Low dose-eplerenone treatment decreases aortic stiffness in patients with resistant hypertension.

Vascular damage is aggravated in animal models of hypertension with mineralocorticoid (MR) excess and in hypertensive patients with primary hyperaldosteronism. MR antagonism has shown to provide effective blood pressure (BP)-control in patients with treatment resistant hypertension (TRH), but the concurrent effects on the vasculature have not been examined. In a randomized, double-blinded, placebo-controlled parallel-group study, 51 patients with TRH received either eplerenone 50 mg or placebo for 6 months together with additional antihypertensives titrated to achieve a BP target of <140/90 mm Hg. Pulse wave velocity (PWV), augmentation index (AIx), augmentation pressure (AP), AP normalized to a heart rate of 75/min (AP@HR75), renal resistive index (RRI), intima-media thickness (IMT) and urinary albumin excretion rate (UAER) were assessed before and after treatment. PWV was reduced only with eplerenone (from 11.3±3.6 to 9.8±2.6 m/s, P˂.001), but not with placebo (10.3±2.0 to 10.1±1.8 m/s, P=.60), despite similar reductions in BP (-35±20/-15±11 mm Hg vs -30±19/-13±7 mm Hg, n.s.). Further, reductions in AP and AP@HR75 were greater with eplerenone, while changes in AIx, RRI, IMT and UAER were similar. Our data show that eplerenone beneficially affects markers of arterial stiffness and wave reflection in patients with TRH, independently of BP lowering. These data add to the evidence that MR antagonism should be the preferred treatment option in TRH.

Dihydropyridine calcium antagonists are associated with increased albuminuria in treatment-resistant hypertensives.

ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) are superior to dihydropyridine calcium-antagonists (DHP) with regard to reduction of albuminuria in patients with diabetic nephropathy. It has been argued that with blood pressure outside the targets DHP may exaggerate albuminuria in hypertensive patients. We addressed the question in an observational study in patients with difficult-to-treat essential hypertension. We analyzed baseline data from patients (n=80) screened for a clinical trial in treatment-resistant hypertension. All patients were treated with an ACEI/ARB, a diuretic and at least a third drug in the highest tolerated dose. We compared 50 patients who were treated with DHPs with 30 who were not. Albuminuria was assessed as albumin excretion in 24-hour urine. Values are given as mean ± SD. All comparisons were made using unpaired t-test. There were no differences with regard to demographic parameters, blood pressure or duration of hypertension between both groups. Albumin excretion was 14.3 ± 16.9 mg/d in patients treated with DHPs and 8.5 ± 6.6 mg/d in patients treated without DHPs (p=0.036). Our data indicate that even in patients treated with ACEI/ARBs DHPs are associated with increased albuminuria. Since increases of albuminuria even in the low range are associated with increased cardiovascular risk, detection of albuminuria should influence the choice of antihypertensive drugs in hypertensive patients with albuminuria.

Renal resistive index--a valid tool to assess renal endothelial function in humans?

BACKGROUND: In humans, renal endothelial function is assessed by the vasoconstrictive response to L-NG-monomethyl arginine (L-NMMA). We hypothesized that Doppler sonographic measurements of the renal resistive index in response to inhibition of nitric oxide synthase offer a new methodological approach for testing renal endothelial function. METHODS: Forty-one patients without nephropathy were included. Para-aminohippurate and inulin clearance were performed under basal conditions and during L-NMMA infusion. In parallel, renal resistive index was assessed by Doppler sonography, and central blood pressure was determined. RESULTS: Following nitric oxide synthase inhibition, renal resistive index increased significantly, and 29% of our patients developed Doppler sonographic diastolic zero flow. Renal plasma flow decreased in response to L-NMMA, and conversely, renal vascular resistance increased. There was no correlation of renal vascular resistance and renal resistive index at baseline and during nitric oxide synthase inhibition. Changes in renal resistive index were not related to changes in renal perfusion or renal vascular resistance. Renal resistive index correlated with central pulse pressure at baseline and during L-NMMA infusion, whereas renal vascular resistance did not correlate with central pulse pressure. CONCLUSION: Our data do not support the hypothesis that renal resistive index is a tool to test renal endothelial function in humans and should not be used interchangeably with renal vascular resistance.

Renal resistive index in addition to low-grade albuminuria complements screening for target organ damage in therapy-resistant hypertension.

