Arnfried U. Klingbeil

Additional Antiproteinuric Effect of Ultrahigh Dose Candesartan: A Double-Blind, Randomized, Prospective Study

Proteinuria indicates future renal and cardiovascular morbidity, and, conversely, its reduction is associated with improved outcome. In a randomized, double-blind trial with parallel group design, the antiproteinuric effect of candesartan at high doses was analyzed. Patients with normal or mildly impaired renal function, protein excretion rate of 1 to 10 g/d, and treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for 3 mo were eligible. After a 4-wk treatment with 16 mg/d candesartan, patients (n = 32) were allocated to double-blind therapy with either 32 or 64 mg/d candesartan for 12 wk (including 4 wk of uptitration), followed again by 4 wk of candesartan 16 mg/d. Proteinuria at study entry was similar in both groups (geometric mean [95% confidence interval (CI)]; 32 mg/d candesartan 2.14 g/d [95% CI, 1.45 to 3.17]; 64 mg/d candesartan 2.54 g/d [95% CI, 1.91 to 3.40]; NS). After the double-blind treatment phase, proteinuria was reduced to 1.42 g/d (0.85 to 2.37) in the 64-mg/d group (P = 0.017), without any change in the 32-mg/d group (2.02 g/d [95% CI, 1.26 to 3.26]). The change in proteinuria differed between the two groups in absolute (P = 0.025) and relative terms (-29 +/- 50 versus -0 +/- 26%; P = 0.012). After downtitration to 16 mg/d candesartan, proteinuria increased again to 2.38 g/d (1.57 to 3.62) in the 64-mg/d group (P = 0.001) but remained unchanged in the 32-mg/d group (2.04 g/d [95% CI, 1.17 to 3.57]; NS). No change in BP was noticed in response to the different doses of candesartan. These data indicate an additive antiproteinuric effect of ultrahigh dose of the angiotensin receptor blocker candesartan compared with standard dose.

Rapid Nongenomic Effects of Aldosterone on Human Forearm Vasculature

Abstract—The impact of aldosterone in cardiovascular disease and hypertension has recently gained new interest. Aldosterone is now suggested to be a more common cause of hypertension than previously believed and has been linked to myocardial fibrosis, independent of its hypertensive effects. Finally, rapid nongenomic aldosterone effects have been proposed to be important in hypertension, in addition to its genomic effects. Forty-eight healthy male volunteers were examined in a randomized, placebo-controlled, double-blind crossover trial to elucidate the rapid nongenomic, vascular effects of aldosterone in humans. Forearm blood flow was measured by venous occlusion plethysmography. First, aldosterone (500 ng/min) and placebo were infused into the brachial artery for 8 minutes. The volunteers then received ascending doses of acetylcholine, NG-monomethyl-l-arginine (L-NMMA), sodium nitroprusside, or phenylephrine. Aldosterone increased forearm blood flow (P <0.001, ANOVA). The maximum effect was an increase in forearm blood flow with aldosterone of 7.9±2.6% compared with 0.1±1.9% with placebo treatment after 8 minutes. With aldosterone, L-NMMA induced a greater vasoconstriction (P <0.05, ANOVA), sodium nitroprusside induced an attenuated vasoconstriction (P <0.01, ANOVA), and phenylephrine induced an exaggerated vasoconstriction (P <0.01, ANOVA) within minutes as compared with placebo. These data suggest that aldosterone acts through rapid nongenomic effects at the endothelium by increasing NO release and at the vascular smooth muscle cells by promoting vasoconstriction. This is consistent with in vitro data showing an increase in intracellular calcium in both cell types. Disturbances of these aldosterone effects on both levels might be important in promoting hypertension.

Effect of AT1 receptor blockade on endothelial function in essential hypertension.

