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 beta-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 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 beta-blocker treatment on cardiovascular mortality in patients with essential hypertension.

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.

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 x 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.

The role of nitric oxide in the regulation of glomerular haemodynamics in humans.

BACKGROUND: According to experimental data, the afferent glomerular arteriole is particularly under control of nitric oxide (NO). By use of pharmacological manoeuvres, we examined whether this finding holds true in the human renal circulation in vivo. METHODS: Seventy-seven volunteers (aged 50+/-9 years) with mild to moderate essential hypertension (n = 57) or arterial normotension (n = 20) were examined. Basal NO activity in the renal circulation was assessed by the change of renal plasma flow (RPF) through systemic infusion of the NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). Hypertensive patients were treated over 8 weeks with either the calcium-channel blocker amlodipine or the AT(1)-receptor blocker valsartan, primarily dilating the afferent and efferent arteriole, respectively. Subsequently, renal haemodynamics and NO activity in the renal circulation were determined again. RESULTS: L-NMMA reduced RPF in normotensive (by 57+/-70 ml/min/1.73 m(2); P<0.01) and hypertensive subjects (by 46+/-56 ml/min/1.73 m(2); P<0.001) with no significant difference between the two groups. The decrease of RPF through L-NMMA was closely related with the glomerular filtration rate (GFR; r = 0.39, P<0.001). Administration of amlodipine increased GFR by 7.1+/-12.1 ml/min/1.73 m(2); (P<0.01) and in parallel reduced the response of RPF to L-NMMA to 19+/-48 ml/min/1.73 m(2); (P<0.05). In contrast, valsartan maintained GFR and left the response of RPF to L-NMMA unchanged. CONCLUSIONS: NO plays an important role in the regulation of human glomerular haemodynamics, probably with a greater contribution to afferent than to efferent arteriolar tone in man.

Direct comparison of the effects of valsartan and amlodipine on renal hemodynamics in human essential hypertension.

BACKGROUND: To elucidate the renoprotective mechanism of AT(1)-receptor blockers, we compared the effects of the AT(1)-receptor blocker valsartan with those of the calcium channel blocker amlodipine on renal hemodynamics and microcirculation. METHODS: A total of 58 patients (50.2 +/- 9.0 years) with mild to moderate essential hypertension were included in a randomized, double-blind study to receive either valsartan (80 to 160 mg) or amlodipine (5 to 10 mg). Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured before and after 8 weeks of treatment. Glomerular hydrostatic pressure (P(Glo)) and resistances of the afferent (R(A)) and efferent (R(E)) arterioles were calculated according to the Gomez formulas. RESULTS: Blood pressure control was similar in both groups. RPF did not change with either treatment. In contrast, GFR increased with amlodipine (+8 +/- 14 mL/min; P <.01) but was preserved with valsartan. Amlodipine caused a more marked increase in the R(E)/R(A) ratio than valsartan (+0.26 +/- 0.26 v +0.13 +/- 0.24, P <.05), which was paralleled by an increase in P(Glo) in patients treated with amlodipine (+1.9 +/- 4.3 mm Hg; P <.05) but not in those treated with valsartan. CONCLUSIONS: At similar blood pressure control, valsartan maintained GFR and P(Glo), whereas amlodipine led to glomerular hyperfiltration and an increase in P(Glo). The results might explain the favorable renal outcome with AT(1)-receptor blocker therapy.

Vitamin C augments the renal response to L-arginine in smokers.

BACKGROUND: In the coronary and the forearm circulations, endothelium-dependent vasomotion is impaired in smokers, but can be augmented by -arginine or vitamin C. We examined whether smoking similarly affects the renal circulation. METHODS: In 20 smokers (age 26 +/- 4 years) and in 20 non-smokers (age 28 +/- 3 years) changes of renal plasma flow (RPF), glomerular filtration rate (GFR), blood pressure and heart rate in response to the subsequent intravenous infusions of N(G)-monomethyl--arginine (L-NMMA), -arginine and -arginine plus vitamin C were studied by use of a constant infusion input clearance technique. RESULTS: Systemic haemodynamic parameters did not differ between smokers and non-smokers during each experimental phase. At baseline, RPF and GFR were similar between the groups. The infusion of L-NMMA led to a similar decrease of RPF, while GFR did not change in either group. During the infusion of -arginine RPF increased similarly. Finally, the co-infusion of -arginine plus vitamin C led to a significantly greater increase of RPF (+277 +/- 395 vs +79 +/- 76 ml/min, P = 0.03) and GFR (+12.1 +/- 10.6 vs +3.4 +/- 11.2 ml/min, P = 0.02) in smokers as compared to non-smokers. CONCLUSIONS: L-NMMA-induced vasoconstriction of the renal vasculature was similar in smokers compared to non-smokers. -arginine alone induced a similar increase of RPF. The co-infusion of vitamin C and -arginine led to a greater increase of RPF and GFR in smokers. This might suggest that oxidative stress is increased in the renal vasculature of smokers.

