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Experimental and clinical data suggest that primary aldosteronism (PA) may be associated with cardiovascular hypertrophy and fibrosis, in part independent of the BP level. Whether PA may also result in specific deleterious effects on the kidneys was less studied. In 25 patients with tumoral PA, renal studies (urinary excretion of proteins, GFR, and effective renal plasma flow [ERPF], as clearances of technetium-labeled diethylene triaminopentaacetic acid and 131 I-ortho iodohippurate, respectively) were performed both before and 6 mo after surgical cure. A control group consisting of patients with essential hypertension (EH) was studied before and after 6 mo of antihypertensive therapy. At baseline, PA and EH patients were similar with respect to demographic data, duration and level of hypertension, and GFR and ERPF. Urinary excretion of albumin and ␤2 microglobulin were higher in PA than EH (88 ؎ 26 versus 39 ؎ 12 and 0.91 ؎ 0.23 versus 0.26 ؎ 0.19 mg/24 h, respectively; both P < 0.05). Adrenalectomy was followed by a decrease in arterial BP (by 28 ؎ 3/13 ؎ 2 mmHg), urinary excretion of albumin and ␤2 microglobulin (by 48 ؎ 19 and 0.53 ؎ 0.21 mg/24 h, respectively), and GFR and ERPF (by 15 ؎ 3 and 54 ؎ 15 ml/min per 1.73 m 2 , respectively). In EH, a similar decrease in pressure was associated with a decrease in albuminuria but no change in GFR or ERPF. In 17 of the 25 PA patients who received a 6-mo treatment of spironolactone, both GFR and ERPF decreased in parallel with BP, similar to what was observed after surgery. These data suggest that PA was associated with relative hyperfiltration, unmasked after suppression of aldosterone excess.J P rimary aldosteronism (PA) is a possibly common form of endocrine hypertension in which aldosterone production is inappropriate and at least partially autonomous with regard to physiologic control by angiotensin. In recent years, the widespread use of the plasma aldosterone/ renin ratio as a screening test for PA has led to a marked increase in the proportion of hypertensive patients identified as such (1). Whether the diagnostic workup of aldosterone-producing adenomas is cost-effective regarding the potential for curability or effective protection of target organs by specific treatment remains controversial (2). Several experimental and, to a lesser extent, clinical studies suggest that long-term exposure to increased aldosterone levels may result in renal as well as cardiac and vascular toxicity that is in part independent of the BP level (3,4). Target organ damage, as assessed by the measurement of left ventricular mass or urinary excretion of albumin, may be inappropriately high with respect to the BP level in patients with PA (5,6). However, the relationship between albuminuria and renal function parameters is not clear. Specifically, it is not known whether PA-associated albuminuria may relate to a state of hyperfiltration suggested in a study in which GFR was assessed by the measurement of creatinine clearance (7). For investigating the effect of aldosterone excess...

The existence of a direct relationship between body mass and arterial pressure is well recognized; however, the effect of obesity on known target organs of hypertension is not clearly understood. We undertook the present studies to assess the influence of obesity on renal function and urinary albumin excretion in 40 normotensive subjects and 80 nevertreated hypertensive patients matched for age, sex, arterial pressure level, and known duration of hypertension in whom an oral glucose tolerance test was within normal limits. Glomerular filtration rate and effective renal plasma flow (expressed as absolute values or values normalized for height) were increased in overweight compared with lean subjects whether normotensive or hypertensive. Glomerular filtration rate was positively correlated with protein intake (as assessed from urinary excretion of urea) and fasting serum insulin level. Urinary excretion of albumin but not IgG and beta 2 microglobulin was higher in hypertensive patients compared with normotensive subjects. The overweight condition clearly enhanced the influence of arterial pressure on albuminuria; in fact, a steeper regression line between albumin excretion rate and arterial pressure was found in overweight compared with lean subjects. These results indicate that the overweight condition is associated with renal hyperfiltration and hyperperfusion, irrespective of the presence of hypertension, and that obesity magnifies the effect of hypertension on albuminuria, thus raising the possibility of an increased susceptibility of obese hypertensive patients to the development of renal damage.

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events.

In addition to its widely contested influence on arterial pressure, dietary sodium may exert some nonpressure-related effects on left ventricular mass in humans. In the present study, we hypothesized that sodium intake (estimated by two consecutive measurements of 24-h urinary sodium excretion) may amplify the effect of arterial pressure on target organ damage (ie, left ventricular mass and microalbuminuria) in a large group of normotensive subjects and patients with never-treated uncomplicated essential hypertension. Left ventricular mass (M-mode echocardiography) and urinary albumin excretion were assessed in 839 subjects (471 men and 368 women) aged 15 to 70 years, with elevated (60%) or normal arterial pressure. In the entire population, multivariate analysis indicated that the relationship between urinary sodium excretion and left ventricular mass index (beta = 0.02, P < .01) as well as urinary albumin excretion (beta = 0.001, P < .0001) was independent from sex, age, body mass index, and systolic arterial pressure. When subjects were divided into quintiles according to urinary sodium excretion, left ventricular mass index and urinary albumin excretion increased significantly from the lowest to the highest quintile in both genders, despite similar values of systolic arterial pressure. The slope of the regression line linking systolic arterial pressure to left ventricular mass index (in men) and urinary albumin excretion (in the entire population) obtained within each quintile of urinary sodium excretion, progressively and linearly increased from the lowest to the highest quintile. These results suggest that sodium intake may amplify the effect of arterial pressure on both the left ventricle and the kidney, and thus suggest that dietary sodium may be an independent factor of cardiovascular risk.

