Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes.

Atherosclerosis is a multifactorial disease for which the molecular etiology of many of the risk factors is still unknown. As no single genetic marker or test accurately predicts cardiovascular death, phenotyping for markers of inflammation may identify the individuals at risk for vascular diseases. Reactive oxygen species (ROS) are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis, starting from the initiation of fatty streak development through lesion progression to ultimate plaque rupture. Various animal models of atherosclerosis support the notion that ROS released from NAD(P)H oxidases, xanthine oxidase, lipoxygenases, and enhanced ROS production from dysfunctional mitochondrial respiratory chain indeed have a causatory role in atherosclerosis and other vascular diseases. Human investigations also support the oxidative stress hypothesis of atherogenesis. This is further supported by the observed impairment of vascular function and enhanced atherogenesis in animal models that have deficiencies in antioxidant enzymes. The importance of oxidative stress in atherosclerosis is further emphasized because of its role as a unifying mechanism across many vascular diseases. The main contraindicator for the role oxidative stress plays in atherosclerosis is the lack of effectiveness of antioxidants in reducing primary endpoints of cardiovascular death and morbidity. However, this lack of effectiveness by itself does not negate the existence or causatory role of oxidative stress in vascular disease. Lack of proven markers of oxidative stress, which could help to identify a subset of population that can benefit from antioxidant supplementation, and the complexity and subcellular localization of redox reactions, are among the factors responsible for the mixed outcomes in the use of antioxidants for the prevention of cardiovascular diseases. To better understand the role of oxidative stress in vascular diseases, future studies should be aimed at using advances in mouse and human genetics to define oxidative stress phenotypes and link phenotype with genotype.

Comparative evaluation of different rat models with co-existing diabetes-mellitus and hypertension.

We have evaluated the suitability of different rat models for the study of effects of antihypertensives on cardiovascular and metabolic complications of diabetes mellitus and hypertension. IDDM was induced in Wistar and spontaneously hypertensive (SH) rats by single tail vein injection of STZ (45 mg/kg, i.v.). Neonatal STZ-diabetes (nSTZ) was induced by administering STZ, 70 mg/kg (i.p.) to 5 day old Wistar rat pups. DOCA-hypertension was induced in Wistar and STZ-diabetic rats using deoxycorticosterone acetate (DOCA, 5 mg/kg, s.c.) and NaCl (2%) in drinking water. Intravenous injection of STZ produced cardinal signs of diabetes mellitus including hyperglycemia, loss of body weight, polyphagia and polydipsia. STZ-diabetic rats also showed hyperlipidemia and hypoinsulinemia. STZ-treated rats developed hypertension and bradycardia. nSTZ rats were found to have mild hyperglycemia and were hypertensive and hyperinsulinemic. The OGTT and ITT revealed that nSTZ rats are insulin resistant. SH rats were also found to be hyperinsulinemic and hypertensive. Although, these rats were found to be insulin resistant, they did not demonstrate hyperglycemia. DOCA-treated STZ-diabetic rats were found to have milder hyperglycemia when compared to STZ-diabetic rats not treated with DOCA. Although, DOCA treatment was not found to alter serum levels of glucose and insulin, results of OGTT revealed enhanced glucose disposal in DOCA-treated Wistar rats, suggesting that DOCA probably produces some effect on glucose homeostasis in rats. The present data also suggest that STZ-diabetic rat may be considered a suitable model for IDDM. On the other hand, nSTZ and SH rats were hyperinsulinemic and insulin resistant and may be used as models to study insulin sensitivity. DOCA-hypertensive rat may not be a suitable model for studying the effects of various drug interventions on glucose homeostasis and insulin sensitivity as DOCA itself appears to influence these factors.

Effects of chronic treatment with amlodipine in streptozotocin-diabetic and spontaneously hypertensive rats.

Calcium antagonists have been reported to alter insulin secretion and insulin sensitivity. However, there still exists a controversy over the benefits of calcium antagonists in the conditions when diabetes mellitus and hypertension coexist. In the present study the effects of six-week chronic amlodipine treatment (5 mg kg-1 p.o.) on insulin sensitivity and serum lipid levels in streptozotocin (STZ)-diabetic and spontaneously hypertensive (SH) rats were investigated. Intravenous injection of STZ produced glucosuria (> 2%). hyperglycaemia, hypoinsulinemia, polydipsia, polyphagia, loss of body weight, hypercholesterolemia, hypertriglyceridaemia, hypertension and bradycardia. SH rats were found to have significantly higher insulin levels compared to their Wistar controls. Treatment of rats with amlodipine in diabetic and diabetic-hypertensive animals significantly prevented STZ-induced loss of body weight, hypertension and bradycardia. It also significantly prevented STZ-induced hyperglycaemia in both STZ-diabetic Wistar and SH rats. The insulin levels were decreased in the non-diabetic treated Wistar rats but were unaltered in the non-diabetic SH and the diabetic Wistar and SH rats. There was a significant reduction in cholesterol levels in diabetic Wistar and SH rats. In conclusion the present study revealed beneficial effects of amlodipine treatment in hyperinsulinemic, diabetic and/or hypertensive rats.

Effects of chronic ramipril treatment in streptozotocin-induced diabetic rats.

The present investigation was undertaken to study the effects of chronic oral ramipril (1 mg/kg) treatment in streptozotocin (STZ) induced diabetic rats. Single tail vein injection of STZ (45 mg/kg, i.v.) produced a diabetic state exhibiting all the cardinal symptoms such as loss of body weight, polydipsia, polyuria, glucosuria, polyphagia, hypoinsulinaemia and hyperglycaemia. The diabetic state was also found to be associated with bradycardia, hypothyroidism, cardiac depression and cardiomyopathy. Ramipril treatment prevented STZ-induced hypertension, bradycardia, hypothyroidism, hyperchosesterolaemia and partially the cardiomayopathy. Ramipril treatment could not, however prevent STZ-induced loss of body weight, polyuria, polydipsia, polyphagia, hyperglycaemia, hypoinsulinaemia, hypertriglyceridaemia and cardiac depression. Our data suggests that ramipril has a few beneficial effects in the STZ-treated diabetic rats.

Effect of chronic treatment with spirapril on biochemical parameters in streptozotocin-diabetic and spontaneously hypertensive rats.

Present investigation was undertaken to study the effects of 6 week treatment with spirapril (2 mg/kg po) on insulin sensitivity, and serum lipid levels in streptozotocin (STZ)-diabetic and spontaneously hypertensive (SH) rats. Treatment of rats with spirapril in diabetic and diabetic with hypertensive animals significantly prevented STZ-induced loss of body weight, hypertension, and bradycardia. It also partially but significantly prevented STZ-induced hyperglycaemia in both diabetic Wistar and SH animals. Insulin level was not altered by spirapril treatment. There was significant reduction in cholesterol levels in the diabetic rats. In conclusion, the present investigation presents a number of beneficial effects of spirapril treatment in diabetic and/or hypertensive rats. Spirapril may be considered as one of the drugs of choice in treatment of hypertension when associated with diabetes