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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. This translates into a reduced mortality, particularly in models exhibiting marked hypertension. The retrieved data on vascular, cardiac and renal function and morphology as well as on glucose and lipid metabolism are discussed to address three main questions: 1. Can ARB effects on blood vessels, heart, kidney and metabolic function be explained by blood pressure lowering alone or are they additionally directly related to blockade of the renin–angiotensin system? 2. Are they shared by other inhibitors of the renin–angiotensin system, e.g. angiotensin converting enzyme inhibitors? 3. Are some effects specific for one or more compounds within the ARB class? Taken together these data profile ARBs as a drug class with unique properties that have beneficial effects far beyond those on blood pressure reduction and, in some cases distinct from those of angiotensin converting enzyme inhibitors. The clinical relevance of angiotensin receptor-independent effects of some ARBs remains to be determined.

These experiments were designed to assess the ability of the new nonpeptide angiotensin II antagonist DuP 753 to inhibit the binding and, particularly, to antagonize the cellular response to angiotensin II in human platelets and primary cultures of rat aortic smooth muscle cells (SMC). The binding of 125I-angiotensin II was competitively inhibited by DuP 753 with a 50% binding inhibition (IC50) of 5 to 6 × 10—8 mol/L in platelets and 1 × 10—8 mol/L in vascular SMC as compared to an IC50 of 5 to 7.5 × 10×9 mol/L with nonlabeled angiotensin II. In vascular SMC, DuP 753 completely abolished the effects of angiotensin II on 45CaCl2 efflux and 45CaCl2 uptake. Moreover, in these latter cells, DuP 753 prevented the angiotensin II but not the vasopressin induced increase in cytosolic calcium. These results demonstrate that DuP 753 competes with angiotensin II binding to its receptor in both animal and human cells and selectively blocks the cellular response to angiotensin II. Am J Hypertens 1991;4:438-443

Neuropeptide Y (NPY) is present in the brain, the adrenal medulla, and peripheral sympathetic nerves. This peptide is released together with catecholamines during sympathoadrenal activation. It possesses direct vasoconstrictor properties that are not dependent on simultaneous adrenergic activation. Moreover, it potentiates the vascular effect of several stimulatory substances and may contribute to the modulation of blood pressure responsiveness under a number of circumstances. NPY may also be indirectly involved in the control of blood pressure through regulating the release of hormones with well-established actions on the cardiovascular system. Am J Hypertens 1988;1:193-199

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. Results: The interference of LCI699 in the renin–angiotensin–aldosterone system occurred with limited target selectivity, as a dose-dependent compensatory stimulation of the hypothalamic-pituitary-adrenal feedback axis was discovered. Thus, LCI699 affected two endocrine feedback loops that converged at a single point, inhibiting the 11β-hydroxylase reaction in the adrenal gland, leading to supraphysiological levels of 11-deoxycortiscosterone. The accumulation of this potent mineralocorticoid may explain the blunted blood pressure response to LCI699. Conclusion: Future aldosterone synthase inhibitors may improve their target selectivity by sparing the 11β-hydroxylase reaction and preferentially inhibiting one of the two other enzymatic reactions mediated by aldosterone synthase.

Introduction Angiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%). With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists. Methods A radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II) antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin. Results The in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists. Conclusion Although the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

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 ro

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. Here, we describe the discovery and development of aliskiren, an orally active renin inhibitor, which became the first drug in its class to receive regulatory approval. In 2007, it was approved for the treatment of hypertension by the US Food and Drug Administration and the European Medicines Agency.

The effects of the endothelium-dependent vasodilator acetylcholine, the endothelium-independent vasodilator nitroglycerin and a drug which inhibits basal nitric oxide (NO) release (L-NG-monomethyl-arginine [L-NMMA]) on the diameter of the radial artery and blood flow were studied in eight patients with hypercholesterolaemia (total cholesterol: 280 +/- 9 mg/dl, age 54 +/- 3 years) and eight healthy subjects of the same age (total cholesterol 197 +/- 12 mg/dl, age 51 +/- 4 years). Arterial diameter was measured by a recently developed high resolution ultrasound technique. Increasing concentrations of acetylcholine (10(-8) to 10(-6) mol/l) produced dose-dependent increases in flow rate in the healthy subjects (maximum +150% +/- 6% at 10(-6) mol/l), but much less in the patients with hypercholesterolaemia (+24% +/- 12%). L-NMMA caused comparable reductions in forearm blood flow in both groups. Nitroglycerin increased blood flow in the hypercholesterolaemia group to a significantly greater extent (+370% +/- 69%) than in the controls (+145 +/- 62%). The effects of acetylcholine, L-NMMA and nitroglycerin on radial artery diameter did not differ significantly between the two groups. The poor response (in terms of blood flow) to acetylcholine in the hypercholesterolaemia group points to an endothelial dysfunction in the arterial microcirculation. The fact that L-NMMA caused similar reductions in forearm blood flow in the controls and hypercholesterolaemia patients alike shows that basal NO synthase activity must be comparable in the two groups and therefore cannot be held responsible for the endothelial dysfunction. This endothelial dysfunction is linked with increased responsiveness to the endothelium-independent vasodilator nitroglycerin.

