Showing papers by "Roland E. Schmieder published in 2006"

Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: The VALUE trial

Abstract: ContextType 2 diabetes is emerging as a major health problem, which tends to cluster with hypertension in individuals at high risk of cardiovascular disease.ObjectiveTo test for the first time the hypothesis that treatment of hypertensive patients at high cardiovascular risk with the angiotensin-rec

Rapid Nongenomic Effects of Aldosterone on the Renal Vasculature in Humans

Abstract: There is increasing evidence for the importance of rapid nongenomic effects of aldosterone on the human vasculature. In vitro animal experiments in renal arterioles also suggest the presence of such effects on the renal vasculature. We conducted a clinical study to explore these effects in vivo in humans. Thirteen healthy male volunteers were examined. Aldosterone (500 μg) or placebo was injected intravenously with or without coinfusion of N(G) monomethyl-l-arginine (l-NMMA) in a randomized, double-blinded 4-fold crossover design. Renal plasma flow and glomerular filtration rate were measured by constant infusion clearance technique using inulin and para -aminohippuric acid. Injection of aldosterone without concomitant infusion of l-NMMA changed the renal plasma flow and glomerular filtration rate not statistically significant compared with placebo. Coinfusion of l-NMMA unmasked the effect of aldosterone: aldosterone with l-NMMA decreased the glomerular filtration rate slightly (−1.4±6.2 mL/min), whereas infusion of l-NMMA alone increased the glomerular filtration rate (8.3±9.8 mL/min; P =0.004). l-NMMA alone decreased renal plasma flow by 58.2±97.5 mL/min, and aldosterone with l-NMMA decreased renal plasma flow by 190.0±213.7 mL/min ( P =0.074). Accordingly, Aldosterone with l-NMMA increased renal vascular resistance much more than l-NMMA alone (1588±237 versus 614±240 dyn×s×cm −5 ; P =0.014). These data indicate that aldosterone acts via rapid nongenomic effects in vivo in humans at the renal vasculature. Antagonizing the endothelial NO synthase unmasks these effects. Therefore, rapid nongenomic aldosterone effects increase renal vascular resistance and thereby mediate arterial hypertension if endothelial dysfunction is present.

Rapid nongenomic effects of aldosterone on the renal vasculature in humans. Commentary

Abstract: There is increasing evidence for the importance of rapid nongenomic effects of aldosterone on the human vasculature. In vitro animal experiments in renal arterioles also suggest the presence of such effects on the renal vasculature. We conducted a clinical study to explore these effects in vivo in humans. Thirteen healthy male volunteers were examined. Aldosterone (500 μg) or placebo was injected intravenously with or without coinfusion of N(G) monomethyl-L-arginine (L-NMMA) in a randomized, double-blinded 4-fold crossover design. Renal plasma flow and glomerular filtration rate were measured by constant infusion clearance technique using inulin and para-aminohippuric acid. Injection of aldosterone without concomitant infusion of L-NMMA changed the renal plasma flow and glomerular filtration rate not statistically significant compared with placebo. Coinfusion of L-NMMA unmasked the effect of aldosterone: aldosterone with L-NMMA decreased the glomerular filtration rate slightly (-1.4±6.2 mL/min), whereas infusion of L-NMMA alone increased the glomerular filtration rate (8.3±9.8 mL/min; P=0.004). L-NMMA alone decreased renal plasma flow by 58.2±97.5 mL/min, and aldosterone with L-NMMA decreased renal plasma flow by 190.0±213.7 mL/min (P=0.074). Accordingly, Aldosterone with L-NMMA increased renal vascular resistance much more than L-NMMA alone (1588±237 versus 614±240 dyn×s×cm -5 ; P=0.014). These data indicate that aldosterone acts via rapid nongenomic effects in vivo in humans at the renal vasculature. Antagonizing the endothelial NO synthase unmasks these effects. Therefore, rapid nongenomic aldosterone effects increase renal vascular resistance and thereby mediate arterial hypertension if endothelial dysfunction is present.

Influences of Norepinephrine Transporter Function on the Distribution of Sympathetic Activity in Humans