A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension.

PURPOSE: Antihypertensive medications have different effects on left ventricular mass. We conducted a meta-analysis of double-blind trials that measured the effects of antihypertensive therapy on left ventricular mass. METHODS: Medical databases and review articles were screened for double-blind, randomized controlled trials (through September 2002) that reported the effects of diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor antagonists on echocardiographic left ventricular mass in essential hypertension. Treatment arms of the same drug class, weighted for the number of patients, were combined. Analysis of covariance was performed to detect differences among drug classes in effects on left ventricular structure. RESULTS: Eighty trials with 146 active treatment arms (n = 3767 patients) and 17 placebo arms (n = 346 patients) were identified. Adjusted for treatment duration and change in diastolic blood pressure, there was a significant difference (P = 0.004) among medication classes: left ventricular mass index decreased by 13% with angiotensin II receptor antagonists (95% confidence interval [CI]: 8% to 18%), by 11% with calcium antagonists (95% CI: 9% to 13%), by 10% with ACE inhibitors (95% CI: 8% to 12%), by 8% with diuretics (95% CI: 5% to 10%), and by 6% with beta-blockers (95% CI: 3% to 8%). In pairwise comparisons, angiotensin II receptor antagonists, calcium antagonists, and ACE inhibitors were more effective at reducing left ventricular mass than were beta-blockers (all P <0.05 with Bonferroni correction). CONCLUSIONS: Antihypertensive drug classes have different effects on left ventricular mass reduction. Whether a greater reduction of left ventricular mass results in better clinical outcomes remains to be determined.

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.

Functional relevance of aldosterone for the determination of left ventricular mass.

In experimental studies, the importance of aldosterone for the development of left ventricular (LV) hypertrophy has been demonstrated. In 120 healthy Caucasian men (aged 25 +/- 3 years; blood pressure, 134 +/- 15/86 +/- 12 mm Hg), we determined LV mass (2-dimensionally guided M-mode echocardiography), urinary aldosterone concentration, and the response of aldosterone to angiotensin II infusion (3.0 ng/kg/min). Seventy-six volunteers took part in a follow-up visit after 2 years when urinary aldosterone concentration and LV mass were determined again. At follow-up, LV mass increased in 42 subjects (by 33 +/- 26 g), whereas in 34 subjects LV mass decreased (by 27 +/- 22 g). Between the 2 groups, only the change in urinary aldosterone concentration over time was significantly different (group with increased LV mass had an increase in urinary aldosterone concentration by 2.5 +/- 5.4 microg/day; group with decreased LV mass had a decrease in urinary aldosterone concentration by 0.7 +/- 4.6; p <0.01 between groups). In accordance, we found significant correlations between changes in LV mass and changes in urinary aldosterone concentration (r = 0.29, p <0.05) and between changes in LV mass and the response of aldosterone to angiotensin II at baseline (r = 0.25, p <0.05). Both changes in aldosterone concentration over time and the response of aldosterone to angiotensin II were related to changes in LV mass over time. These data underscore the importance of aldosterone for the development of LV hypertrophy. This process is already evident in young subjects with apparently small changes in LV mass over a mean follow-up period of 2 years.

AT1-receptor blockade improves augmentation index: a double-blind, randomized, controlled study.

OBJECTIVE: Arterial hypertension leads to vascular structural and functional adaptive processes that are influenced by angiotensin II. To analyze the effects of AT receptor blockade on vascular function we determined augmentation index. METHODS AND DESIGN: A total of 60 patients (53 +/- 10 years) with essential hypertension mean [blood pressure (BP) 173 +/- 9/102 +/- 3 mmHg] were randomized to 6 weeks double-blind therapy with either valsartan 80 mg, hydrochlorothiazide (HCTZ) 25 mg or placebo once daily. Radial artery pressure wave was determined by applanation tonometry before and after therapy. The central aortic pressure wave and augmentation index were derived by a generalized transfer function. RESULTS: Active therapy similarly reduced systolic and diastolic blood pressure (SBP, DBP) (valsartan: -22 +/- 18/-11 +/- 11 mmHg, HCTZ: -22 +/- 23/-14 +/- 14 mmHg, all P < 0.001). However, only valsartan, but no HCTZ reduced the augmentation index (valsartan: from 148 +/- 18 to 126 +/- 24, < 0.001; HCTZ: from 145 +/- 19 to 142 +/- 18, NS). Augmentation index reduction was greater with valsartan (-22 +/- 11) than with HCTZ (-3 +/- 11) and placebo (0 +/- 13) (P < 0.01 for pairwise comparison of valsartan versus HCTZ and placebo after Bonferroni correction). Differences remained significant after taking changes in supine BP into account (covariance, P < 0.01). CONCLUSIONS: Blood pressure reduction with the AT receptor antagonist valsartan but not with hydrochlorothiazide reduced the augmentation index in essential hypertension.

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/m(2); 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.