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. Baseline characteristics were similar in the valsartan (N=3263) and amlodipine (N=3817) groups. Time on monotherapy was 3.2 years (78% of treatment exposure time). The average in-trial blood pressure was similar in both groups. Event rates in the monotherapy group were 16% to 39% lower than in the main VALUE trial. In the first analysis, we censored patients when they discontinued monotherapy (“censored”); in the second, we counted events regardless of subsequent therapy (intention-to-treat principle). We also assessed the impact of duration of monotherapy on outcomes. No difference was found in primary composite cardiac end points, strokes, myocardial infarctions, and all-cause deaths with both analyses. Heart failure in the valsartan group was lower both in the censored and intention-to-treat analyses (hazard ratios: 0.63, P =0.004 and 0.78, P =0.045, respectively). Longer duration of monotherapy amplified between-group differences in heart failure. New-onset diabetes was lower in the valsartan group with both analyses (odds ratios: 0.78, P =0.012 and 0.82, P =0.034). Thus, despite lower absolute event rates in monotherapy patients, the relative risks of heart failure and new-onset diabetes favored valsartan. Moreover, these findings support the feasibility of comparative prospective trials in lower-risk hypertensive patients.

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 (20 mg once daily) compared with candesartan cilexetil (8 mg 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. Changes from baseline during the last 4 and 2 hours of ambulatory BP measurement (ABPM) after 1, 2 and 8 weeks of treatment were compared between the two groups. In addition, the proportions of patients who achieved various ABPM goals, including those suggested by the European Society of Hypertension/European Society of Cardiology (ESH/ESC) [Results.After 8 weeks, significantly greater proportions of patients treated with olmesartan medoxomil 20 mg achieved 24-hour and daytime ABPM goals recommended by the guidelines of the ESH/ESC (25,6 % and 18,3 %, respectively) and JSH (37,5 % and 26,6 %, respectively) compared with candesartan cilexetil 8 mg (24-hour ESH/ESC goal 14,9 %,pp=0,003; daytime ESH/ESC goal 9,6 %,p=0,002; daytime JSH goal 16,4 %,p=0,002). During the last 4 hours of 24-hour ABPM, the proportions of patients who achieved the ESH/ESC and JSH ABPM goals were significantly greater with olmesartan medoxomil (33,3 % and 39,1 %, respectively) than with candesartan cilexetil (22,9 %,pp=0,047, respectively). Similarly, during the last 2 hours of 24-hour ABPM, the proportions of patients who achieved these BP goals were either significantly greater (JSH) or approached statistical significance (ESH/ESC) with olmesartan medoxomil (26,9 % and 19,9 %, respectively), compared with candesartan cilexetil (19,6 %,p=0,028 and 14,3 %,p=0,061, respectively).Conclusion. Compared with candesartan cilexetil 8 mg, greater proportions of olmesartan medoxomil-treated patients (20 mg) achieved ESH/ESC and JSH ABPM goals over 24 hours. The superior BP control of olmesartan medoxomil was also reflected in the larger proportions of olmesartan medoxomil-treated patients who achieved the ESH/ESC and JSH ABPM goals during the early morning surge period. This not only demonstrates that olmesartan medoxomil 20 mg provides superior 24-hour BP reduction, but also suggests that olmesartan medoxomil may provide greater protection against the increased risk of cardiovascular events associated with the early morning BP surge period.

Valsartan is a widely used, efficacious and very well-tolerated antihypertensive agent. By specifically blocking the action of angiotensin II on the angiotensin Type 1 receptor, valsartan reduces unwanted effects of angiotensin II, such as aldosterone, vasopressin and endothelin secretion, vasoconstriction, diuresis, endothelial cell hyperplasia, mitogenesis, induction of growth factors and production of collagen. Valsartan has a simple pharmacokinetic profile and requires no metabolism to become active. The dose-related efficacy of valsartan has been clearly demonstrated and the tolerability profile is similar to placebo. Clinical trials in elderly patients show good efficacy and high responder rates with the same doses as in younger patients. Valsartan is available as 80-, 160- and 320-mg tablets, and also in the same doses in combination with hydrochlorothiazide, 12.5 or 25 mg. Availability varies between countries. Beyond the reduction of blood pressure, valsartan is indicated for use in several countries in patients with heart failure and in patients post myocardial infarction, based on the results of the large-scale Valsartan Heart Failure Trial and VALsartan In Acute myocardial iNfarcTion trials. Valsartan has also been shown, in the Valsartan Antihypertensive Long-term Evaluation trial, to reduce the risk of developing new-onset diabetes in hypertensive patients at high risk of cardiac events.