Abstract: Previous studies suggest that neuronal norepinephrine transporter function may regulate the distribution of sympathetic activity among blood vessels, heart, and kidney; we tested the functional relevance in humans. Sixteen healthy men (26+/-1 years) ingested 8 mg of the selective norepinephrine reuptake transporter inhibitor reboxetine or a matching placebo on 2 separate days in a double-blind, randomized, crossover fashion. We monitored heart rate, thoracic bioimpedance, blood pressure, glomerular filtration rate, and renal blood flow. Ninety minutes after ingestion of the test medication, subjects were tilted to a 45 degrees head-up position, where they remained for an additional 30 minutes. Reboxetine increased supine systolic blood pressure through an increase in cardiac output whereas systemic vascular resistance decreased. Furthermore, reboxetine increased heart rate, particularly with a head-up tilt. Supine plasma renin activity was 0.71+/-0.15 ng angiotensin (Ang)/L per mL/h with placebo and 0.36+/-0.07 ngAng/L per mL/h with reboxetine (P<0.01). Supine plasma Ang II concentrations were also decreased with reboxetine. Both plasma renin activity and Ang II concentrations remained suppressed during head-up tilt. On placebo, renal vascular resistance increased with head-up tilt. The response was abolished with norepinephrine reuptake inhibition. We conclude that norepinephrine reuptake function profoundly influences the distribution of sympathetic activity between the heart, vasculature, and kidney in humans. All of these changes are physiologically relevant because they lead to corresponding changes in organ function.

Endothelial dysfunction: how can one intervene at the beginning of the cardiovascular continuum?

Abstract: Endothelial dysfunction, characterized by impaired nitric oxide activity, constitutes an early step in the pathogenesis of atherosclerotic disease. Prospective studies have shown that impaired endothelium-dependent vasorelaxation and the vasodilatory response of coronary arteries to acetylcholine predict cardiovascular events. Microalbuminuria and estimated glomerular filtration rate, which are both deeply influenced by renal nitric oxide activity, are predictors of cardiovascular outcome and total mortality but develop at a later stage of renal impairment. Endothelial dysfunction reflects early stage renal involvement in the atherosclerotic processes. The Telmisartan versus Ramipril in renal ENdothelium DYsfunction (TRENDY) trial examined endothelial function of the renal vasculature as a therapeutic target in patients with hypertension and type 2 diabetes, but without albuminuria. The rationale was that blockade of the renin-angiotensin system (RAS) is cardio- and renoprotective at later stages of the disease, but the impact of blockade of the RAS at earlier stages of disease is unknown. The results of TRENDY indicate that the endothelial function, as assessed by basal nitric oxide activity, can be improved after RAS blockade. These data complement the results of the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) trial, which demonstrated that telmisartan and enalapril similarly decelerate the progression of overt diabetic nephropathy. The results of TRENDY are in accordance with the observed changes in peripheral circulation. Endothelium-dependent vasorelaxation could be improved with angiotensin II receptor blockers, but not with diuretics or beta-blockers, in hypertensive patients. Intervention at the beginning of the renal and cardiovascular continuum offers the opportunity to prevent the fatal development towards renal and cardiac failure.

[Shared decision-making with hypertensive patients. Results of an implementation in Germany].

Abstract: BACKGROUND AND OBJECTIVE Lack of compliance is a common problem in the treatment of hypertension. Ineffective physician-patient-communication and a lack of patients involvement can play a crucial role. We tested the hypothesis that shared decision-making (SDM) results in higher involvement of patients in their blood pressure lowering therapy and evaluated the effects of SDM on the control of blood pressure. PATIENTS AND METHODS Two groups of 84 hypertensives were compared: an intervention group (26 women and 13 men, age 61 +/- 10 years) treated by 15 specially SDM-trained primary care physicians, and a control group of 45 hypertensives. All 84 patients were enrolled in a patient education programme. Changes of blood pressure were assessed after one year by self-measurements. Questionnaires about their attitude to patient autonomy, the SDM process, quality of life, physician-patient-relationship and life-style changes were analysed as well. RESULTS After one year the blood pressure had decreased in both the intervention group (-9.26 +/- 10.2/-5.3 +/- 9.5 mmHg, p < 0.001) and in the control group (-6.0 +/- 11.8/-3.0 +/- 8.3 mmHg, p < 0.05), without a significant difference between the two groups. Among a subgroup of patients with a marked preference for SDM there was a close correlation between an increase of SDM and a decrease in systolic blood pressure (p = 0.016). Also, the numbers of antihypertensive drugs increased more in the intervention group (p = 0.022) than in control patients. Furthermore, increase in knowledge about hypertension and its treatment was greater in the intervention group (P=0.006). CONCLUSION Implementation of SDM had a significant effect on systolic blood pressure control only in the subgroup of patients with marked preference for SDM. Thus, the identification of patients with a preference for SDM may improve blood pressure control and their adherence to the prescribed drug therapy.

Effect of nos inhibition on retinal arterial and capillary circulation in early arterial hypertension.

