Patients with chronic kidney disease (CKD) show a high cardiovascular morbidity and mortality. This seems to be consequence of the cardiovascular risk factor clustering in CKD patients. Non traditional risk factors such as oxidative stress and inflammation are also far more prevalent in this population than in normal subjects. Renal disease is associated with a graded increase in oxidative stress markers even in early CKD. This could be consequence of an increase in reactive oxygen species as well as a decrease in antioxidant defence. This oxidative stress can accelerate renal injury progression. Inflammatory markers such as C reactive protein and cytokines increase with renal function deterioration suggesting that CKD is a low-grade inflammatory process. In fact, inflammation facilitates renal function deterioration. Several factors can be involved in triggering the inflammatory process including oxidative stress. Statin administration is accompanied by risk reduction in all major vascular events in patients with CKD that are considered high-risk patients. These beneficial effects seem to be consequence of not only their hypolipidemic effect but especially their pleitropic actions that involve modulation of oxidative stress and inflammation.

The dose-dependent effects of intravenous infusions of nitric oxide (NO) synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.1, 1, 10, and 50 micrograms.kg-1.min-1), were studied in anesthetized rats to determine whether the inhibitory actions of L-NAME are manifested primarily in alterations of renal function or whether they are the consequences of the increase in systemic blood pressure. Mean arterial pressure (MAP) was not altered by the intravenous L-NAME infusions of 0.1 and 1.0 microgram.kg-1.min-1. However, 0.1 microgram.kg-1.min-1 L-NAME induced a 30% decrease in urine flow rate (UV). The administration of 1.0 microgram.kg-1.min-1 L-NAME, in addition to decreasing UV, also decreased urinary sodium excretion (UNaV) and renal plasma flow (RPF). The intravenous L-NAME infusions of 10.0 and 50.0 microgram.kg-1.min-1 intravenous L-NAME infusions of 10.0 and 50.0 microgram.kg-1.min-1 produced significant increases in MAP that reversed the initial fall in UV and UNaV, despite decreasing RPF and glomerular filtration rate (GFR). The administration of L-arginine alone (10 micrograms.kg-1.min-1) did not modify any of the parameters measured, but it effectively prevented all the hemodynamic and renal changes induced by the infusion of 50 micrograms.kg-1.min-1 L-NAME. These results suggest that the decrease in nitric oxide production induced by the intravenous infusion of L-NAME affects renal excretion of sodium and water in the absence of any significant change in blood pressure. At larger doses, L-NAME also produces hypertension that overrides the initial antinatriuretic effect.

Mitochondria are essential for the maintenance of normal physiological function of tissue cells. Mitochondria are subject to dynamic processes in order to establish a control system related to survival or cell death and adaptation to changes in the metabolic environment of cells. Mitochondrial dynamics includes fusion and fission processes, biogenesis, and mitophagy. Modifications of mitochondrial dynamics in organs involved in energy metabolism such as the pancreas, liver, skeletal muscle, and white adipose tissue could be of relevance for the development of insulin resistance, obesity, and type 2 diabetes. Mitochondrial dynamics and the factors involved in its regulation are also critical for neuronal development, survival, and function. Modifications in mitochondrial dynamics in either agouti-related peptide (AgRP) or pro-opiomelanocortin (POMC), circuits which regulates feeding behavior, are related to changes of food intake, energy balance, and obesity development. Activation of the sympathetic nervous system has been considered as a crucial point in the pathogenesis of hypertension among obese individuals and it also plays a key role in cardiac remodeling. Hypertension-related cardiac hypertrophy is associated with changes in metabolic substrate utilization, dysfunction of the electron transport chain, and ATP synthesis. Alterations in both mitochondrial dynamics and ROS production have been associated with endothelial dysfunction, development of hypertension, and cardiac hypertrophy. Finally, it might be postulated that alterations of mitochondrial dynamics in white adipose tissue could contribute to the development and maintenance of hypertension in obesity situations through leptin overproduction. Leptin, together with insulin, will induce activation of sympathetic nervous system with consequences at renal, vascular, and cardiac levels, driving to sodium retention, hypertension, and left ventricular hypertrophy. Moreover, both leptin and insulin will induce mitochondrial alterations into arcuate nucleus leading to signals driving to increased food intake and reduced energy expenditure. This, in turn would perpetuate white adipose tissue excess and its well-known metabolic and cardiovascular consequences.

We investigated the role of angiotensin II in vascular and circulating inflammatory markers in spontaneously hypertensive rats (SHR). IL-1beta, IL-6, and TNF-alpha aortic mRNA expression and plasma levels were measured in adult SHR untreated or treated with the angiotensin II receptor antagonist candesartan (2 mg.kg(-1).day(-1)) or antihypertensive triple therapy (TT; in mg.kg(-1).day(-1): 20 hydralazine + 7 type 1 hydrochlorothiazide + 0.15 reserpine) for 10 wk. Likewise, aortic expression of NF-kappaB p50 subunit precursor p105 and its inhibitor (IkappaB) were measured. Age-matched Wistar-Kyoto rats (WKY) served as normotensive reference. High blood pressure levels were associated with increased (P < 0.05) aortic mRNA expression of IL-1beta, IL-6, and TNF-alpha. Hypertension was also accompanied by increased IL-1beta and IL-6 plasma levels. No differences were observed in circulating TNF-alpha levels between SHR and WKY. SHR presented elevated aortic mRNA expression of the transcription factor NF-kappaB and reduction in its inhibitor, IkappaB. Candesartan decreased (P < 0.05) blood pressure levels, aortic mRNA expression of IL-1beta, IL-6, and TNF-alpha, and (P < 0.05) IL-1beta and IL-6 plasma concentration. However, although arterial pressure decrease was comparable for the treatments, TT only partially reduced the increments in inflammatory markers. In fact, candesartan-treated rats showed significantly lower levels of circulating and vascular inflammatory markers than TT-treated animals. The treatments increased IkappaB mRNA expression similarly. However, only candesartan reduced NF-kappaB mRNA expression. In summary, 1) SHR presented a vascular inflammatory process; 2) angiotensin II, and increased hemodynamic forces associated with hypertension, seems to be involved in stimulation of inflammatory mediators through NF-kappaB system activation; and 3) reduction of inflammatory mediators produced by candesartan in SHR could be partially due to both downregulation of NF-kappaB and upregulation of IkappaB.

Atherosclerosis and its complications represent the major cause of death in developed countries. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase and consequently inhibitors of cholesterol biosynthesis. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. In clinical trials, statins are beneficial in primary and secondary prevention of coronary heart disease. Statins, were initially designed as cholesterol-lowering drugs. However, these drugs, besides their lipid-lowering properties, exert a number of protective effects on the cardiovascular system that emerged over the past years. The benefits observed with statin treatment appear to be greater than that might be expected from reduction in lipid levels alone, suggesting effects beyond cholesterol lowering. These cholesterol-independent effects have been called "pleiotropic". The cholesterol-independent or "pleiotropic" effects of statins involve improvement of endothelial function, stability of atherosclerotic plaques, decrease of oxidative stress and inflammation, and inhibition of thrombogenic response. These pleiotropic effects of statins have been proposed as key properties of these drugs to reduce cardiovascular morbidity and mortality. The present review will emphasize the molecular mechanisms underlying the effects of statins on endothelial function and oxidative stress. In particular, inhibition of small GTP-binding proteins, Rho, Ras and Rac, which are regulated by isoprenoids [farnesyl pyrophosphate and geranylgeranyl pyrophosphate], seems to play an important role in mediating the pleiotropic effects of statins.