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. To study the contribution of angiotensin II in plaque vulnerability, we generated hypertensive hypercholesterolemic ApoE −/− mice with either normal or endogenously increased angiotensin II production (renovascular hypertension models). Hypertensive high angiotensin II ApoE −/− mice developed unstable plaques, whereas in hypertensive normal angiotensin II ApoE −/− mice plaques showed a stable phenotype. Vulnerable plaques from high angiotensin II ApoE −/− mice had thinner fibrous cap ( P P P −/− mice. Moreover, in mice with high angiotensin II, a skewed T helper type 1-like phenotype was observed. Splenocytes from high angiotensin II ApoE −/− mice produced significantly higher amounts of interferon (IFN)-γ than those from ApoE −/− mice with normal angiotensin II; secretion of IL4 and IL10 was not different. In addition, we provide evidence for a direct stimulating effect of angiotensin II on lymphocyte IFN-γ production. These findings suggest a new mechanism in plaque vulnerability demonstrating that angiotensin II, within the context of hypertension and hypercholesterolemia, independently from its hemodynamic effect behaves as a local modulator promoting the induction of vulnerable plaques probably via a T helper switch.

Background: The Vaisartan Antihypertensive Longterm Use evaluation (Value) study compares cardiovascular outcomes in 15,314 eligible patients from 31 countries randomized to valsartan or amlodipine-based treatment. Methods: The blood pressure (BP) trends are analyzed in 13,449 of value study patients who had baseline BP and 24 months BP and treatment data. Results: In a cohort of 12,570 patients, baseline 24 and 30 months BP, but 30 months treatment data, were available. Of 13,449 patients, 92% (n= 12,398) received antihypertensive therapy at baseline, the baseline BPwas 153,5/86,9 mm Hg in treated compared to 168,1,8/95,3 mm Hg in 1051 untreated patients. After 6 months both groups had indistinguishable BP values. At 12 months the BP decreased to 141,2/82,9 mm Hg (p

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.BackgroundDepending 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.MethodsTwenty healthy men were submitted to three levels of LBNP (0, -10, and -20mbar or 0, -7.5, and -15mm Hg) for 1hour according to a crossover design with a minimum of 2days between each level of LBNP. Ten subjects were randomly allocated to receive a placebo and ten others were treated with candesartan 16mg orally for 10days before and during the three levels of LBNP. Systemic and renal hemodynamics, renal sodium excretions, and the hormonal response were measured hourly before, during, and for 2hours after LBNP.ResultsDuring placebo, LBNP induced no change in systemic and renal hemodynamics, but sodium excretion decreased dose dependently with higher levels of LBNP. At -20 mbar, cumulative 3-hour sodium balance was negative at –2.3 ± 2.3mmol (mean ± SEM). With candesartan, mean blood pressure decreased (76 ± 1mm Hg vs. 83 ± 3mm Hg, candesartan vs. placebo, P < 0.05) and renal plasma flow increased (858 ± 52mL/min vs. 639 ± 36mL/min, candesartan vs. placebo, P < 0.05). Glomerular filtration rate (GFR) was not significantly higher with candesartan (127 ± 7mL/min in placebo vs. 144 ± 12mL/min in candesartan). No significant decrease in sodium and water excretion was found during LBNP in candesartan-treated subjects. At –20 mbar, the 3-hour cumulative sodium excretion was + 4.6 ± 1.4mmol in the candesartan group (P = 0.02 vs. placebo).ConclusionSelective blockade of angiotensin II type 1 (AT1) receptors with candesartan increases renal blood flow and prevents the antinatriuresis during sustained lower body negative pressure despite a modest decrease in blood pressure. These results thus provide interesting insights into potential benefits of AT1 receptor blockade in sodium-retaining states such as congestive heart failure.

