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Renovascular hypertension (RVH) caused by atherosclerotic renal artery stenosis (ARAS) is one of the most common forms of secondary hypertension. The prognosis for patients with RVH is much worse compared to patients with primary hypertension, and caused by a high cardiovascular morbidity. The aim of this thesis was to increase our knowledge about the pathophysiology of RVH and to identify novel treatment targets that could reduce cardiovascular risk in these patients. We investigated: 1) whether systemic inflammation and endothelin-1 (ET-1) are increased in patients with RVH and evaluated how treatment with percutaneous transluminal renal angioplasty (PTRA) affected these variables; 2) lipoprotein abnormalities in patients with atherosclerotic renovascular disease (ARVD) and analyzed whether angiotensin II (Ang II) receptor antagonism with candesartan influenced lipoprotein levels; 3) whether plasma levels of brain natriuretic peptides (BNP) are increased in patients with ARAS and may predict favorable outcome of PTRA; and 4) the long-term effects of candesartan on kidney function, inflammatory biomarkers and ET-1 in patients with ARVD and residual hypertension after PTRA. In patients with significant renal artery stenosis (RAS) we found increased plasma levels of inflammatory biomarkers and ET-1 compared to healthy subjects. Intervention with PTRA triggered a rapid, transient increase in hs-CRP and IL-6. However, one month after PTRA, both IL-6 and ET-1 had decreased compared to before intervention. Patients with ARVD had elevated levels of atherogenic, triglyceride-rich, ApoC-III-containing lipoproteins in spite of ongoing treatment with statins. Treatment with candesartan did not correct these abnormalities. Patients with ARAS had increased plasma levels of BNP compared to healthy controls, but BNP concentrations were not affected by PTRA. Plasma levels of BNP could not be used to predict the outcome of PTRA on blood pressure. Candesartan did not have any significant effects on kidney function, inflammatory biomarkers or ET-1 in patients with ARVD during 35 months of follow up. In conclusion, patients with ARAS had increased levels of inflammatory biomarkers, ET-1, and ApoC-III-containing lipoproteins that may contribute to progressive atherosclerosis and accelerated cardiovascular disease. Intervention with PTRA reduced plasma levels of IL-6 and ET-1 indicating beneficial effects on inflammation and the endothelin system. Plasma concentrations of BNP could not be used to identify patients with a favorable outcome to PTRA.

A choice of many antihypertensive strategies is not offered for the treatment of the hypertensive patient with renal insufficiency. Angiotensin-converting enzyme (ACE) inhibitors appear to be the drugs of choice since they not only lower blood pressure but also reduce some important risk factors that may cause progressive loss of renal function, such as intraglomerular hypertension, angiotensin II (ANG II)-induced glomerular growth, proteinuria and hypertension, angiotensin II (ANG II)-induced glomerular growth, proteinuria and hyperlipidemia. Indeed, several clinical studies now show that ACE inhibitors offer renal protection beyond the lowering of systemic blood pressure. The new class of Ang II receptor antagonists and its first representative losartan has not yet been tested antagonists and its first representative losartan has not yet been tested clinically for its renal protective efficacy. The first signs, however, look promising, since losartan appears to induce changes in several identified risk factors to the same extent as ACE inhibitors, such as renal vasodilation, and a fall in proteinuria and serum lipids. The challenge will be to discover the differences between ACE inhibitors and Ang II receptor antagonists and to use them to the future advantage of the renal patient.

A choice of many antihypertensive strategies is not offered for the treatment of the hypertensive patient with renal insufficiency. Angiotensin-converting enzyme (ACE) inhibitors appear to be the drugs of choice since they not only lower blood pressure but also reduce some important risk factors that may cause progressive loss of renal function, such as intraglomerular hypertension, angiotensin II (ANG II)-induced glomerular growth, proteinuria and hypertension, angiotensin II (ANG II)-induced glomerular growth, proteinuria and hyperlipidemia. Indeed, several clinical studies now show that ACE inhibitors offer renal protection beyond the lowering of systemic blood pressure. The new class of Ang II receptor antagonists and its first representative losartan has not yet been tested antagonists and its first representative losartan has not yet been tested clinically for its renal protective efficacy. The first signs, however, look promising, since losartan appears to induce changes in several identified risk factors to the same extent as ACE inhibitors, such as renal vasodilation, and a fall in proteinuria and serum lipids. The challenge will be to discover the differences between ACE inhibitors and Ang II receptor antagonists and to use them to the future advantage of the renal patient.

Introduction Circulating endothelial progenitor cells (EPCs) provide an endogenous repair mechanism of the dysfunctional endothelium and therefore can play a crucial role in the pathophysiology of coronary artery disease (CAD). Angiotensin II receptor antagonism has been shown to be able to increase EPCs in hypertension but its effect in patients with CAD is unknown. Aim of this study was to evaluate whether telmisartan, an angiotensin II receptor antagonist, can modify the number of subpopulations of EPCs and may in turn affect the endothelial function of normotensive patients with CAD. Methods In a prospective double-blind parallel group study, 40 normotensive patients with CAD were randomly treated with telmisartan (80mg) or placebo for 4 weeks at time of coronary angiography. Measurements of EPCs and assessment of flow-mediated dilatation (FMD) of the brachial artery was performed before and after therapy. Results Absolute number of EPCs was similar at baseline in the telmisartan and placebo groups. After 4 weeks treatment, CD34+/KDR+/CD45− cells increased significantly in the telmisartan group (from 0.010±0.003 to 0.014±0.004%, P =0.0001) but not in the placebo group (from 0.009±0.004 to 0.009±0.005%, NS). Similarly, CD133+/KDR+/CD45− cells raised significantly with telmisartan (from 0.003±0.002 to 0.006±0.002%, P =0.0001) but not with placebo (from 0.004±0.003 to 0.003±0.002%, NS). Also, CD14+/CD45+ cells increased significantly with telmisartan (from 0.005±0.002 to 0.008±0.002%, P =0.0001) and were unchanged with placebo (0.006±0.002 vs. 0.005±0.003%, NS). FMD improved significantly in patients who received telmisartan (10.4±3.9%, P =0.0015 vs. baseline) but did not change in the placebo group (5.9±2.8%; P =0.32 vs. baseline; telmisartan vs. placebo, P =0.002). A significant positive correlation was found in the telmisartan group between the improvement in FMD and the increase in CD34+/KDR+/CD45− cells and CD133+/KDR+/CD45− cells ( r =0.55, P r =0.49, P Conclusion Angiotensin II receptor antagonism with telmisartan increases the number of regenerative EPCs and improves endothelial function in normotensive patients with CAD. These novel effects are interrelated and can explain, at least in part, why telmisartan has beneficial cardiovascular effects independent of its blood pressure lowering action.