BACKGROUND Angiotensin II adversely affects endothelial function and NO availability. We analyzed the effect of AT(1) receptor blockade on endothelium-dependent vasodilation and basal nitric oxide (NO) production and release in hypertensive patients. METHODS AND RESULTS Sixty patients (53 +/- 10 years) with essential hypertension were randomized to 6 weeks of double-blind therapy with either valsartan (80 mg), hydrochlorothiazide (HCTZ) (25 mg), or placebo once daily. Basal NO production and release was assessed by measuring forearm blood flow (FBF) in response to intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA), and endothelium-dependent vasodilation by measuring FBF in response to intra-arterial administration of acetylcholine, respectively. Intra-arterial infusion of noradrenaline and sodium nitroprusside was used to assess endothelium-independent changes in FBF. Blood pressure (BP) similarly decreased with active treatments (P < .001). After valsartan treatment, the decrease of FBF in response to L-NMMA was augmented (4 micromol/min L-NMMA, -1.3 +/- 1.2 after v -0.5 +/- 1.1 mL/min/100 mL before therapy, P < .02; 8 micromol/min L-NMMA: -1.7 +/- 1.3 after v -1.1 +/- 1.2 mL/min 100 mL before therapy, P < .05). No improvement was found after placebo or HCTZ treatment. Changes in L-NMMA-induced decrease of FBF with valsartan treatment were not related to BP changes. Neither drug substantially modified the response of FBF induced by intra-arterial infusion of acetylcholine, noradrenaline, and sodium nitroprusside. CONCLUSIONS The AT(1) receptor blockade with valsartan improved basal NO production and release. The effect seems to be BP independent, as BP reduction with HCTZ failed to increase NO availability.

Normalization of circadian blood pressure profiles after renal transplantation.

Most patients with secondary hypertension due to renal disease or on maintenance hemodialysis have lost the physiologic fall of blood pressure during sleep. To test the notion that kidney transplantation normalizes the blood pressure profile, we monitored ambulatory blood pressure over 24 hr in 45 patients (29 males and 16 females) after successful renal transplantation. The longer the time after renal transplantation, the more marked was the decrease of blood pressure during sleep (r=0.38, P<0.01). This effect of time after renal transplantation on the fall of blood pressure during sleep was independent of the prevailing level of 24-hr ambulatory blood pressure. The prevalence of dippers (defined by a fall in mean blood pressure during sleep of 10% or more of the awake mean) increased from 27% in the early phase (< 7 months) to 73% in the late phase (≥ 1 year) after renal transplantation (P<0.01). Again, this effect was not attributable to the level of 24-hr ambulatory blood pressure and concomitant antihypertensive or immunosuppressive medication. We conclude that renal transplantation leads to a normalization of the circadian blood pressure profile with a marked decrease of blood pressure during sleep. As a consequence, the lower hemodynamic load imposed on the cardiovascular system may in turn lead to a reduction of cardiovascular morbidity and mortality.

Effect of Irbesartan Versus Atenolol on Left Ventricular Mass and Voltage: Results of the CardioVascular Irbesartan Project

Regression of hypertensive left ventricular hypertrophy (LVH) is associated with improved prognosis. The aim of this trial was to compare the effects of irbesartan versus atenolol on LVH in subjects with essential hypertension. Because electrocardiographic and echocardiographic parameters of LVH carry disparate prognostic information, both methods were applied in this trial. In the randomized, double-blind, multicenter trial CardioVascular Irbesartan Project, 240 patients with essential hypertension were treated with irbesartan or atenolol for 18 months. Voltage criteria used for LVH were Sokolow index, Cornell index, Cornell voltage×QRS duration product and Lewis index. In parallel, left ventricular mass (LVM) was determined by 2-dimensional guided M-mode echocardiography. After 6 and 18 months, reductions of LVM and voltage criteria for LVH were only found in subjects treated with irbesartan. However, a reduction of LVM was only detectable in subjects within the highest quartile of baseline LVM but not overall. In contrast, reductions of voltage criteria for LVH were detectable after 6 and 18 months even within commonly used normal limits. In conclusion, treatment of hypertension with irbesartan resulted in a significant reduction in the voltage criteria for LVH, although an effect on LVM was only seen in subjects with high baseline LVM. In contrast, atenolol did not lead to reductions in electrocardiographic or echocardiographic parameters of LVH. Because voltage criteria for LVH have been shown to predict cardiovascular outcome independently from LVM, we suggest that both methods should be used to accurately assess the benefits of antihypertensive treatment.

Natriuresis-pressure relationship in polycystic kidney disease.