Olmesartan medoxomil is an angiotensin II receptor antagonist that selectively and competitively inhibits the angiotensin II type 1 receptor.This article reviews the results of some key studies that assessed the efficacy and tolerability of olmesartan in patients with hypertension.Olmesartan has been investigated in several clinical studies. This article reports on data from 1 such study with a prospective, randomized, double-blind, placebo-controlled, parallel-group, dose-finding design in patients with mild to moderate hypertension (baseline mean sitting diastolic blood pressure, 100-114 mm Hg). The results from a meta-analysis of 7 randomized, double-blind, placebo-controlled studies are also presented.In the dose-finding study, 792 patients were randomized to olmesartan (2.5-80 mg) or placebo once daily, and changes were recorded in trough mean sitting diastolic and systolic blood pressures from baseline to the end of a 12-week treatment period. For the meta-analysis, 3055 patients were randomized to treatment; 2511 received olmesartan. In the dose-finding study as well as in the meta-analysis, olmesartan (2.5-80 mg once daily) produced a dose-dependent decrease in diastolic and systolic blood pressures, and at a dose of 10 to 80 mg showed significant superiority in reducing diastolic blood pressure over placebo (P0.05). The 20-mg dose was considered optimal, with a responder rate of 70%. Furthermore, in a 2-year study with 462 patients, olmesartan had a good safety profile and was well tolerated. The results of the clinical studies in3000 patients receiving olmesartan showed that the frequency and profile of adverse events with olmesartan were generally similar to those with placebo; the frequency of adverse events was not dose related. Olmesartan, with or without hydrochlorothiazide, was well tolerated over 2 years of treatment.

To observe the long-term (3 years) consumption of enriched potassium salt (KCL/NaCL = 1:1 by weight) on all causes mortality and target organ damage in Chinese living in nursing houses. The study was designed as a single blind prospective intervention. Participants were living in 22 nursing houses in northern China. The nursing houses were randomized into 2 groups: normal salt (control group) and enriched potassium salt (intervention group). The study salt was calculated and dispensed to each nursing house every 3 months. The six-time follow-up visits were carried out during 3 years. Items of the follow-up included questionnaire, physical examination, blood sample and spot urine collection. Data of people moving in or out and of death were collected. The mortality was calculated by observed person-year (p-y). Totally 1839 people (intervention group 1032, control 807) were analyzed. The baselines of age, SBP, DBP, and urinary sodium to potassium ratio (UNa/K) were not different between control and intervention groups. After using study salt for 3 years, the mean age, blood pressure and UNa/K are listed below. The proportion of impaired kidney function (ratio of microalbumin to creatinine> = 30 mg/g) was 26.8% and 16.2% for control and intervention group respectively (Chi square = 21.683, P

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). In 12 Wistar rats, the endothelin-1 level increased from 0.68 ± 0.13 to 1.19 ± 0.17 fmol/mL (mean ± SEM, P < .0001, paired data). Thus, acute volume load by rapid saline infusion increases plasma endothelin-1 levels. Vasoconstriction induced by endothelin-1 may counteract enhanced circumferential stretch created by volume expansion. Am J Hypertens 2003;16:1057-1061 @ 2003 American Journal of Hypertension, Ltd

Renal hemodynamic and tubular responses to salt in women using oral contraceptives.BackgroundThe use of oral contraceptives is associated with an increased risk of developing hypertension but the mechanisms of this hypertensive effect are not completely defined. The purpose of the present study was to assess prospectively the systemic and renal hemodynamic and tubular responses to salt in women taking oral contraceptives.MethodsTwenty seven young healthy normotensive women taking oral contraceptives containing monophasic combination of 30 μg ethynilestradiol and 150 μg desogestrel for>6 months were enrolled. All women were assigned at random to receive a low (40mmol/day) or a high (250mmol/day) sodium diet for 1 week on two consecutive menstrual cycles during the active oral contraceptive phase. At the end of each diet period, 24-hour ambulatory blood pressure, renal hemodynamics, sodium handling, and hormonal profile were measured.ResultsThe blood pressure response to salt on oral contraceptives was characterized by a salt-resistant pattern with a normal circadian rhythm. Salt loading results in an increase in glomerular filtration rate (GFR) (P < 0.05 vs. low salt), with no change in the renal plasma flow, thus leading to an increase in the filtration fraction (P < 0.05). At the tubular level, women on oral contraceptives responded to a low salt intake with a marked increased in proximal sodium conservation (P < 0.01 vs. high salt) and with an almost complete reabsorption of sodium reaching the distal tubule. After sodium loading, both the proximal and the distal reabsorption of sodium decreased significantly (P < 0.01).ConclusionThe use of oral contraceptives is not associated with an increased blood pressure response to salt in young normotensive women. However, oral contraceptives affect the renal hemodynamic response to salt, a high salt intake leading to an increase in GFR and filtration fraction. This effect is possibly mediated by the estrogen-induced activation of the renin-angiotensin system. Oral contraceptives also appear to increase the tubular responsiveness to changes in sodium intake. Taken together, these data point out evidence that synthetic sex steroids have a significant impact on renal function in women. The renal effects of oral contraceptives should be taken into account when managing young women with renal diseases.