Renoprotective effects of losartan in diabetic nephropathy: Interaction with ACE insertion/deletion genotype?BackgroundThe beneficial short- and long-term renoprotective effects of angiotensin I-converting enzyme (ACE) inhibition are lower in albuminuric diabetic patients homozygous for the deletion compared to the insertion polymorphism of the ACE gene. In an attempt to overcome this interaction, we evaluated the short-term renoprotective effect in diabetic nephropathy of the angiotensin II receptor antagonist losartan in patients homozygous for the insertion or the deletion allele.MethodsFifty-four hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion (I; N = 26) or the deletion (D; N = 28) allele of the ACE/ID polymorphism were included. After four weeks of washout, the patients received losartan 50 mg daily followed by 100 mg in two treatment periods each lasting two months. Patients and investigators were blinded to ACE genotypes. At baseline and in the end of the treatment periods, 24-hour blood pressure, albuminuria and glomerular filtration rate values were determined.ResultsAt baseline, blood pressure, albuminuria and glomerular filtration rate (GFR) values were similar in the two genotype groups [II vs. DD, 1134 (238 to 5302) vs. 1451 (227 to 8129) mg/24 h, median (range); 156/82 (17/9) vs. 153/80 (17/11) mm Hg, mean (SD); and 86 (22) vs. 88 (24) mL/min/1.73 m2, respectively]. Both doses of losartan significantly lowered blood pressure, albuminuria, and GFR (P < 0.05 vs. baseline). Losartan 100 mg was more effective than 50 mg in reducing albuminuria, 51% (95% CI; 40 to 61) versus 33% (23 to 42), respectively (P < 0.01). No differences in the impact of losartan between the II and DD groups were observed: Losartan 100 mg lowered systolic/diastolic blood pressure by 12/6 and 10/4 mm Hg, whereas albuminuria decreased by 55% (35 to 68) and 46% (28 to 61), in the II and DD groups, respectively (P = NS).ConclusionOur data suggest that losartan offers similar short-term renoprotective and blood pressure lowering effects in albuminuric hypertensive type 1 diabetic patients with the ACE II and DD genotypes. However, the long-term renoprotective effects remain to be evaluated.

A choice of many antihypertensive strategies is not offered for the treatment of the hypertensive patient with renal insufficiency. Angiotensin-converting enzyme (ACE) inhibitors appear to be the drugs of choice since they not only lower blood pressure but also reduce some important risk factors that may cause progressive loss of renal function, such as intraglomerular hypertension, angiotensin II (ANG II)-induced glomerular growth, proteinuria and hypertension, angiotensin II (ANG II)-induced glomerular growth, proteinuria and hyperlipidemia. Indeed, several clinical studies now show that ACE inhibitors offer renal protection beyond the lowering of systemic blood pressure. The new class of Ang II receptor antagonists and its first representative losartan has not yet been tested antagonists and its first representative losartan has not yet been tested clinically for its renal protective efficacy. The first signs, however, look promising, since losartan appears to induce changes in several identified risk factors to the same extent as ACE inhibitors, such as renal vasodilation, and a fall in proteinuria and serum lipids. The challenge will be to discover the differences between ACE inhibitors and Ang II receptor antagonists and to use them to the future advantage of the renal patient.

Protein trafficking across the glomerular capillary has a pathogenic role in subsequent renal damage. Despite evidence that angiotensin-converting enzyme (ACE) inhibitors improve glomerular size-selectivity, whether this effect is solely due to ANG II blocking or if other mediators also play a contributory role is not clear yet. We studied 20 proteinuric patients with IgA nephropathy, who received either enalapril (20 mg/day) or the ANG II receptor blocker irbesartan (100 mg/day) for 28 days in a randomized double-blind study. Measurements of blood pressure, renal hemodynamics, and fractional clearance of neutral dextran of graded sizes were performed before and after 28 days of treatment. Both enalapril and irbesartan significantly reduced blood pressure over baseline. This reduction reached the maximum effect 4–6 h after drug administration but did not last for the entire 24-h period. Despite transient antihypertensive effect, proteinuria was effectively reduced by both treatments to comparable extents. Neither enalapril nor irbesartan modified the sieving coefficients of small dextran molecules, but both effectively reduced transglomerular passage of large test macromolecules. Theoretical analysis of sieving coefficients showed that neither drug affected significantly the mean pore radius or the spread of the pore-size distribution, but both importantly and comparably reduced the importance of a nonselective shunt pathway. These data suggest that antagonism of ANG II is the key mechanism by which ACE inhibitors exert their beneficial effect on glomerular size-selective function and consequently on glomerular filtration and urinary output of plasma proteins.