Effects of the simultaneous use of drug-eluting stents and statins in an atherosclerotic animal model.

INTRODUCTION: The use of statins and medicated stents (MS) is the best available therapy for the treatment of severe coronary disease in selected cases. However, the vascular effects of the simultaneous use of both therapies are unknown. MATERIALS AND METHODS: An experimental study was carried out on 60 NZ rabbits with advanced atherosclerosis, distributed in four groups of 15 animals each. Group 1: Control. Group 2: paclitaxel-eluting stent (PES) in the thoracic aorta. Group 3: Atorvastatin 2.5mg/day po+PES implant, and Group 4: Atorvastatin 2.5mg/day po. They were followed up at 30, 60 and 90 days. Histo-morphometric analyses were carried out. RESULTS: A total of 60 PES were successfully implanted. One animal from Group 3 died due to respiratory infection. PES increased the lumen diameter and area, as well as the vessel area; atorvastatin induced a potent plaque regression. In the PES group, the lumen diameter was 4.25±0.0mm, lumen area was 14.2±0.4mm(2), vessel area was 16.7±0.0mm(2), and plaque/media area ratio was 0.1±0.0. In the PES+atorvastatin group the measurements were 4.9±0.1mm (p<0.001), 18.6±0.8mm(2) (p=0.005), 21.6±0.9mm(2) (p=0.007) and 0.8±0.08 (p=0.032), respectively. CONCLUSIONS: Our results confirm the potent synergistic mechanical effect of the PES and plaque regression of the statins in an animal model with advanced atherosclerosis.

The role of potassium channels in the vasodilatory effect of caffeine in human internal mammary arteries.

There is little information about the direct effect of caffeine in human blood vessels. The purpose of this study was to evaluate the direct vascular effect of caffeine on human internal mammary artery (IMA) and the involvement of potassium channels in this response. Segments of IMA were obtained from 29 patients who underwent coronary artery bypass graft surgery. They were cut into rings, suspended between two wire hooks in organ bath chambers and constricted submaximally with norepinephrine. Caffeine (3.16x10(-9) to 10(-4) mol/L) was added in a cumulative fashion to rings with or without functional endothelium and concentration response curves were constructed. The response to caffeine was also evaluated after incubation with adenosine 3',5'-triphosphate (ATP)-dependent potassium channel blocker glibenclamide, voltage-dependent potassium channel blocker 4-aminopyridine and large-conductance calcium-activated potassium channel inhibitor tetraethylammonium. Caffeine produced a potent, concentration-dependent relaxation of IMA. The relaxant responses did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation with different potassium channel inhibitors (glibenclamide, 4-aminopyridine and tetraethylammonium) did not cause significant alterations in the relaxant responses to caffeine. These results suggest that the vasodilatory response to caffeine in human IMA is independent of endothelial function and is not mediated by potassium channels.

[In vitro effect of caffeine on internal mammary artery rings used in cardiac revascularization surgery]. / Acción in vitro de la cafeína en anillos de arteria mamaria interna utilizada en cirugía de revascularización cardiaca.

INTRODUCTION: The vasodilator effect of caffeine in animal models arteries has been demonstrated previously. However, studies with the same methodology using human arteries in vitro have not been performed. OBJECTIVES: The in vitro vasoactive effects of caffeine was evaluated on human internal mammary arteries. MATERIALS AND METHODS: Internal mammary artery rings were used (n = 20). Endothelial function was evaluated with acetylcholine at a concentration of 3.16 x 10 -6 M, nitroglycerine at cumulative concentrations of 10 -11 M to 10 -4 M and caffeine with cumulative concentrations of 10 -8 M to 10 -4 M. RESULTS: Nitroglycerin produced a maximum relaxation percentage of 87.4 +/- 12.3%, caffeine a percentage of 86.9 +/- 21.0% in arteries with functional endothelium, and of 71.6 +/- 28.6% in arteries with endothelial dysfunction. No differences were detected among the three groups ( p=0.289). Similarly, no differences were found between EC 50 in arteries with functional endothelium (1.66 x 10 -5 +/-1.57 x 10 -5 M) and dysfunctional arteries (7.8 x 10 -5 +/-14.6 x 10 -5 M). Nitroglycerine proved more potent than caffeine (EC 50 = 4.3 x 10 -9 +/-4.4 x 10 -9 M) ( p=0.013). CONCLUSIONS: Although nitroglycerin was a more potent vasodilator, caffeine had a strong arterial vasodilator effect regardless of endothelial function in human arteries.