Poor compliance with antihypertensive drug regimens is one recognized cause of inadequate blood pressure control. Compliance is difficult to measure, so poor adherence to treatment remains largely undiagnosed in clinical practice. When the therapeutic response to a drug is not the one expected, it is a major challenge for many physicians to decide whether the patient is a non-responder or a non-complier. Poor compliance is therefore often incorrectly interpreted as a lack of response to treatment. Not detecting non-compliance can lead to the wrong measures being taken. Electronic monitoring of compliance provides important longitudinal information about drug-intake behaviour that cannot be obtained in the clinic. Such monitoring can improve both compliance and blood pressure control, and help physicians to make more rational therapeutic decisions. A reliable assessment of compliance could have a great impact on medical costs by preventing unnecessary investigations or dose adaptations in patients who are not taking their drugs adequately, or potentially reducing the number of hospitalizations. Side-effects and lack of effectiveness are two frequent causes of poor compliance. The right choice of antihypertensive drug can therefore contribute to compliance. In this respect, it is important to find a drug regimen that is effective, long-acting and well tolerated. Long-acting antihypertensive drugs that provide good blood pressure control beyond the 24-h dosing period should perhaps be considered as drugs of choice in non-compliant patients with hypertension because they help to prevent the consequences of occasional drug omissions.

To investigate the signals governing routing of biologically active peptides to the regulated secretory pathway, we have expressed mutated and non-mutated proneuropeptide Y (ProNPY) in pituitary-derived AtT20 cells. The mutations were carried out on dibasic cleavage site and or ProNPY C-terminal sequence. Targeting to the regulated secretory pathway was studied using protein kinase A (8-BrcAMP), protein kinase C (phorbol myristate acetate) specific activators and protein synthesis inhibitor cycloheximide, and by pulse chase. The analysis of expressed peptides in cells and culture media indicated that: neuropeptide Y (NPY) and ProNPY were differently secreted, whilst NPY was exclusively secreted via regulatory pathway; ProNPY was secreted via regulated and constitutive-like secretory pathways. ProNPY secretion behaviour was not Proteolytic cleavage efficiency-dependent. The dibasic cleavage was essential for ProNPY and NPY cAMP-dependent regulated secretion and may have function as a retention signal.

SummaryHemodynamic forces play a critical role in the pathogenesis of atherosclerosis as evidenced by the focal nature of the disease. Oscillatory shear stress characterizes the hemodynamic environment of plaque-prone areas as opposed to unidirectional shear stress typical of plaque-free areas. These particular flow conditions modulate atherosclerosis-related genes. Tissue factor (TF) initiates blood coagulation, contributes to vascular remodeling, and is therefore a potential contributor in the development/progression of atherosclerosis. We investigated the effect of oscillatory and unidirectional flows on TF using an in vitro perfusion system. Human endothelial cells exposed for 24 h to oscillatory shear stress, significantly increased TF mRNA, and TF protein expression (1.5-and 1.75-fold, respectively, p

Objectives We have reported previously that 80 mg valsartan and 50 mg losartan provide less receptor blockade than 150 mg irbesartan in normotensive subjects. In this study we investigated the importance of drug dosing in mediating these differences by comparing the AT1-receptor blockade induced by 3 doses of valsartan with that obtained with 3 other antagonists at given doses. Methods Valsartan (80, 160, and 320 mg), 50 mg losartan, 150 mg irbesartan, and 8 mg candesartan were administered to 24 healthy subjects in a randomized, open-label, 3-period crossover study. All doses were given once daily for 8 days. The angiotensin II receptor blockade was assessed with two techniques, the reactive rise in plasma renin activity and an in vitro radioreceptor binding assay that quantified the displacement of angiotensin II by the blocking agents. Measurements were obtained before and 4 and 24 hours after drug intake on days 1 and 8. Results At 4 and 24 hours, valsartan induced a dose-dependent “blockade” of AT1 receptors. Compared with other antagonists, 80 mg valsartan and 50 mg losartan had a comparable profile. The 160-mg and 320-mg doses of valsartan blocked AT1 receptors at 4 hours by 80%, which was similar to the effect of 150 mg irbesartan. At trough, however, the valsartan-induced blockade was slightly less than that obtained with irbesartan. With use of plasma renin activity as a marker of receptor blockade, on day 8, 160 mg valsartan was equivalent to 150 mg irbesartan and 8 mg candesartan. Conclusions These results show that the differences in angiotensin II receptor blockade observed with the various AT1 antagonists are explained mainly by differences in dosing. When 160-mg or 320-mg doses were investigated, the effects of valsartan hardly differed from those obtained with recommended doses of irbesartan and candesartan. Clinical Pharmacology & Therapeutics (2002) 71, 68–76; doi: 10.1067/mcp.2002.121425

