Reactive oxygen species (ROS) are important signaling molecules in the vasculature. However, when there is imbalance between their occurrence and antioxidant defense mechanisms, ROS can contribute to the vascular abnormalities that lead to hypertension. Evidence accumulated in the last decade strongly supports the notion that ROS are generated in the vasculature mainly by NAD(P)H oxidase in a mechanism that is angiotensin II-dependent. Activation of this enzyme leads to superoxide production and uncouples endothedial NO synthase (eNOS), which sustains oxidative stress while increasing the levels of tissue-damaging peroxynitrite. The latter can result in vascular dysfunction. NAD(P)H-dependent ROS formation, in particular H(2)O(2), could also contribute to vascular injury by sustaining NAD(P)H oxidase activation, promoting inflammatory gene expression, extracellular matrix reorganization, and growth (hypertrophy/hyperplasia) of vascular smooth muscle cells. The effect of ROS appears to be mediated by redox-sensitive targets such as tyrosine kinases and phosphatases, mitogen-activated protein kinases, transcription factors, matrix metalloproteinases, peroxisome proliferator activated receptor-alpha, poly(ADP-ribose)polymerase-1, Ca(2+) signaling mechanisms and secreted factors such as cyclophilin A and heat shock protein 90-alpha. Redox-sensitive targets appear to play a central role in normal vascular function, but can also lead to remodeling of the vascular wall, increasing vascular reactivity and hypertension. Polymorphisms in the p22phox gene promoter could determine susceptibility to NAD(P)H-mediated oxidative stress in humans and animals with hypertension. Although ROS are strongly implicated in the etiology of hypertension, clinical trials with antioxidants are inconclusive regarding their effectiveness in treating the disease. New drugs with both antihypertensive action and antioxidant properties (Celiprolol, Carvedilol) offer promising results in the management of hypertension.

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The association between nitric oxide synthase (eNOS and iNOS) status, oxidative stress, and cardiac function was evaluated in streptozotocin (STZ)-diabetic rats to understand the etiology of diabetic cardiomyopathy. Cardiac function was determined by echocardiography. eNOS and iNOS status and superoxide production were assessed by immunohistochemistry and chemiluminescence, respectively. In STZ-diabetic rats, stroke volume, cardiac output, and left ventricular ejection fraction were significantly lower than in controls (CT, P < .05), whereas left ventricular end-systolic volume was higher. Cardiac NOS activity increased from 161 +/- 18 cpm/mg tissue in CT rats to 286 +/- 20 cpm/mg tissue (P < .001) in STZ-diabetic rats. Furthermore, superoxide production and cardiac eNOS and iNOS levels were higher in STZ-diabetic rats than in CT rats (P < .05). An increased activation of cardiac eNOS and iNOS is observed concomitantly with decreased cardiac function. Thus, increased oxidative stress in the heart may be implicated in the development of dilated cardiomyopathy in STZ-diabetic rats.

The precise mechanisms involved in the etiology of cardiovascular complications in diabetes are undefined. Recent evidence suggests that the renin-angiotensin system plays a predominant role in the genesis of these complications. The temporal evolution of vascular angiotensin-converting enzyme (ACE) activity was evaluated in streptozotocin-diabetic rats 2 and 4 weeks following the induction of diabetes. Vascular ACE activity was correlated with acetylcholine-induced relaxation, systolic blood pressure, and cardiac output index, establishing a possible link between these variables. Age-matched Sprague-Dawley rats were used as controls. ACE activity in aortic homogenates doubled in rats after 2 weeks of diabetes as compared with controls (0.46 ± 0.06 vs. 0.19 ± 0.02 nmol/mg × min, n = 8, p < 0.05). In contrast, no difference was observed between rats 4 weeks following diabetes onset (0.20 ± 0.05 nmol/mg × min) and controls (n = 8, p > 0.05). Impaired endothelial function was also observed in the aorta of diabetic animals. The maximal aortic relaxation with 10 µmol/l acetylcholine was reduced by 40% in diabetic rats 2 weeks after onset and by 41% after 4 weeks when compared to controls (n = 8, p < 0.05). Two weeks following diabetes induction, the cardiac output index decreased by 16% and after 4 weeks by 30% (n = 4, p < 0.05). Systolic blood pressure increased from 116 ± 12 mm Hg before diabetes to 158 ± 4 mm Hg (p < 0.05) after 2 weeks and to 182 ± 5 mm Hg after 4 weeks (p < 0.05). Together, these results suggest that a local renin-angiotensin system plays an important role in the genesis of vascular dysfunction and cardiac deterioration within the first stages of diabetes. A high vascular ACE activity may promote progressive deterioration of the cardiovascular system in streptozotocin-diabetic rats from the earliest stages by increasing peripheral resistance, blood pressure, preload, afterload, and cardiac work.

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