Enhanced tumor therapy via drug co-delivery and in situ vascular-promoting strategy.

Conventional tumor starving therapy by reducing its vessel density may be effective at early treatment but potentially contributes to tumor hypoxia, drug resistance and metastasis. A new strategy through enhancing tumor angiogenesis in combination with effective chemotherapeutic drugs, has shown successful tumor growth and spread inhibition. To achieve in situ release of angiogenic and antitumor drugs in tumor, we designed a precise ratiometric polymeric hybrid micelle system for co-delivering nitric oxide and paclitaxel. The hybrid micelles could accumulate in tumor via the long blood circulation and enhanced permeability and retention (EPR) effect, promote the drug accumulation and penetration in tumor by in situ increased vascular permeability, blood perfusion and vessel density, achieve the synergistic antitumor effect of nitric oxide and paclitaxel through modified tumor microenvironment, overcome multidrug resistance and inhibit metastasis. This study presents a combinational therapy against tumor progression and spread, which shows great potential in cancer therapy of the future.

Effect of tetrahydrobiopterin and exercise training on endothelium-dependent vasorelaxation in SHR

We examined whether the improvement of impaired NO-dependent vasorelaxation by exercise training could be mediated through a BH4-dependent mechanism. Male spontaneously hypertensive rats (SHR, n = 20) and Wistar-Kyoto rats (WKY, n = 20) were trained (Tr) for 9 weeks on a treadmill and compared to age-matched sedentary animals (Sed). Endothelium-dependent vasorelaxation (EDV) was assessed with acetylcholine by measuring isometric tension in rings of femoral artery precontracted with 10−5 M phenylephrine. EDV was impaired in SHR-Sed as compared to WKY-Sed (p = 0.02). Training alone improved EDV in both WKY (p = 0.01) and SHR (p = 0.0001). Moreover, EDV was not different in trained SHR than in trained WKY (p = 0.934). Pretreatment of rings with L-NAME (50 ìM) cancelled the difference in ACh-induced relaxation between all groups, suggesting that NO pathway is involved in these differences. The presence of 10−5 M BH4 in the organ bath significantly improved EDV for sedentary SHR (p = 0.030) but not WKY group (p = 0.815). Exercise training turned the beneficial effect of BH4 on SHR to impairment of ACh-induced vasorelaxation in both SHR-Tr (p = 0.01) and WKY-Tr groups (p = 0.04). These results suggest that beneficial effect of exercise training on endothelial function is due partly to a BH4-dependent mechanism in established hypertension (AU)

Vascular reactivity in diabetes mellitus

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Controlled delivery of nitric oxide inhibits leukocyte migration and prevents vasospasm in haptoglobin 2-2 mice after subarachnoid hemorrhage.

OBJECTIVE: Cerebral vasospasm is the leading cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH) occurs. The haptoglobin 2-2 genotype likely increases the risk for developing posthemorrhagic vasospasm, but potential treatments for vasospasm have never been tested in an animal model of this genotype. We used the nitric oxide (NO) donor diethylenetriamine (DETA)/NO incorporated into ethylene/vinyl acetate (EVAc) polymers to evaluate the efficacy of controlled NO repletion in a haptoglobin 2-2 mouse basilar artery SAH model. METHODS: Mice were randomized to 3 groups: autologous blood injection and empty polymer implantation into the subarachnoid space (n = 16); blood injection and 30% DETA/NO-EVAc implantation (n = 20); and sham operation (n = 19). At 24 hours after surgery, activity level was assessed on a 3-point scale, and basilar arteries were processed for morphometric measurements. Leukocyte extravasation was assessed by immunohistochemistry (n = 12). RESULTS: Treatment with controlled release of NO from DETA/NO-EVAc polymers after SAH resulted in a significant increase in basilar artery lumen patency (73.3% +/- 4.3% versus 96.5% +/- 4.3%, mean +/- standard error of the mean; P = 0.01), a significant improvement in activity after experimental SAH (2.14 +/- 0.14 versus 2.56 +/- 0.10 points; P = 0.025), and a significant decrease in extravasated leukocytes (21 +/- 4.55 versus 6.75 +/- 3.77 leukocytes per high-power field, untreated versus treated mice; P = 0.001). CONCLUSION: Treatment with controlled release of NO prevented posthemorrhagic vasospasm in haptoglobin 2-2 mice, and mitigated neurological deficits, suggesting that DETA/NO-EVAc would be an effective therapy in patients with a genotype that confers higher risk for vasospasm after SAH. In addition to smooth muscle relaxation, inhibition of leukocyte migration may contribute to the therapeutic mechanism of NO.

Efecto de la ingesta de sal sobre la función endotelial y su relación con el fenómeno de la sensibilidad a la sal en la hipertensión arterial esencial / Effect of salt intake upon endothelial function and its relationship with the salt sensitivity phenomenon in essential hypertension

El objetivo del presente trabajo ha sido el de evaluar las alteraciones en la función de la célula endotelial inducidas por el consumo de sal en pacientes hipertensos esenciales caracterizados en funcion de la presencia de sensibilidad o resistencia a la sal. Para ello hemos incluido a 60 pacientes hipertensos esenciales de ambos sexos, con una media de 42 años, sometidos a ingesta de baja (50 mmol/día) y elevada (250 mmol/día) cantidad de sal, evaluando los cambios en los productos derivados del endotelio. La evaluación funcional de la función endotelial se ha realizado mediante pletismografía de oclusión venosa frente a infusiones intraarteriales de acetilcolina, nitroprusiato sódico y el inhibidor de la síntesis de óxido nítrico, L-NMMA. Los resultados muestran que en el conjunto de los pacientes estudiados, una elevada ingesta de sal induce un descenso estadísticamente significativo en la concentración plasmática de nitratos (p < 0,001) de endotelina (p = 0,005). Además los pacientes sensibles a la sal mostraron un descenso estadísticamente significativo de la excreción urinaria de nitratos (p = 0,045), inducidos por la ingesta de sal. Finalmente, el estudio mediante pletismografía mostró que los pacientes sensibles a la sal presentaban una menor vasodilatación dependiente del endotelio inducida por acetilcolina (p = 0,008) en comparación con los resistentes a la sal. Además, la infusión de L-NMMA indujo a un menor descenso en la respuesta vasodilatadora a acetilcolina en los pacientes sensibles a la sal (p = 0,013). En conclusión, la ingesta de una dieta rica en sal ejerce en los pacientes hipertensos un efecto inhibitorio sobre la secreción de la célula endotelial. Hay que añadir que los pacientes sensibles a la sal presentan mayores alteraciones en la función de la célula endotelial. Estos resultados apoyan la existencia de una relación entre la disfunción endotelial y el desarrollo de la hipertensión sensible a la sal (AU)

Historia del Descubrimiento de la Vía L-arginina: Oxido Nítrico

En la última década se ha podido establecer que el Oxido Nítrico (ON) corresponde al llamado Factor Relajante Derivado del Endotelio, dado que mediante el uso de inhibidores competitivos del ON se inducía contracción vascular, efecto revertido por el tratamiento con L-arginina, precursor de la biosíntesis del ON, mediada ésta por la acción de la ON Sintetasa. El ON ha sido implicado entre muchos aspectos, en la generación de daño tisular y patogénesis de algunas condiciones vasculares como vasoespasmo, ateroesclerosis, diabetes mellitus, hipertensión esencial y preeclampsia; de igual forma han sido planteadas novedosas aplicaciones de la inhibición de la ON Sintetasa en el enfoque terapéutico de la inflamación y el shock