Renal and neurohormonal responses to increasing levels of lower body negative pressure in men.BackgroundThe stimulation of efferent renal sympathetic nerve activity induces sequential changes in renin secretion, sodium excretion, and renal hemodynamics that are proportional to the magnitude of the stimulation of sympathetic nerves. This study in men investigated the sequence of the changes in proximal and distal renal sodium handling, renal and systemic hemodynamics, as well as the hormonal profile occurring during a sustained activation of the sympathetic nervous system induced by various levels of lower body negative pressure (LBNP).MethodsTen healthy subjects were submitted to three levels of LBNP ranging between 0 and -22.5mm Hg for one hour according to a triple crossover design, with a minimum of five days between each level of LBNP. Systemic and renal hemodynamics, renal water and sodium handling (using the endogenous lithium clearance technique), and the neurohormonal profile were measured before, during, and after LBNP.ResultsLBNP (0 to -22.5mm Hg) induced an important hormonal response characterized by a significant stimulation of the sympathetic nervous system and gradual activations of the vasopressin and the renin-angiotensin systems. LBNP also gradually reduced water excretion and increased urinary osmolality. A significant decrease in sodium excretion was apparent only at -22.5mm Hg. It was independent of any change in the glomerular filtration rate and was mediated essentially by an increased sodium reabsorption in the proximal tubule (a significant decrease in lithium clearance, P < 0.05). No significant change in renal hemodynamics was found at the tested levels of LBNP. As observed experimentally, there appeared to be a clear sequence of responses to LBNP, the neurohormonal response occurring before the changes in water and sodium excretion, these latter preceding any change in renal hemodynamics.ConclusionsThese data show that the renal sodium retention developing during LBNP, and thus sympathetic nervous stimulation, is due mainly to an increase in sodium reabsorption by the proximal segments of the nephron. Our results in humans also confirm that, depending on its magnitude, LBNP leads to a step-by-step activation of neurohormonal, renal tubular, and renal hemodynamic responses.

Losartan has been shown to increase urinary uric acid excretion and hence to lower serum uric acid levels. The purposes of the present study were: (1) to evaluate the effects of losartan on serum uric acid in hypertensive patients with hyperuricemia and gout, (2) to compare the effects of losartan with those of irbesartan, another angiotensin II receptor antagonist and (3) to evaluate whether losartan 50 mg b.i.d. has a greater impact on serum uric acid levels than losartan 50 mg once a day.Thirteen hypertensive patients with hyperuricaemia and gout completed this prospective, randomized, double-blind, cross-over study. Uric acid-lowering drugs were stopped 3 weeks before the beginning of the study. Patients were randomized to receive either losartan 50 mg or irbesartan 150 mg once a day, for 4 weeks. During this phase, a placebo was given in the evening. After 4 weeks, the dose was increased to losartan 50 mg b.i.d., or irbesartan 150 mg b.i.d. for another 4 week period. Subsequently, the patients were switched to the alternative treatment modality. Enalapril (20 mg o.d.) was given during the run-in period and between the two treatment phases. Serum and urinary uric acid were measured at the beginning and at the end of each treatment phase.Our results show that losartan 50 mg once daily decreased serum uric acid levels from 538 +/- 26 to 491 +/- 20 micromol/l (P0.01). Irbesartan had no effect on serum uric acid. Increasing the dose of losartan from 50 mg o.d. to 50 mg twice a day, did not further decrease serum uric acid. This may in part be due to a low compliance to the evening dose as measured with an electronic device. Indeed, whatever the prescribed drug, the mean compliance of the evening dose was always significantly lower than that of the morning dose. The uricosuric effect of losartan appears to decrease with time when a new steady state of lower serum uric acid is reached.In contrast to irbesartan, losartan was uricosuric and decreased serum uric acid levels. Losartan 50 mg b.i.d. did not produce a greater fall in serum uric acid than losartan once a day. Losartan might be a useful therapeutic tool to control blood pressure and reduce serum uric acid levels in hypertensive patients with hyperuricaemia and gout.

Cardiac hypertrophy is common in hypertension but its development is influenced by angiotensin II, sodium intake aldosterone, and the time of day blood pressure (BP) is elevated. This study examined and compared cardiac hypertrophy in the 2 kidney-1 clip (2K-1C) and 1 kidney-1 clip (1K-1C) Goldblatt models of hypertension. Blood pressure was measured by telemetry in a selected group of rats. Rats were placed on a high (4%) or reduced (0.2%) salt intake and were given captopril (75 mg/kg per day) or losartan (10 mg/kg per day). Appropriate sham-operated and untreated controls were used. Cardiac hypertrophy was greater in the 1K-1C than in the 2K-1C model. Day and sleep BP were also higher. In the 2K-1C model BP was lower on the reduced salt intake and BP decreased with captopril in both reduced and high salt groups. Cardiac weight and index decreased significantly only in the reduced salt and captopril group and was less than the size before treatment. In the 1K-1C model captopril caused all BP measures to decrease in the reduced salt group but had no significant effect in the high salt group. Cardiac weight and index were reduced only in the reduced salt + captopril group and cardiac weight was less than the pretreatment control. Losartan had a similar effect in the 1K-1C model to that achieved with captopril. The responses achieved correlated in part with renin status and dependency level. There is no prime determinant of cardiac hypertrophy. Blood pressure, sodium intake, and hormonal status are all important. It is postulated that the common pathway may be alterations in cell composition that signal the nucleus to increase cell growth. Am J Hypertens 2001;14:914-920 © 2001 American Journal of Hypertension, Ltd

