Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease.

We have reviewed the effects of angiotensin II type 1 receptor antagonists (ARBs) in various animal models of hypertension, atherosclerosis, cardiac function, hypertrophy and fibrosis, glucose and lipid metabolism, and renal function and morphology. Those of azilsartan and telmisartan have been included comprehensively whereas those of other ARBs have been included systematically but without intention of completeness. ARBs as a class lower blood pressure in established hypertension and prevent hypertension development in all applicable animal models except those with a markedly suppressed renin-angiotensin system; blood pressure lowering even persists for a considerable time after discontinuation of treatment.

Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy.

Context: We describe the clinical investigation of the first generation aldosterone synthase inhibitor, LCI699, in patients with essential, uncontrolled, resistant, or secondary hypertension. LCI699 competitively reduced blood pressure at lower doses yet counterintuitive effects were observed at higher doses.

Objective And Method: An extensive endocrine biomarker analysis was performed to better understand the pharmacological mechanism of the drug.

A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists.

Angiotensin II type 1 receptor antagonists (ARBs) have become an important drug class in the treatment of hypertension and heart failure and the protection from diabetic nephropathy. Eight ARBs are clinically available [azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan]. Azilsartan (in some countries), candesartan, and olmesartan are orally administered as prodrugs, whereas the blocking action of some is mediated through active metabolites.

Cardiovascular outcomes in hypertensive patients: comparing single-agent therapy with combination therapy.

Objectives: To determine whether blood pressure (BP) control in hypertensive patients achieved with combination drug therapy provides the same cardiovascular benefits as with single-agent therapy.

Background: Drug combinations, most often including hydrochlorothiazide (HCTZ), are now recommended for routine BP management, but their effects on cardiovascular event rates have not been compared with effective monotherapy.

Methods: We conducted retrospective analyses of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) data.

Usefulness of heart rate to predict cardiac events in treated patients with high-risk systemic hypertension.

A high heart rate (HR) predicts future cardiovascular events. We explored the predictive value of HR in patients with high-risk hypertension and examined whether blood pressure reduction modifies this association. The participants were 15,193 patients with hypertension enrolled in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and followed up for 5 years.

Practical solutions to the challenges of uncontrolled hypertension: a white paper.

This white paper is an urgent call to action from an international group of physicians. The continued failure to control hypertension takes an unacceptable toll on patients, families and society and it must be addressed. Any patient with blood pressure of 140/90 mmHg or greater can be characterized as a 'challenging patient', is at significant risk, and requires persistent optimization of therapy until target blood pressure is achieved.

Under pressure: future prospects in hypertension management. Interview by Laura Dormer.

Professor Hans Rudolf Brunner Born in 1937, Professor Brunner is a Swiss citizen. He is a Professor Emeritus of Medicine at the University of Lausanne, Switzerland. He has been at the forefront of research on the role of renin and the renin-angiotensin system in blood pressure regulation.

Aliskiren: the first renin inhibitor for clinical treatment.

The first evidence of the existence of renin was presented over 100 years ago. However, the importance of renin and the renin-angiotensin system in the pathogenesis of cardiovascular disease was only fully realized in the 1970s. It was another 20 years before the first inhibitors of renin were available for clinical research.

Antihypertensive efficacy of olmesartan medoxomil and candesartan cilexetil assessed by 24-hour ambulatory blood pressure monitoring in patients with essential hypertension.

Objective: To compare the antihypertensive efficacy of olmesartan medoxomil with that of candesartan cilexetil after 1, 2 and 8 weeks of treatment.

Design And Setting: Randomised, double-blind, parallel-group study conducted at 44 centres in Germany, Poland and the Czech Republic.

Patients: 643 patients (aged 19-86 years) with mainly mild-to-moderate essential hypertension received active double-blind treatment.

Olmesartan medoxomil: current status of its use in monotherapy.

Olmesartan medoxomil is an angiotensin II receptor antagonist. In pooled analyses of seven randomized, double-blind trials, 8 weeks' treatment with olmesartan medoxomil was significantly more effective than placebo in terms of the response rate, proportion of patients achieving target blood pressure (BP) and mean change from baseline in diastolic (DBP) and systolic blood pressure (SBP). Olmesartan medoxomil had a fast onset of action, with significant between-group differences evident from 2 weeks onwards.

Antihypertensive efficacy of olmesartan medoxomil and candesartan cilexetil in achieving 24-hour blood pressure reductions and ambulatory blood pressure goals.

Background: For patients with hypertension, effective 24-hour blood pressure (BP) control is vital to ensure protection against the early morning surge in BP and the associated increased risk of cardiovascular events. The aim of this analysis was to assess the 24-hour antihypertensive efficacy of olmesartan medoxomil (20mg once daily) compared with candesartan cilexetil (8mg once daily), with particular emphasis on BP control during the early morning period.

Methods: This is an additional analysis of a previously reported randomised, double-blind study in which 635 patients with mainly mild to moderate hypertension were randomised to 8 weeks of treatment with either olmesartan medoxomil 20 mg/day or candesartan cilexetil 8 mg/day.

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy.

In the main Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) report, we investigated outcomes in 15 245 high-risk hypertensive subjects treated with valsartan- or amlodipine-based regimens. In this report, we analyzed outcomes in 7080 patients (46.4%) who, at the end of the initial drug adjustment period (6 months), remained on monotherapy.

