico (10 µg/mL). También se comparó el efecto de las fracciones acuosa, butanólica y diclometanólica (10 µg/mL), obtenidas del extracto etanólico, en anillos estimulados con PE. Además, se efectuó un tamizado fitoquímico del extracto. Resultados: Prazosin y el extracto de A. bogotensis redujeron notablemente el efecto de PE mientras su efecto inhibitorio sobre la contracción inducida por KCl fue menor. El extracto etanólico mostró una ostensible capacidad para reducir el efecto contráctil inducido por PE (pD2 ´: 5.51) así como una eficacia total para relajar anillos previamente contraídos con PE. La potencia y eficacia de relajación del extracto de A. bogotensis frente a anillos previamente contraídos con KCl fue notablemente menor. L-NAME revirtió parcialmente el efecto inhibitorio del extracto de A. bogotensis. Las fracciones acuosa, butanólica y diclorometanólica arrojaron respuestas inhibitorias menores que las inducidas por el extracto etanólico. El tamizado fitoquímico del extracto de A. bogotensis mostró la presencia de metabolitos de naturaleza flavonoide y terponoide. Conclusiones: Estos resultados muestran que la especie A. bogotensis ejerce efectos relajantes sobre el músculo liso vinculados con mecanismos de tipo antiadrenérgico alfa-1. Esta respuesta depende en parte de la presencia de NO y parece deberse a la interacción de metabolitos de naturaleza flavonoide y/o terpenoide.

The Labdane Ent-3-Acetoxy-Labda-8(17), 13-Dien-15-Oic Decreases Blood Pressure In Hypertensive Rats / O Labdano Ácido Ent-3-Acetóxi-Labda-8(17), 13-Dieno-15-Óico Reduz Pressão Arterial Em Ratos Hipertensos

Abstract Background: Labdane-type diterpenes induce lower blood pressure via relaxation of vascular smooth muscle; however, there are no studies describing the effects of labdanes in hypertensive rats. Objective: The present study was designed to investigate the cardiovascular actions of the labdane-type diterpene ent-3-acetoxy-labda-8(17), 13-dien-15-oic acid (labda-15-oic acid) in two-kidney 1 clip (2K-1C) renal hypertension. Methods: Vascular reactivity experiments were performed in aortic rings isolated from 2K-1C and normotensive (2K) male Wistar rats. Nitrate/nitrite (NOx) measurement was performed in aortas by colorimetric assay. Blood pressure measurements were performed in conscious rats. Results: Labda-15-oic acid (0.1-300 µmol/l) and forskolin (0.1 nmol/l - 1 µmol/l) relaxed endothelium-intact and endothelium-denuded aortas from both 2K-1C and 2K rats. Labda-15-oic acid was more effective at inducing relaxation in endothelium-intact aortas from 2K pre-contracted with phenylephrine when compared to the endothelium-denuded ones. Forskolin was more potent than labda-15-oic acid at inducing vascular relaxation in arteries from both 2K and 2K-1C rats. Labda-15-oic acid-induced increase in NOx levels was lower in arteries from 2K-1C rats when compared to 2K rats. Intravenous administration of labda-15-oic acid (0.3-3 mg/kg) or forskolin (0.1-1 mg/kg) induced hypotension in conscious 2K-1C and 2K rats. Conclusion: The present findings show that labda-15-oic acid induces vascular relaxation and hypotension in hypertensive rats.

Resumo Fundamento: Diterpenos do tipo labdano induzem uma queda da pressão arterial por meio do relaxamento do músculo liso vascular; todavia, não há estudos que descrevam os efeitos de labdanos em ratos hipertensos. Objetivo: O presente estudo foi desenvolvido para investigar as ações cardiovasculares do labdano ácido ent-3-acetóxi-labda-8(17),13-dieno-15-óico (labda-15-óico) na hipertensão renal dois rins-1 clipe (2R-1C). Métodos: Foram feitos experimentos de reatividade vascular em anéis aórticos isolados de ratos machos 2R-1C e normotensos (2R). A medição de Nitrato/Nitrito (NOx) foi feita nas aortas por meio de ensaio colorimétrico. As medidas de pressão arterial foram feitas em ratos conscientes. Resultados: O ácido labda-15-óico (0,1 - 300 µmol/l) e a forscolina (0,1 nmol/l - 1 µmol/l) relaxaram as aortas com endotélio intacto e as aortas sem endotélio dos ratos 2R-1C e 2R. O labda-15-óico mostrou-se mais eficaz na indução do relaxamento em aortas com endotélio intacto de 2R pré-contraídas com fenilefrina em comparação àquelas sem endotélio. A forscolina mostrou-se mais potente do que o ácido labda-15-óico na indução do relaxamento vascular nas artérias tanto de ratos 2R-1C quanto de ratos 2R. O aumento dos níveis de NOx induzido pelo ácido labda-15-óico foi menor nas artérias de ratos 2R-1C em comparação a ratos 2R. A administração intravenosa de ácido labda-15-óico (0,3-3 mg/kg) ou forscolina (0,1-1 mg/kg) induziu hipertensão em ratos 2R-1C e 2R conscientes. Conclusão: Os presentes resultados mostram que o labda-15-óico induz relaxamento vascular e hipotensão em ratos hipertensos.