Background: Plasma free metanephrines are a more reliable analyte to measure than catecholamines for the biochemical diagnosis of pheochromocytomas. We hypothesized that the long persistence of total (sulfate-conjugated plus free) metanephrines in the blood might have a significant diagnostic value. Methods: We measured plasma concentrations of catecholamines and total metanephrines (sulfate-conjugated plus free forms) by HPLC with amperometric detection, and neuropeptide Y (NPY) by an amplified ELISA in seven patients before and after removal of their pheochromocytomas. The results for catecholamine, total metanephrines, and NPY in each patient were analyzed for up to 120 min, starting from the time of tumor vessel clamping. The persistence of analytes was quantified as the area under the concentration–time curve over 120 min. Results: On the basis of the upper reference limit for each variable, plasma free norepinephrine (NE) and epinephrine (E) concentrations were increased preoperatively in at least one sample in seven and six patients, respectively. Total normetanephrine (NMN) and metanephrine (MN) were increased in all samples in seven and six patients, respectively. NPY was increased 2- to 465-fold. After removal of the tumor, MN and NMN showed a higher average relative increase above the upper limit of the reference interval than NE and E (P = 0.05), whereas NPY was intermediate. The persistence of increased values was significantly shorter for catecholamines than for metanephrines. The half-life estimated by nonlinear regression was 12.3 ± 7.8 min for NPY. Significant correlations were observed among NE, E, NMN, MN, and NPY concentrations, but parent markers (E and MN or NE and NMN) did not appear significantly intercorrelated. Conclusions: A larger increase and a longer persistence of total metanephrines (reflecting predominantly sulfo-conjugated metanephrines) than catecholamines and NPY in plasma may contribute to their greater diagnostic accuracy in pheochromocytoma.

Background: The renal enzyme renin cleaves from the hepatic α2-globulin angiotensinogen angiotensin-(1–10) decapeptide [Ang-(1–10)], which is further metabolized to smaller peptides that help maintain cardiovascular homeostasis. The Ang-(1–7) heptapeptide has been reported to have several physiological effects, including natriuresis, diuresis, vasodilation, and release of vasopressin and prostaglandins.Methods: To investigate Ang-(1–7) in clinical settings, we developed a method to measure immunoreactive (ir-) Ang-(1–7) in 2 mL of human blood and to estimate plasma concentrations by correcting for the hematocrit. A sensitive and specific antiserum against Ang-(1–7) was raised in a rabbit. Human blood was collected in the presence of an inhibitor mixture including a renin inhibitor to prevent peptide generation in vitro. Ang-(1–7) was extracted into ethanol and purified on phenylsilylsilica. The peptide was quantified by radioimmunoassay. Increasing doses of Ang-(1–7) were infused into volunteers, and plasma concentrations of the peptide were measured.Results: The detection limit for plasma ir-Ang-(1–7) was 1 pmol/L. CVs for high and low blood concentrations were 4% and 20%, respectively, and between-assay CVs were 8% and 13%, respectively. Reference values for human plasma concentrations of ir-Ang-(1–7) were 1.0–9.5 pmol/L (median, 4.7 pmol/L) and increased linearly during infusion of increasing doses of Ang-(1–7).Conclusions: Reliable measurement of plasma ir-Ang-(1–7) is achieved with efficient inhibition of enzymes that generate or metabolize Ang-(1–7) after blood sampling, extraction in ethanol, and purification on phenylsilylsilica, and by use of a specific antiserum.

Mice lacking NPY Y1 receptors develop obesity without hyperphagia indicating increased energy storage and/or decreased energy expenditure. Then, we investigated glucose utilization in these animals at the onset of obesity. Fasted NPY Y1 knockouts showed hyperinsulinemia associated with increased whole body and adipose tissue glucose utilization and glycogen synthesis but normal glycolysis. Since leptin modulates NPY actions, we studied whether the lack of NPY Y1 receptor affected leptin-mediated regulation of glucose metabolism. Leptin infusion normalized hyperinsulinemia and glucose turnover. These results suggest a possible mechanism for the development of obesity without hyperphagia via dysfunction in regulatory loops involving NPY, leptin and insulin.