Sustained 24-hour blockade of the renin-angiotensin system: a high dose of a long-acting blocker is as effective as a lower dose combined with an angiotensin-converting enzyme inhibitor.

Whether a higher dose of a long-acting angiotensin II receptor blocker (ARB) can provide as much blockade of the renin-angiotensin system over a 24-hour period as the combination of an angiotensin-converting enzyme inhibitor and a lower dose of ARB has not been formally demonstrated so far. In this randomized double-blind study we investigated renin-angiotensin system blockade obtained with 3 doses of olmesartan medoxomil (20, 40, and 80 mg every day) in 30 normal subjects and compared it with that obtained with lisinopril alone (20 mg every day) or combined with olmesartan medoxomil (20 or 40 mg). Each subject received 2 dose regimens for 1 week according to a crossover design with a 1-week washout period between doses.

Neuropeptide Y expression, localization and cellular transducing effects in HUVEC.

Background Information: NPY (neuropeptide Y) may have an effect on the properties of vascular endothelial cells such as pro-angiogenic effects and potentiation of noradrenaline-induced vasoconstriction. In HUVEC (human umbilical-vein endothelial cells), immunoreactive neuropeptide Y has been detected, but NPY synthesis, storage and secretion have not been studied. The aim of the present study was to establish NPY expression, storage and cellular transducing effects in HUVEC.

Renal endothelin receptor type B upregulation in rats with low or high renin hypertension.

Objectives: To evaluate the role of endothelin-1 (ET-1) in hypertension, we investigated density and distribution of ETA and ETB receptors in hearts and kidneys of deoxycorticosterone acetate (DOCA)-salt and 1 kidney -- 1 clip (1K1C) hypertensive rats.

Methods: Five groups of uninephrectomized Wistar rats were put on a low salt diet. Three groups of rats drank tap water and two groups received saline.

Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE-/- mice.

Rupture of vulnerable plaques is the main cause of acute cardiovascular events. However, mechanisms responsible for transforming a stable into a vulnerable plaque remain elusive. Angiotensin II, a key regulator of blood pressure homeostasis, has a potential role in atherosclerosis.

Clinical efficacy and tolerability of olmesartan.

Background: Olmesartan medoxomil is an angiotensin II receptor antagonist that selectively and competitively inhibits the angiotensin II type 1 receptor.

Objective: This article reviews the results of some key studies that assessed the efficacy and tolerability of olmesartan in patients with hypertension.

Methods: Olmesartan has been investigated in several clinical studies.

Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test whether, for the same achieved blood pressures, regimens based on valsartan or amlodipine would have differing effects on cardiovascular endpoints in high risk hypertension. But inequalities in blood pressure, favouring amlodipine, throughout the multiyear trial precluded comparison of outcomes. A technique of serial median matching, applied at 6 months when treatment adjustments intended to achieve control of blood pressure were complete, created 5006 valsartan-amlodipine patient pairs matched exactly for systolic blood pressure, age, sex, and the presence or absence of previous coronary disease, stroke, or diabetes.

Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.

Background: The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk.

Methods: 15?245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomised, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint, defined as a composite of cardiac mortality and morbidity.

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.

Background: Depending on its magnitude, lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal, renal tubular, and renal hemodynamic responses, thereby mimicking the renal responses observed in clinical conditions characterized by a low effective arterial volume such as congestive heart failure. Our objective was to evaluate the impact of angiotensin II receptor blockade with candesartan on the renal hemodynamic and urinary excretory responses to a progressive orthostatic stress in normal subjects.

Methods: Twenty healthy men were submitted to three levels of LBNP (0, -10, and -20 mbar or 0, -7.

Volume expansion enhances plasma endothelin-1.

We hypothesized that acute volume expansion by saline infusion triggers the release of endothelin-1. Bolus intravenous saline infusion (8 mL/min) in six groups of conscious Wistar rats and spontaneously hypertensive rats did not change mean arterial pressure or heart rate (n = 8 to 12). At 1 min after infusion, the plasma endothelin-1 level was significantly increased in Wistar rats and in spontaneously hypertensive rats by 42% and 61%, respectively (unpaired data).

NPY, NPY receptors, and DPP IV activity are modulated by LPS, TNF-alpha and IFN-gamma in HUVEC.

Since NPY increases endothelial cell (EC) stickiness for leukocytes, we studied the effects of LPS, TNF-alpha and IFN-gamma on its expression and action in HUVEC. Cytokines raised NPY and pro-NPY intracellular content and dipeptidyl peptidase IV (DPP IV) activity. Y1 and Y2 receptors were expressed in basal conditions, and LPS, TNF-alpha and IFN-gamma induced Y5 receptor expression with a concomitant extinction of Y2 receptor expression.

Determination of cardiac contractility in awake unsedated mice with a fluid-filled catheter.

Today, cardiac contractility in mice is exclusively measured under anesthesia or in sedated animals because the catheters available are too rigid to be used in awake mice. We therefore developed a new catheter (Pebax 03) to measure cardiac contractility in conscious mice. In this study, we evaluated the accuracy and utility of this new catheter for assessment of cardiac contractility in anesthetized and conscious mice.