Abstract-The influence of the HMG-CoA reductase inhibitor simvastatin was assessed on the cardiovascular alterations and production of free radicals associated with chronic angiotensin II (Ang II) infusion. Simvastatin (60 mg/kg per day PO) or placebo were given concomitantly for 10 days in Sprague-Dawley rats infused with Ang II (200 ng/kg per minute SC, osmotic pump). In addition, simvastatin or placebo was also given in vehicle-infused rats. Tail-cuff pressure and albuminuria were measured before and at the end of the treatment period. Cardiac weight, carotid structure, production of reactive oxygen species (ROS, by chemiluminescence) by polymorphonuclear leukocytes and aortic wall as well as protein and lipid oxidation products were determined at the end of the study. Ang II increased tail-cuff pressure by 56Ϯ12 mm Hg and simvastatin blunted the development of hypertension by Ϸ70% (19Ϯ5 mm Hg). Increases in heart weight index and carotid cross-sectional area induced by Ang II were obliterated by simvastatin (3.18Ϯ0.09 versus 3.46Ϯ0.11 mg/g body wt and 0.125Ϯ0.010 versus 0.177Ϯ0.010 mm 2 , respectively). The Ang II-induced increases in leukocyte and aortic production of ROS as well as protein and lipid oxidation products were prevented by simvastatin. No effect of simvastatin was detected in non-Ang II-infused rats. These results indicate that simvastatin prevented the development of hypertension and cardiovascular hypertrophy together with inhibition of the induced angiotensin II production of ROS. Therefore, inhibition of HMG CoA reductase by statins may have a beneficial effect on cardiovascular alterations through its antioxidant action in experimental Ang II-dependent hypertension. A ngiotensin II (Ang II) exerts multiple effects on the cardiovascular system including hypertension and cardiovascular hypertrophy, and free radical production has been proposed as a mechanism participating in Ang II-induced cardiovascular alterations. 1 Through stimulation of its type 1 receptor, Ang II was shown to be associated with an overexpression of cytosolic proteins involved in the activation of the NAD(P)H oxidase of vascular endothelial cells, smooth muscle cells, and leukocytes. 2,3 In these cells, Ang II favors the production of reactive oxygen species (ROS) such as superoxide anions, hydrogen peroxide, and hydroxyl radicals. 2 Together with leukocyte adhesion and proliferation and migration of various cell types, these events may lead to phenotype transformation of the arterial wall and vascular hypertrophy.Experimental evidence and clinical studies strongly suggest that 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase inhibitors (statins) might have antiatherosclerotic effects independent of low-density lipoprotein (LDL) cholesterol reduction. Among the pleiotropic effects of statins are inhibition of smooth muscle cell proliferation (except for pravastatin), 4 reduction of matrix metalloproteinase expression, 5 and stimulation of the antithrombotic system. 6,7 In addition, it has been shown that an inhibitor...

OBJECTIVE -One of the earliest signs of vascular change is endothelial dysfunction, which is also known to provoke albuminuria and to predict cardiovascular prognosis. The aim of this study was to analyze the effects of renin-angiotensin system (RAS) blockade on renal endothelial function.RESEARCH DESIGN AND METHODS -In a multicenter, prospective, double-blind, forced-titration, randomized study, 96 patients with type 2 diabetes, hypertension, glomerular filtration rate Ͼ80 ml/min, and normo-or microalbuminuria were treated once daily with 40/80 mg telmisartan or 5/10 mg ramipril for 9 weeks. RESULTS -The mean, reflecting the magnitude of nitric oxide (NO) activity, increased with telmisartan from 71.9 Ϯ 9.0 ml/min before therapy to 105.2 Ϯ 9.7 ml/min at the end of treatment (P Ͻ 0.001). With ramipril, RPF response to L-NMMA increased from 60.1 Ϯ 12.2 to 87.8 Ϯ 9.2 ml/min (P ϭ 0.018). The adjusted difference between treatments was Ϫ17.1 Ϯ 13.7 ml/min (P ϭ 0.214). In accordance, telmisartan increased RPF at rest (i.e., without L-NMMA) from 652.0 Ϯ 27.0 to 696.1 Ϯ 31.0 ml/min (P ϭ 0.047), whereas ramipril produced no significant changes in RPF. The more the basal NO activity improved, the greater was the vasodilatory effect on renal vasculature (r ϭ 0.47, P Ͻ 0.001).CONCLUSIONS -In patients with type 2 diabetes, telmisartan and ramipril both increased NO activity of the renal endothelium significantly, which in turn may support the preservation of cardiovascular and renal function. Diabetes Care 30:1351-1356, 2007T he close link between cardiovascular and renal changes due to cardiovascular risk factors, such as arterial hypertension and diabetes, has stimulated increasing interest (1-3). Albuminuria and decreased renal function, which are both primarily known to predict renal outcome, have now been identified as excellent predictors of cardiovascular morbidity and mortality (2-4). Most surprisingly, their predictive power surpasses that of classic risk markers of cardiovascular and atherosclerotic disease (5). Albuminuria is related to intrarenal hydraulic pressure, podocyte function, electric charge, and increased permeability, provoked by endothelial dysfunction (6). Prospective studies have demonstrated the predictive value of endothelial dysfunction for future cardiovascular morbid events when assessed in the peripheral and coronary circulation (7-9) and most likely, although not yet proven, in the renal circulation.The endothelium is a major regulator of vascular homeostasis, with functional integrity being essential for the maintenance of blood flow and antithrombotic activity (10). Nitric oxide (NO), formed from L-arginine in the presence of NO synthase, is released by the vascular endothelial cells and brings about relaxation of vascular tissue and inhibition of platelet aggregation and adhesion (11). Endothelial dysfunction occurs as a result of impairment of NO synthesis or increased NO degradation and has been detected in patients with hypertension, peripheral arterial occlusive disease, and chronic re...