OBJECTIVE: We examined the value of renal resistive index (RRI) for prevalence of cardiovascular target organ damage in therapy-resistant hypertension in comparison to low-grade albuminuria. METHODS: Eighty-four patients with therapy-resistant hypertension (age 59.7 +/- 8.1 years) were screened for cardiovascular target organ damage with coronary computed tomography, cardiac magnetic resonance imaging (MRI), Doppler sonography for the assessment of carotid intima media thickness and, RRI, pulse wave velocity and for low-grade albuminuria of at least 10 mg/day in men and 15 mg/day in women, respectively. RESULTS: In patients with RRI greater than 0.7 pulse wave velocity (11.6 +/- 3.7 vs. 9.8 +/- 2.2 m/s; P = 0.02) intima media thickness (0.85 +/- 0.09 vs. 0.76 +/- 0.1 mm; P = 0.007) and Agatston score of coronary calcification (640 +/- 915 vs. 129 +/- 256; P = 0.05) were increased, whereas left ventricular mass (127 +/- 24.5 vs. 125 +/- 15.0 g; P = 0.70) was similar between the two groups. When patients were categorized according to low-grade albuminuria left ventricular mass was significantly higher in those with low-grade albuminuria (123 +/- 25.8 vs. 135 +/- 15.7 g; P = 0.01), whereas vascular parameters (intima media thickness, Agatston score, pulse wave velocity) did not differ between the two groups. CONCLUSION: In patients with therapy-resistant hypertension RRI reflects functional and structural vascular parameters, whereas low-grade albuminuria is related to cardiac structural changes. Thus, measurement of RRI in addition to low-grade albuminuria complements screening for target organ damage in therapy-resistant hypertension.

High sodium intake modulates left ventricular mass in patients with G expression of +1675 G/A angiotensin II receptor type 2 gene.

OBJECTIVES: In patients with hypertension left ventricular hypertrophy (LVH) is associated with genetic variations of the angiotensin type 2 receptor (AT2R). Hypertension and LVH are often aggravated by salt intake. Our objective was to assess the relationship between AT2R gene variation and salt intake and their impact on left ventricular mass (LVM). METHODS AND RESULTS: In 205 subjects with normal or mildly elevated blood pressure, we assessed sodium intake and left ventricular structure and function by echocardiography. Intronic +1,675 G/A polymorphism of the AT2R gene was investigated. A-allele carriers had a greater LVM (P = 0.049) than G-allele carriers. Independent of diet, septal wall thickness was higher in A-allele carriers (P = 0.001). Fractional fibre shortening was greater in A-allele carriers (P = 0.034), and the velocity of circumferential fibre shortening tended to be greater in A-allele carriers (P = 0.057). When the two groups were stratified according to their salt intake, only G-allele carriers displayed a modulating effect of salt intake on LVM. Covariance analysis revealed that there was a trend towards a modulating effect of salt intake on LVM, even after taking blood pressure into account (P = 0.054). CONCLUSION: Our data clearly support the notion that LVM is influenced by AT2R polymorphisms. Furthermore, G-allele carriers in particular appear to be susceptible to a modifying effect of increased salt intake on LVM.

Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension.

BACKGROUND: It is not known whether the beneficial effects of N-acetylcysteine (NAC) in conditions associated with increased oxidative stress are caused by direct superoxide scavenging. We therefore compared the acute superoxide scavenging efficacy of NAC against vitamin C (VITC) on impaired endothelium-dependent vasodilation in subjects with essential hypertension. METHODS: In a cross-over randomized study, the effects of intra-arterial administration of either NAC (48 mg/min) or VITC (18 mg/min) were examined in 15 subjects with essential hypertension and in 15 normotensive control subjects. Both endothelium-dependent and endothelium-independent vasodilation were determined as forearm blood flow (FBF) response to the intra-arterial administration of acetylcholine (Ach) and sodium nitroprusside (NP) in doses of 12 and 48 mug/min and 3.2 and 12.8 mug/min, respectively. RESULTS: Subjects with essential hypertension had impaired responses to both doses of Ach (Delta% FBF to higher dose of Ach: 325 +/- 146 in subjects with essential hypertension v 540 +/- 199 in control subjects; P = .02) and an impaired response to the higher dose of NP (330 +/- 108 v 500 +/- 199; P = .03). The intra-arterial administration of NAC had no effect on these responses (higher dose of Ach: 325 +/- 146 without v 338 +/- 112 with NAC, NS). In contrast, intra-arterial VITC improved both the response to Ach (320 +/- 132 without v 400 +/- 185 with VITC, P = .05) and to NP (383 +/- 162 v 447 +/- 170, P = .05). CONCLUSIONS: We found that NAC showed no statistically significant effect on either endothelium-dependent or endothelium-independent vasodilation in hypertensive subjects, whereas VITC did. We conclude that NAC is therefore not an effective superoxide scavenger in vivo. Other, nonimmediate effects such as the generation of glutathione may explain the beneficial effects of NAC in conditions associated with oxidative stress.