Lipoic acid, but not tempol, preserves vascular compliance and decreases medial calcification in a model of elastocalcinosis

Vascular calcification decreases compliance and increases morbidity. Mechanisms of this process are unclear. The role of oxidative stress and effects of antioxidants have been poorly explored. We investigated effects of the antioxidants lipoic acid (LA) and tempol in a model of atherosclerosis associated with elastocalcinosis. Male New Zealand white rabbits (2.5-3.0 kg) were fed regular chow (controls) or a 0.5% cholesterol (chol) diet+104 IU/day vitamin D2 (vitD) for 12 weeks, and assigned to treatment with water (vehicle, n=20), 0.12 mmol·kg-1·day-1 LA (n=11) or 0.1 mmol·kg-1·day-1 tempol (n=15). Chol+vitD-fed rabbits developed atherosclerotic plaques associated with expansive remodeling, elastic fiber disruption, medial calcification, and increased aortic stiffness. Histologically, LA prevented medial calcification by ∼60% and aortic stiffening by ∼60%. LA also preserved responsiveness to constrictor agents, while intima-media thickening was increased. In contrast to LA, tempol was associated with increased plaque collagen content, medial calcification and aortic stiffness, and produced differential changes in vasoactive responses in the chol+vitD group. Both LA and tempol prevented superoxide signals with chol+vitD. However, only LA prevented hydrogen peroxide-related signals with chol+vitD, while tempol enhanced them. These data suggest that LA, opposite to tempol, can minimize calcification and compliance loss in elastocalcionosis by inhibition of hydrogen peroxide generation.

Warfarin use has no effect on blood pressure of patients with Diabetes and hypertension / Uso da warfarina não tem efeitos sobre a pressão arterial em pacientes com diabetes e hipertensão arterial sistêmica

Introduction: Warfarin causes arterial calcification, arterial stiffness and systolic hypertension in animals. Early evidence in humans indicates that a similar effect may occur in patients with diabetes mellitus (DM) and/or hypertension. Objective: To evaluate whether warfarin use causes elevated blood pressure and pulse pressure in patients with both DM and hypertension. Methods: Cross-sectional study of 159 subjects with both DM and hypertension who received warfarin for at least 2 years and 159 age-matched control subjects with DM and hypertension never exposed to warfarin. The primary focus of analysis was the difference in systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) between the two groups. Results: Average age was 73±10 years in both groups. Patients in the warfarin group had received it for an average of 5.5±3.1 years. Subjects in the warfarin group had higher rates of coronary disease and heart failure. SBP and PP were lower in the warfarin group (SBP 130±14 mmHg vs. 134±12 mmHg, P=0.003; PP 58±12 mmHg vs. 62±11 mmHg, P=0.004), while DBP was not different (72±8 vs. 72±7 mmHg, P=0.64). Warfarin patients received more antihypertensive drugsand were seen more often than controls. Multiple regression analyses adjusting for relevant variables did not disclose an association between warfarin useand higher BP; on the contrary, exposure to warfarin was associated with lower SBP and PP on the multivariable models. Conclusion: Use of warfarin in conventional doses for an average of 5.5 years was not associated with increased BP in this cross-sectional study of patients with DM and hypertension.

Introdução: Em animais, a warfarina provoca calcificação arterial, rigidez arterial e hipertensão arterial (HA) sistólica. Dados preliminares em humanos sugerem que o mesmo efeito pode acontecer em pacientes com diabetes mellitus (DM) e/ou HA. Objetivo: Determinar se o uso da warfarina em pacientescom DM e HA resulta em elevação da pressão arterial ou pressão de pulso. Métodos: Estudo transversal de 159 pacientes com DM e HA que haviam sidotratados com warfarina por pelo menos 2 anos, e 159 controles pareados por idade, com DM e HA, mas que nunca haviam usado warfarina. O enfoqueprincipal na análise foi a diferença na pressão arterial sistólica (PAS), diastólica (PAD) e pressão de pulso (PP) entre os dois grupos. Resultados: A média de idade foi 73±10 anos em ambos os grupos. Os pacientes no grupo da warfarina haviam usado a droga por 5.5±3.1 anos. Pacientes no grupo da warfarina tinham uma prevalência maior de doença coronariana e insuficiência cardíaca. A PAS e PP foram mais baixas no grupo warfarina (PAS 130±14 mmHgvs. 134±12 mmHg, P=0.003; PP 58±12 mmHg vs. 62±11 mmHg, P=0.004), mas a PAD não diferiu entre os grupos (72±8 vs. 72±7 mmHg, P=0.64).Pacientes do grupo warfarina usaram mais drogas antihipertensivas e foram avaliados clinicamente com maior freqüência do que os controles. Regressão múltipla ajustada para fatores de relevância clínica não demonstrou nenhuma associação entre o uso da warfarina e elevação da pressão arterial. Pelo contrário, nos modelos de regressão múltipla, a exposição à warfarina associou-se a valores mais baixos de PAS e PP. Conclusão: O uso da warfarina em doses convencionais, por 5.5 anos, não associou-se a um aumento da pressão arterial neste estudo tranversal de pacientes com DM e hipertensão.