We studied, under outpatient conditions, nine patients with autosomal dominant polycystic kidney disease who were hypertensive on their usual diet, and nine normotensive healthy probands. The subjects were examined in random order on the 7th day after equilibration on a low-sodium diet (20 mmol/day) and again on the 7th day after equilibration on the same diet but with added sodium to yield a final intake of 200 mmol/day (or vice versa). Blood pressure was monitored non-invasively for 2 h at 4-min intervals using an automatic system. In healthy probands, mean arterial pressure (MAP) was similar on the low- and the high-sodium diets (92.7 versus 91.9 mmHg). In hypertensive patients, a significant (P less than 0.02) increase in mean MAP (107.2 versus 111.2 mmHg) and in systolic blood pressure (140.6 versus 148.7 mmHg) was observed irrespective of whether the glomerular filtration rate (GFR) was normal or reduced. The natriuresis pressure curve showed an upward shift (resetting) and a positive slope (sodium sensitivity). Patients with a reduced GFR as shown by inulin clearance differed from probands and patients with a normal GFR, by showing greater proportional changes in GFR and body weight. In hypertensive patients, atrial natriuretic factor (ANF) levels were higher at baseline and showed an exaggerated response to sodium loading. Changes in angiotensin II (Ang II) or in Ang II binding sites on platelets were similar in patients and controls and changed appropriately with the sodium intake. These data show a resetting of the natriuresis-blood pressure relationship and an increased blood pressure sensitivity to sodium in hypertensive patients with adult, dominant, polycystic kidney disease.

Plasma endothelin is increased in early essential hypertension

Local vascular generation of endothelin-1 (ET-1) may contribute to elevated peripheral resistance in hypertension. We tested the hypothesis that immunoreactive ET production in the forearm circulation is increased in early essential hypertensive subjects. Ten young, previously untreated male patients with mild essential hypertension and no signs of target organ damage were compared with matched normotensive subjects in an outpatient setting. Arterial and venous samples were obtained from indwelling catheters in the brachial artery and the medial cubital vein, respectively. Samples were collected at baseline and after induction of endothelium-dependent (acetylcholine) vasodilation. Immunoreactive ET (ET) was measured after column extraction by a sensitive radioimmunoassay employing a C-terminal ET-1 antibody with negligible cross-reaction to big-ET. Individual recovery rates were determined for each sample. Basal ET was significantly higher in hypertensive than in normotensive subjects, both in venous and arterial samples (P < .01). This difference was also present after correction for recovery (P < .01). There was no significant difference between venous and arterial ET concentrations. Local vasodilation did not change arterial or venous ET levels. In conclusion, plasma ET is increased in young, untreated, essential hypertensive subjects with no signs of target organ damage. The increased circulating immunoreactive ET may point to a role for the peptide early in the development of high blood pressure.

Altered aldosterone response to salt intake and angiotensin II infusion in young normotensive men with parental history of arterial hypertension

Objective An increased sensitivity to angiotensin II (Ang II) has been observed in patients with established hypertension. In the current study we tested whether young normotensive subjects with positive family history of arterial hypertension exhibit an increased sensitivity to Ang II, thereby potentially contributing to the pathogenesis of essential hypertension in these subjects. Methods and design Normotensive young men (25 ± 2 years) with positive family history (PFH) (n = 28) and negative family history (NFH) (n = 60) of arterial hypertension were investigated to study aldosterone response, and systemic and renal haemodynamic changes (p-aminohippurate- and inulin-clearance) to Ang II infusion (0.5 and 3.0 ng/min per kg). In addition, aldosterone response to salt loading (5 g/day for 1 week) was analysed. Results Ambulatory blood pressure (ABP) (mean: 84 ± 4 versus 83 ± 4 mmHg; NS), body mass index (23.5 ± 2.5 versus 24.1 ± 2.4 kg/m2; NS), and urinary sodium excretion (191 ± 55 versus 170 ± 73 mmol/24 h; NS) did not differ between PFH and NFH at baseline. Changes in BP, urinary sodium and potassium excretion were similar between PFH and NFH in response to salt loading. However, salt loading did not result in an adequate suppression of aldosterone in PFH compared with NFH (8 ± 62 versus −32 ± 39 pg/ml;P < 0.001). Baseline values and changes in mean arterial BP (NFH: +13.4 ± 7.6; PFH: +14.4 ± 5.3 mmHg; NS), renal plasma flow (NFH: – 113 ± 68; PFH: – 122 ± 64 ml/min; NS) and glomerular filtration rate (NFH: +5.0 ± 5.3; PFH: +4.2 ± 8.3 ml/min; NS) in response to Ang II (3.0 ng/min per kg) were similar between the two groups. In contrast, the increases in serum aldosterone (PFH: 63.6 ± 70.1 versus NFH: 37.7 ± 46.8 pg/ml;P < 0.05) and urinary potassium excretion (PFH: 0.05 ± 0.1 versus NFH: −0.01 ± 0.07 mmol/min;P < 0.05) 30 min after stopping Ang II infusion were more pronounced and prolonged in PFH than in NFH. Conclusions Our findings suggest that young normotensive subjects with parental history of arterial hypertension are characterized by an inadequate suppression of aldosterone production in response to salt loading and an exaggerated and prolonged hyper-responsiveness of aldosterone secretion in response to Ang II. This might contribute to the increased risk for the development of essential hypertension in subjects with positive family history of arterial hypertension.