Pharmacological study of the mechanisms involved in the vasodilator effect produced by the acute application of triiodothyronine to rat aortic rings

A relationship between thyroid hormones and the cardiovascular system has been well established in the literature. The present in vitro study aimed to investigate the mechanisms involved in the vasodilator effect produced by the acute application of 10-8–10-4 M triiodothyronine (T3) to isolated rat aortic rings. Thoracic aortic rings from 80 adult male Wistar rats were isolated and mounted in tissue chambers filled with Krebs-Henseleit bicarbonate buffer in order to analyze the influence of endothelial tissue, inhibitors and blockers on the vascular effect produced by T3. T3 induced a vasorelaxant response in phenylephrine-precontracted rat aortic rings at higher concentrations (10-4.5–10-4.0 M). This outcome was unaffected by 3.1×10-7 M glibenclamide, 10-3 M 4-aminopyridine (4-AP), 10-5 M indomethacin, or 10-5 M cycloheximide. Contrarily, vasorelaxant responses to T3 were significantly (P<0.05) attenuated by endothelium removal or the application of 10-6 M atropine, 10-5 M L-NG-nitroarginine methyl ester (L-NAME), 10-7 M 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), 10-6 M (9S,10R,12R)-2,3,9,10,11,12-Hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i](1,6)benzodiazocine-10-carboxylic acid, methyl ester KT 5823, 10-2 M tetraethylammonium (TEA), or 10-7 M apamin plus 10-7 M charybdotoxin. The results suggest the involvement of endothelial mechanisms in the vasodilator effect produced by the acute in vitro application of T3 to rat aortic rings. Possible mechanisms include the stimulation of muscarinic receptors, activation of the NO-cGMP-PKG pathway, and opening of Ca2+-activated K+ channels.

Effects of One Resistance Exercise Session on Vascular Smooth Muscle of Hypertensive Rats / Efeitos de uma Sessão de Exercício Resistido sobre o Músculo Liso Vascular de Ratos Hipertensos

AbstractBackground:Hypertension is a public health problem and increases the incidence of cardiovascular diseases.Objective:To evaluate the effects of a resistance exercise session on the contractile and relaxing mechanisms of vascular smooth muscle in mesenteric arteries of NG-nitro L-arginine methyl ester (L-NAME)-induced hypertensive rats.Methods:Wistar rats were divided into three groups: control (C), hypertensive (H), and exercised hypertensive (EH). Hypertension was induced by administration of 20 mg/kg of L-NAME for 7 days prior to experimental protocols. The resistance exercise protocol consisted of 10 sets of 10 repetitions and intensity of 40% of one repetition maximum. The reactivity of vascular smooth muscle was evaluated by concentration‑response curves to phenylephrine (PHEN), potassium chloride (KCl) and sodium nitroprusside (SNP).Results:Rats treated with L-NAME showed an increase (p < 0.001) in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) compared to the initial period of induction. No difference in PHEN sensitivity was observed between groups H and EH. Acute resistance exercise reduced (p < 0.001) the contractile response induced by KCl at concentrations of 40 and 60 mM in group EH. Greater (p < 0.01) smooth muscle sensitivity to NPS was observed in group EH as compared to group H.Conclusion:One resistance exercise session reduces the contractile response induced by KCl in addition to increasing the sensitivity of smooth muscle to NO in mesenteric arteries of hypertensive rats.

ResumoFundamento:A hipertensão é um problema de saúde pública e faz aumentar a incidência das doenças cardiovasculares.Objetivo:Avaliar os efeitos de uma sessão de exercício resistido sobre os mecanismos contráteis e relaxantes do músculo liso vascular em artéria mesentérica de ratos hipertensos induzidos por L-NAME.Métodos:Ratos Wistar foram divididos em três grupos: Controle (C), Hipertenso (H) e Hipertenso Exercitado (HE). A hipertensão foi induzida pela administração de 20 mg/kg de NG-nitro L-arginina metil éster (L-NAME) durante sete dias antes dos protocolos experimentais. O protocolo de exercício resistido consistiu em dez séries de dez repetições e intensidade de 40% de uma repetição máxima. A reatividade do músculo liso vascular foi avaliada através de curvas concentração-resposta para a fenilefrina (FEN), cloreto de potássio (KCl) e nitroprussiato de sódio (NPS).Resultados:Os ratos tratados com L-NAME apresentaram aumento (p < 0,001) da Pressão Arterial Sistólica (PAS), da Pressão Arterial Diastólica (PAD) e da Pressão Arterial Média (PAM) quando comparados ao período inicial da indução. Não foi observada diferença na sensibilidade da FEN entre os grupos H e HE. O exercício resistido agudo reduziu (p < 0,001) a resposta contrátil induzida pelo KCl nas concentrações de 40 e 60 mM do grupo HE quando comparado ao grupo H. Foi observado maior (p < 0,01) sensibilidade do músculo liso ao NPS no grupo HE quando comparado ao grupo H.Conclusão:Uma sessão de exercício resistido reduz as respostas contráteis induzidas pelo KCl, além de aumentar a sensibilidade do músculo liso ao NO em artéria mesentérica de ratos hipertensos.