Acción in vitro de la cafeína en anillos de arteria mamaria interna utilizada en cirugía de revascularización cardiaca / In vitro effect of caffeine on internal mammary artery rings used in cardiac revascularization surgery

Introducción. El efecto vasodilatador de la cafeína en las arterias de modelos animales ya ha sido demostrado. Se desconocen estudios con la misma metodología in vitro utilizando arterias humanas. Objetivos. Evaluar los efectos vasoactivos in vitro de la cafeína en la arteria mamaria interna de humanos. Materiales y métodos. Se utilizaron 80 anillos de arteria mamaria interna (n=20 pacientes). La funcionalidad del endotelio se evaluó con acetilcolina a una concentración de 3,16x10 -6 M, de nitroglicerina con dosis acumulativas de 10 –11 M a 10 –4 M y de cafeína con concentraciones acumulativas de 10 –8 M a 10 –4 M. Resultados. La nitroglicerina indujo un porcentaje máximo de relajación de 87,4±12,3 por ciento, la cafeína, de 86,9±21,0 por ciento en arterias con endotelio funcional y de 71,6±28,6 por ciento en arterias con disfunción endotelial. No se encontraron diferencias entre los tres grupos ( p=0,289). Tampoco se encontraron diferencias en la EC 50 en arterias con endotelio funcional (1,66x10 -5 ±1,57x10 -5 M) y arterias disfuncionales (7,75x10 -5 ±14,64x10 -5 M). La nitroglicerina resultó más potente que la cafeína (EC 50 = 4,30x10 -9 ±4,35x10 -9 M) ( p=0,013). Conclusiones. Aunque la nitroglicerina fue un vasodilatador más potente, la cafeína tuvo un fuerte efecto vasodilatador arterial in vitro independientemente de la funcionalidad del endotelio en arterias humanas.

Efecto morfológico y funcional vascular de los andrógenos endógenos en un modelo experimental en conejos ateroscleróticos / Vascular morphologic and functional effect of endogenous androgens in an experimental atherosclerotic rabbits' model

Estudios clínicos y experimentales previos, sugieren que los andrógenos podrían tener un efecto adverso, neutral o benéfico, sobre la aterosclerosis y sus manifestaciones clínicas. Métodos: se realizó un estudio experimental aleatorizado y controlado en 40 conejos de raza Nueva Zelanda. 20 animales se sometieron a orquidectomía y 20 se alimentaron con dieta aterogénica durante 20 semanas. Se distribuyeron en cuatro grupos: 1: no castrados sometidos a dieta normal; 2: castrados sometidos a dieta normal; 3: no castrados sometidos a dieta aterogénica y 4: castrados sometidos a dieta aterogénica. Se hicieron mediciones de colesterol total y testosterona libre. Después de la eutanasia, se cuantificó en aorta la relajación arterial independiente de endotelio y dependiente de endotelio in-vitro, y se hicieron análisis histomorfométricos de la aorta torácica para cuantificar la formación de placa aterosclerótica. Resultados: los animales sometidos a dieta normal (n=20) tuvieron colesterol total de 51,1 ± 8,5 mg/dL y los sometidos a dieta aterogénica de 429,2 ± 262,0 mg/dL (p < 0,001). Los niveles de testosterona en el grupo no castrados fueron 2,1 ± 0,3 ng/mL y en los castrados 0,8 ± 0,4 ng/ml (p = 0,024). En conejos no castrados, el efecto de la hipercolesterolemia (366 ± 226,1 mg/dL) fue muy leve en inducir placa aterosclerótica y alteración vascular funcional. En cambio, en conejos castrados la dieta aterogénica indujo un incremento en el colesterol total de 387,6 ± 292,7 mg/dL (p < 0,001), y severos cambios morfológicos como área de placa 2,6 ± 2,3 mm2 (p < 0,001), índice de área de placa/área del vaso de 0,25 ± 0,1 (p < 0,001) e índice de área de la placa/área de la media de 0,4 ± 0,3 (p < 0,001). El porcentaje de relajación independiente de endotelio fue de 85,5 ± 14,3% (p = NS) y el de relajación dependiente de endotelio de 38,5 ± 20,1% (p = 0,03). Conclusión: en este estudio realizado en conejos, se demuestra que la testosterona endógena podría tener un efecto preventivo sobre la aterosclerosis y favorecer la relajación vascular dependiente de endotelio en presencia de hipercolesterolemia severa.