Effect of angiotensin receptor blockade on central haemodynamics in essential hypertension: results of a randomised trial.

Objective. Angiotensin-converting enzyme (ACE) inhibitors have been shown to lower central augmentation index (cAI), an index of arterial wave reflection, more than β-blockers. We tested whether this is also true for long-term treatment with an angiotensin receptor blocker (ARB). Methods. One-hundred and fifty-six subjects with essential hypertension were randomised to treatment with either irbesartan or atenolol. cAI and central blood pressure (BP) were determined by pulse wave analysis from the radial and the carotid artery after six and after 18 months treatment. Results. Peripheral and central systolic and diastolic BP were reduced to a similar extent A in the two groups. cAI was reduced with irbesartan, but increased with atenolol (derived from the carotid artery: -6±10 vs. -4±12% after six months, p<0.001; —4±12 vs. +1±11% after 18 months; p=0.011). Furthermore, central to peripheral pulse pressure (PP) amplification was unaffected by treatment with irbesartan, but decreased with atenolol. Conclusions. Although treatment with irbesartan and atenolol similarly decreased peripheral and central BP, only treatment with irbesartan had beneficial effects on arterial wave reflection and preserved PP amplification. These haemodynamic effects may at least partly explain the reported differential effects of ARB versus β-blocker treatment on cardiovascular mortality in patients with essential hypertension.

Low-density lipoprotein-cholesterol determines vascular responsiveness to angiotensin II in normocholesterolaemic humans.

OBJECTIVE Both LDL-cholesterol and angiotensin II have been shown to increase the risk for and severity of cardiovascular disease. In hypercholesterolaemia, experimental studies have demonstrated an increased angiotensin type 1 (AT1) receptor expression on vascular smooth muscle cells and an increased vascular responsiveness to vasopressors has been documented in humans. We investigated in a normocholesterolaemic young population whether vascular responsiveness to angiotensin II (Ang II) infusion depends on LDL-cholesterol serum levels in the systemic and renal circulation. DESIGN AND METHODS Changes in systolic and diastolic blood pressure (deltaBP) to Ang II infusion (0.5 and 3.0 ng/kg per min) were investigated in 103 normocholesterolaemic (LDL-cholesterol < 160 mg/dl) young white men (26+/-3 years; 24 h BP: 128+/-10/75+/-7 mmHg) without cardiovascular disease. According to their LDL-cholesterol levels, participants were classified into tertiles (lower tertile < 85 mg/dl, middle tertile 85-111 mg/dl, upper tertile > 111 mg/dl). RESULTS Blood pressure (BP) responses to Ang II infusion 3.0 ng/kg per min were enhanced in the group with the highest LDL-cholesterol levels (delta systolic BP: +12.8+/-6.7, +13.2+/-8.6, +17.9+/-9.6, P < 0.02; delta diastolic BP: +11.1+/-5.8, +11.5+/-6.5, +16.5+/-8.3, P < 0.01, for the lower, middle and upper tertiles, respectively). This holds true when baseline BP was taken into account as a confounding covariable (P < 0.015). BP responses to Ang II infusion were related to LDL-cholesterol serum levels (delta systolic BP: r = 0.26, P = 0.01; delta diastolic BP: r = 0.32, P = 0.001). In multiple stepwise regression analysis, LDL-cholesterol emerged as the strongest determinant of vascular responsiveness to Ang II (delta systolic BP: P < 0.01; delta diastolic BP: P < 0.001). CONCLUSION In young male subjects, responsiveness to Ang II is determined by the LDL-cholesterol serum level even in the normal range of LDL-cholesterol, thereby potentially contributing to the cardiovascular risk of LDL-cholesterol even within the so-called normal range.