Abstract: BACKGROUND: Arterial hypertension is involved in the pathogenesis of end organ damage by influencing the ability of the vascular endothelium to produce nitric oxide (NO). This study analyzes changes of retinal and systemic NO-dependent circulation parameters by inhibiting nitric oxide synthase (NOS) in both hypertensive and normotensive individuals. METHODS: In a double-blind crossover trial, 19 hypertensive patients (H, age 28.2 +/- 0.9 years) and 19 normotensive controls (N, age 26.9 +/- 0.9 years) were randomized treated either with candesartan or placebo. Both retinal capillary flow (RCF) and mean blood flow velocity of the central retinal artery (VCRA) were registered before and after NOS inhibition with N-monomethyl-L-arginine (L-NMMA, 3 mg/kg). In a subpopulation mean arterial pressure (MAP), cardiac output (CO), and the total peripheral resistance (TPR) were determined simultaneously. RESULTS: Changes from baseline: In normotensive and hypertensive subjects infusion of L-NMMA led to an increase of MAP (N, +13.3 +/- 1.8%, P < 0.01; H, +14.3 +/- 2.4%, P < 0.01) and TPR (N, +36.9 +/- 3.8%, P < 0.01; H, +45.0 +/- 4.5%, P < 0.01), and to a decrease of CO (N, -21.1 +/- 1.5%, P < 0.01; H, -24.6 +/- 2.3%, P < 0.01). The L-NMMA effect on VCRA and RCF differed between controls and hypertensives. VCRA changed by + 17.3 +/- 6.2% (P < 0.05) and RCF by -7.3 +/- 3.0% (P < 0.05) in controls. In hypertensive subjects corresponding results were + 9.5 +/- 5.2% (P = NS) and + 2.7 +/- 3.8% (P = NS), respectively. The decrease of RCF due to L-NMMA was reduced in hypertension as compared to controls (P < 0.05). The calculated cross-sectional area of CRA was reduced by -58.7% in controls and increased by + 31.1% in hypertensive subjects. There was no significant correlation between the flow in the systemic and retinal circulation. CONCLUSION: Only normotensives L-NMMA induces an acceleration of VCRA due to a probable vasoconstriction of the central retinal artery and despite of a reduced RCF. Already in early hypertension the NOS-dependent vascular tone in retinal arteries and capillaries is impaired. The regulation of the retinal capillary flow appeared to be independent from systemic circulation.

Valsartan and retinal endothelial function in elderly hypertensive patients

Abstract: Background. The aim of this study was to investigate the impact of short‐term treatment with the angiotensin II receptor blocker (ARB) valsartan on retinal endothelial function in elderly patients with mild to moderate essential hypertension. Methods. In an open‐labeled study, 20 elderly, male patients with arterial hypertension (WHO I–II) were treated with the ARB valsartan (80–160 mg once daily) over 8 days. Central retinal artery perfusion at rest and during flicker light stimulation was measured before and after treatment using pulsed wave Doppler sonography. Retinal capillary flow was assessed with scanning laser Doppler flowmetry at rest and following systemic infusion of the nitric oxide synthase (NOS) inhibitor NG‐monomethyl‐l‐arginine (L‐NMMA). Results. While valsartan significantly lowered blood pressure, central retinal artery perfusion at rest as well as after flicker light stimulation was similar before and after treatment. Similarly, retinal capillary flow at rest and after infusion of L‐NMM...

Aliskiren: a clinical profile

Abstract: Aliskiren is a novel oral antihypertensive agent, and the first in the new class of direct renin inhibitors. Here we review the key criteria that a new antihypertensive drug should possess, notably effective blood pressure lowering as monotherapy and combination therapy, 24-hour blood pressure control, safety and tolerability, end-organ protective effects, minimal drug interaction and efficacy during long-term use. Aliskiren fulfils key criteria for a new antihypertensive agent.The drug demonstrates effective blood lowering in a number of studies as monotherapy and in combination with a thiazide diuretic (hydrochlorothiazide), an angiotensin-converting enzyme inhibitor (ramipril) and a calcium channel blocker (amlodipine). Other studies applying ambulatory blood pressure monitoring show that aliskiren maintains blood pressure control for more than 24 hours.Aliskiren, 150 mg and 300 mg have demonstrated a placebo-like safety and tolerability profile, with no interactions with a wide range of commonly used drugs.Three studies (AVOID,ALOFT and ALLAY) are ongoing with aliskiren to assess end-organ protective properties.

Angiotensin Receptor Blockers: Cardiovascular Protection in the Metabolic Syndrome

Abstract: It is well recognised that the metabolic syndrome, a constellation of risk factors including obesity, hypertension, insulin resistance and dyslipidaemia, is associated with an increased risk of cardiovascular complications and the development of Type 2 diabetes. Consequently, timely identification and management of all components of the metabolic syndrome is warranted. In particular, guidelines have emphasised the importance of targeting elevated blood pressure (BP) and dyslipidaemia as a method of reducing global cardiovascular risk. Findings from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial show that the angiotensin receptor blocker, valsartan, reduces cardiovascular events and the development of Type 2 diabetes in high-risk individuals. This profile is being further explored in the ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Given the potential advantages to patients and physicians of tackling more than one of the components of the metabolic syndrome, antihypertensive agents such as valsartan would appear to be and important addition to the management of vulnerable patients at high risk of cardiovascular events.