Uncoupling protein 2 (UCP2) is an important regulator of intracellular reactive oxygen species (ROS) production. We determined the effects of calorie restriction (CR) on the dynamic aspects of mitochondrial ROS production, UCP2, and the nitric oxide (NO)-cGMP pathway in the cardiovascular tissues of type II diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Some rats were on restricted diets (30% reduction from free intake) from age 29 to 42 weeks. Blood glucose, hemoglobin A1c, plasma levels of free fatty acid, triacylglycerol, and plasminogen activator inhibitor-1 in OLETF rats were significantly higher than those in nondiabetic control [Long-Evans Tokushima Otsuka (LETO)] rats at 29 weeks. Mitochondrial ROS production and UCP2 expression significantly increased in the heart and aorta of OLETF rats compared with those in LETO rats. A fibrogenic growth factor, transforming growth factor (TGF)-1 in the coronary vessels, endothelial nitric-oxide synthase, and aortic nitrotyrosine were increased in OLETF rats at 42 weeks. In contrast, an index of the NO-cGMP pathway, phosphorylated vasodilator-stimulated phosphoprotein, and superoxide dismutase activity in the aorta were significantly diminished. The relationship between UCP2 and ROS production in the cardiovascular function of diabetic rats being fed a calorie-restricted diet is unknown. These abnormalities in OLETF rats were reversed to normal levels by CR. CR significantly improved the NO-cGMP pathway via normalizing ROS generation in OLETF rats. A decrease in UCP2 expression by CR may be a compensatory mechanism to counteract decreased intracellular oxidative stress. The data suggest that CR may prevent cardiovascular tissues from oxidative stress provoked by diabetes mellitus.Calorie restriction (CR) is shown to improve some diabetic abnormalities in this article. Cardiovascular disease is prevalent in patients with diabetes mellitus. High blood glucose levels, altered insulin signaling, reactive oxygen species (ROS), inflammation, and protein kinase C activation may lead to a decrease in nitric oxide (NO) bioavailability (Endemann and Schiffrin, 2004). It is well known that diabetes mellitus provokes an increase in oxidative stress in vascular cells and cardiomyocytes. High glucose concentrations, which contribute to the pathogenesis of atherosclerosis in patients with diabetes, lead to intracellular oxidative stress (Baynes, 1991;Baynes and Thorpe, 1999).The Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of spontaneous type II diabetes, develops hyperglycemic obesity with hyperinsulinemia and insulin resistance after the age of 25 weeks, similar to patients with noninsulindependent diabetes mellitus. In the aorta from OLETF rats,
This study determined the effects of alpha- and gamma-tocopherol supplementation on metabolic control and oxidative stress in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Blood glucose, haemoglobin A1c (HbA1c), urinary protein, plasma free fatty acid, triacylglycerol and plasminogen activator inhibitor-1 (PAI-1) levels in OLETF rats were significantly higher than in non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats. Alpha-tocopherol inhibited the increase in urinary protein, blood glucose, HbA1c and PAI-1 levels, but gamma-tocopherol did not. Plasma and hepatic lipid peroxidation and hepatic steatosis were increased in OLETF rats. alpha-Tocopherol decreased lipid peroxidation. Mitochondrial reactive oxygen species production and uncoupling protein 2 (UCP2) expression were significantly increased in the heart and aorta of OLETF rats compared with LETO rats. Endothelial NO synthase and aortic nitrotyrosine were increased in OLETF rats. In contrast, the expression of phosphorylated vasodilator-stimulated phosphoprotein and glucose transporter 4 in the aorta was significantly decreased in OLETF rats. These abnormalities were reversed by alpha-tocopherol. These findings suggest that alpha-tocopherol may prevent cardiovascular tissues from oxidative stress and insulin signalling disorder resulting from diabetes mellitus.
OBJECTIVE: This open-label, randomized controlled trial investigated the effects of cilnidipine, an L/N-type calcium channel blocker (CCB), in patients with chronic kidney disease (CKD). METHODS: Sixty patients with CKD and well-controlled hypertension being treated with a reninangiotensin system (RAS) inhibitor and an L-type CCB (L-CCB) were randomly assigned either to switch from the L-CCB to cilnidipine after a 4-week observation period or to continue with L-CCB treatment. Blood pressure, heart rate and renal function were monitored for 12 months. Data were available for analysis from 50 patients: 24 from the cilnidipine group and 26 from the L-CCB group. RESULTS: Blood pressure was well controlled in both groups. After 12 months, proteinuria and heart rate were significantly decreased in the cilnidipine group, but proteinuria increased and heart rate remained unchanged in the L-CCB group. There was a significant positive correlation between the percentage changes in proteinuria and heart rate. CONCLUSIONS: Cilnidipine has antihypertensive effects equivalent to those of L-CCBs. In patients with CKD, proteinuria can be decreased by switching from an L-CCB to cilnidipine, thereby improving renal function.
Di(2-ethylhexyl) phthalate is an excellent plasticizer for polyvinyl chloride but a known endocrine disrupting chemical. To investigate whether tubing containing no diethylhexyl phthalate reduces the overall extraction of this plasticizer during cardiopulmonary bypass, 16 patients undergoing coronary artery bypass grafting were randomly divided into 2 groups of 8 each. Group A had tubing containing diethylhexyl phthalate in the circuit, and group B had no diethylhexyl phthalate in the tubing. The plasma diethylhexyl phthalate level at the end of cardiopulmonary bypass was significantly increased compared to before anesthesia in both groups (group A: 103 +/- 60 to 2,094 +/- 1,046 ng x mL(-1); group B: 135 +/- 60 to 472 +/- 141 ng x mL(-1)), and it was significantly higher in group A than group B. This study demonstrates that using tubing free from diethylhexyl phthalate significantly reduces the release of this agent during cardiopulmonary bypass, which may minimize exposure to diethylhexyl phthalate.
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