Summary: previous clinical and experimental studies suggest that androgens could have an adverse, neutral or beneficial effect on atherosclerosis and its clinical manifestations. Methods: an experimental, randomized controlled study in 40 New Zealand white male rabbits was realized. 20 rabbits underwent orchiectomy and 20 were fed with an atherogenic diet for 20 weeks. These were distributed in four groups: 1. non-castrated under normal diet, 2. castrated under normal diet, 3. non-castrated under atherogenic diet, and 4. castrated under atherogenic diet. Total cholesterol and free testosterone were measured. After euthanasia, arterial relaxation independent of endothelium was quantified in aorta, as well as the one depending on endothelium, in vitro, and histomorphometric analysis of thoracic aorta were made in order to quantify the atherosclerotic plaque formation. Results: animals that had a normal diet (n=20) had total cholesterol of 51.1 ± 8.5 mg/dl and those with atherogenic diet, of 429.2 ± 262.0 mg/dl (p< 0.001). Testosterone levels in the non- castrated group were 2.1 ± 0.3 ng/mL and in the castrated were 0.8 ± 0.4 ng/mL (p= 0.024). In non-castrated rabbits the effect of hypercholesteremia (366 ± 226.1 mg/dL) inducing atherosclerotic plaque and functional vascular alteration was mild. On the other hand, atherogenic diet in castrated rabbits induced an increment in total cholesterol from 387.6 ± 292.7 mg/dL (p <0.001) and severe morphological changes such as plaque area 2.6 ± 2.3mm² (p <0.001), vessel plaque/area 0.25 ± 0.1 (p <0.001) and area index of plaque/area of the media 0.4 ± 0.3 (p <0.001). Endothelium independent relaxation percentage was 85.5 ± 14.3% (p = NS) and endothelium dependent relaxation was 38.5 ± 20.1% (p = 0.03). Conclusion: this study realized in rabbits demonstrates that endogenous testosterone might have a preventive effect on atherosclerosis and favor endothelium dependent vascular relaxation in the presence of severe hypercholesterolemia.

Micro-organismos efectivos (EM-X): acción in-vivo sobre aorta de conejos hipercolesterolémicos / Effective microorganisms (EM-X): in-vitro action on aorta of hypercholesterolemic rabbits

Antecedentes y objetivos: EM-X es una bebida antioxidante derivada del salvado de arroz y extractos de algas marinas fermentadas con micro-organismos efectivos. El objetivo de este estudio fue determinar si el EM-X previene la formación de placa aterosclerótica y favorece la relajación vascular in-vitro en un modelo de aterosclerosis temprana en conejos hipercolesterolémicos.Métodos: la población se dividió en cuatro grupos: 1: conejos ateroscleróticos con administración de EM-X; 2: conejos ateroscleróticos sin administración de EM-X; 3: conejos sanos sin administración de EM-X; y 4: conejos sanos con administración de EM-X. A cada conejo se le midió el colesterol sérico y se le extrajeron anillos aórticos para análisis in-vitro de la relajación vascular dependiente e independiente de endotelio. Se realizaron análisis histomorfométricos y cuantificación de la endotelización arterial.

Background: EM-X is an antioxidant beverage obtained from rice bran and seaweed extracts fermented with Effective Microorganisms. The purpose of this study was to determine if EM-X prevents atherosclerotic plaque formation and favours in vitro vascular relaxation in a model of early atherosclerosis in hypercholesterolemic rabbits. Methods: The study population was divided in four groups: 1. atherosclerotic rabbits administered with EM-X, 2: atherosclerotic rabbits not administered with EM-X; 3: healthy rabbits not administered with EM-X; and 4: healthy rabbits administered with EM-X. Serum cholesterol was measured in each rabbit and vascular rings were obtained for conducting the endothelium dependent relaxation (EDR) in vitro analysis. Additionally, hystomorphometrical analysis and endothelial cell quantification were performed. Results: Whole cholesterol measurements differed significantly in groups 1 vs. 2 and 3 vs. 4 (p>0.05). EDR did not differ significantly between groups 1 and 2 (p = 0.181), or between groups 3 and 4 (p = 0.349). Hystomorphometrical characteristics did not show significant differences neither in groups 1 and 2 (p=0.85) nor in groups 3 and 4 (p=0.95). The immunohystochemical analysis did not show significant differences between any groups (p=0.85). Conclusion: The results found do not demonstrate the benefits of EM-X as antioxidant therapy in the prevention of atherosclerotic plaque formation and in vitro endothelium dependent vascular relaxation in healthy animals or with endothelial dysfunction and atherosclerosis.

Disfunción edoltelial inducida por hipercolesterolemia: esudio in vitroen un modelo animal / Endothelial dysfunction induced by hypercholesterolemia: in vitro study ina animal model

Los factores de riesgo tradicionales como hipercolesterolemia afectan la producción endotelial o acción de sustancias vasoactivas fundamentales como el óxido nítrico (NO). Este fenómeno tiene efectos proa terogénicos y protombóricos. El objetivo del presente estudio fue evaluar los efectos in vitro de la hipercolesterolemia sobre la función endotelial y la formación de placa ateroesclerótica en tejido aórtico proveniente de conejos hipercolesterolémicos.Los resultados encontrados sugieren que los niveles elevados de colesterol sérico producen una alteración en la vasodilatación arterial dependiente de endotelio funcional, la cual se presenta sin cambios morfológicos de las células endoteliales. Se corrobora que la hipercolesterolemia es un factor de riesgo independiente de ateroesclerosis el cual contribuye a la disfunción como evento inicial en la génesis del proceso