Aterosclerosis experimental: cambios bioquímicos y vasculares / Experimental atherosclerosis: biochemical and vascular changes

Se estudió el desarrollo de placas ateros-clerósicas en conejos Nueva Zelanda alimentados con una dieta rica en colesterol. Para ello se comparó el contenido sérico de lípidos y glucosa en conejos sanos y conejos alimentados con 1 y 10 por ciento de colesterol por 10 semanas. Además, se hicieron estudios histológicos de las aortas de dichos animales para evaluar las lesiones ateromatosas. En los animales que recibían una dieta con 10 por ciento de colesterol, los niveles séricos de éste aumentaron significativamente de 26.3 ñ 8.1 mg/dL a 1485 ñ 26.8 mg/dL (p < 0.05). El colesterol asociado con LDL también se incrementó, de 15.9 ñ 5.9 a 1383.8 ñ 58.9 (p < 0.5); y los triglicéridos de 88.3 ñ 35.6 a 411 ñ 154.5. Se encontraron lesiones ateros-clerósicas solamente en los conejos alimentados con 10 por ciento de colesterol. Este modelo es reproducible y puede ser útil en el estudio de la aterosclerosis per se y de la aterogénesis asociada con enfermedades como la diabetes mellitus

Influence of components of oral contraceptive on lipid metabolism.

Oral contraceptives (OC) have been shown to enhance the risk of atherosclerosis. In the present study we sought to determine which component of the OC (containing 0.067 mg estrogen and 0.667 mg of progestin) counts for alteration in lipids profile. Female rats were administered with 0.067 mg of 17 beta-estradiol and 0.667 mg of norethindron acetate/kg body weight. Estrogen treatment exhibited higher levels of lipids in the serum and tissues. LDL-cholesterol increased by three folds but HDL-cholesterol decreased significantly, while progestin group showed decreased levels of lipids and LDL cholesterol. Elevated hepatic cholesterogenesis was observed as indicated by increased activity of HMG-CoA reductase and elevated incorporation of labelled acetate into liver cholesterol in estrogen group. On the other hand, progestin treatment did not alter the activity of HMG-CoA reductase and the rate of incorporation of labelled acetate into hepatic cholesterol. Hepatic degradation of cholesterol to bile acids however, decreased with estrogen treatment. No considerable changes were observed in hepatic bile acid levels in progestin group. Release of lipoprotein into circulation increased but their clearance from the circulation decreased as revealed by the activity of lipoprotein lipase (LPL) of extrahepatic tissues in estrogen group. With progestin treatment, activity of LPL increased significantly in adipose tissue. Activity of hepatic malic enzyme and glucose 6-phosphate dehydrogenase enhanced considerably in estrogen group, while activities of these enzymes were depressed with progestin administration. Thus results indicate that estrogen component of oral pills counts for major changes in lipid and lipoprotein metabolism favouring the development of atherosclerosis.

The role of cadmium in induction of atherosclerosis in rabbits.

Experiments were carried out in rabbits to determine the effects of prolonged treatment of cadmium (8 mg/kg/day) for a period of 6 months on histopathological changes and biochemical alterations of lipid profiles in various tissues compared to normal rabbits. No ECG changes were observed before and at the end of cadmium treatment. Histopathological studies of the coronary artery revealed atherosclerotic changes. Total lipids, cholesterol, free fatty acids and phospholipids were significantly increased in heart and kidney, but decreased in serum and liver. Triglyceride content was increased significantly in heart and kidney with a significant depletion in liver and serum. It is postulated that atherosclerotic changes in rabbits probably occurred through toxic effects of cadmium but the exact mechanism needs to be elucidated.

Preventive effect of trifluoperazine on atherosclerosis induced by cholesterol & adrenaline in rabbits.

Studies on the preventive role of trifluoperazine on cholesterol and adrenaline-induced experimental atherosclerosis in rabbits, revealed that trifluoperazine completely prevented the development of atherosclerotic lesions in both the aorta and coronary arteries of animals administered atherogenic diet and adrenaline (im) despite the fact that this drug had no significant effect on the elevated serum lipid profile induced by atherogenic diet. These findings confirm earlier observations of the authors that trifluoperazine has an inherent capacity to prevent atherogenesis.