Neuropeptide Y (NPY) regulates neurotransmitter release through activation of the Y2 receptor subtype. We have recently characterized a human glioblastoma cell line, LN319, that expresses exclusively NPY Y2 receptors and have demonstrated that NPY triggers transient decreases in cAMP and increases in intracellular calcium responses. The present study was designed to further characterize calcium signalling by NPY and bradykinin (BK) in LN319 cells. Both agonists elevated free intracellular calcium ([Ca(2+)](i)) without soliciting calcium influx. NPY appeared to activate two distinct signalling cascades that liberate calcium from thapsigargin- and ryanodine-insensitive compartments. One pathway proceeded through phospholipase C (PLC)-dependent phosphatidylinositol turnover, while the other triggered calcium release through a so far unidentified mediator. Part of the response was sensitive to pertussis toxin (PTX) under conditions where the toxin totally abolished the NPY-mediated effects on cAMP. The calcium release induced by BK on the other hand was largely PTX-insensitive, PLC-dependent, and from both thapsigargin- and ryanodine-sensitive stores. Following stimulation with NPY, subsequent [Ca(2+)](i) responses to NPY were strongly depressed. Partial heterologous desensitization occurred, when BK was used as the first agonist, whereas NPY had no effect on a subsequent stimulation with BK. These data suggest that NPY-induced calcium mobilization in LN319 cells involves two different G proteins and signalling mediators, and a hitherto unidentified calcium compartment. Homologous desensitization of NPY signalling might be explained by receptor-G protein uncoupling, while heterologous desensitization by BK could be the result of either transient depletion or inhibition of a mediator in the calcium signalling cascades activated by NPY.

Incomplete compliance is one of several possible causes of uncontrolled hypertension. Yet, non-compliance remains largely unrecognized and is falsely interpreted as treatment resistance, because it is difficult to confirm or exclude objectively. The goal of this study was to evaluate the potential benefits of electronic monitoring of drug compliance in the management of patients with resistant hypertension.Forty-one hypertensive patients resistant to a three-drug regimen (average blood pressure 156/ 106 +/- 23/11 mmHg, mean +/- SD) were studied prospectively. They were informed that for the next 2 months, their presently prescribed drugs would be provided in electronic monitors, without any change in treatment, so as to provide the treating physician with a measure of their compliance. Thereafter, patients were offered the possibility of prolonging the monitoring of compliance for another 2 month period, during which treatment was adapted if necessary.Monitoring of compliance alone was associated with a significant improvement of blood pressure at 2 months (145/97 +/- 20/15 mmHg, P0.01). During monitoring, blood pressure was normalized (systolic140 mmHg or diastolic90 mmHg) in one-third of the patients and insufficient compliance was unmasked in another 20%. When analysed according to tertiles of compliance, patients with the lowest compliance exhibited significantly higher achieved diastolic blood pressures (P = 0.04). In 30 patients, compliance was monitored up to 4 months and drug therapy was adapted whenever necessary. In these patients, a further significant decrease in blood pressure was obtained (from 150/100 +/- 18/15 to 143/94 +/- 22/11 mmHg, P = 0.04/0.02).These results suggest that objective monitoring of compliance using electronic devices may be a useful step in the management of patients with refractory hypertension, as it enables physicians to take rational decisions based on reliable and objective data of drug compliance and hence to improve blood pressure control.

This is a personal historical account relating the events that led to the first application of angiotensin inhibition (either by ACE inhibitors or by angiotensin receptor blockade) to the investigation of the pathogenesis and treatment of hypertension, ischemic heart disease, and heart failure. Included are animal experiments, clinical observations, and the earliest clinical experimental studies that helped define some of the detrimental effects of angiotensin II and the beneficial hemodynamic results of its inhibition, which have been subsequently corroborated and amplified by large randomized outcome trials.

Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca(2+)/calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.

OBJECTIVES: Renal tubular sodium handling was measured in healthy subjects submitted to acute and chronic salt-repletion/salt-depletion protocols. The goal was to compare the changes in proximal and distal sodium handling induced by the two procedures using the lithium clearance technique. METHODS: In nine subjects, acute salt loading was obtained with a 2 h infusion of isotonic saline, and salt depletion was induced with a low-salt diet and furosemide. In the chronic protocol, 15 subjects randomly received a low-, a regular- and a high-sodium diet for 1 week. In both protocols, renal and systemic haemodynamics and urinary electrolyte excretion were measured after an acute water load. In the chronic study, sodium handling was also determined, based on 12 h day- and night-time urine collections. RESULTS: The acute and chronic protocols induced comparable changes in sodium excretion, renal haemodynamics and hormonal responses. Yet, the relative contribution of the proximal and distal nephrons to sodium excretion in response to salt loading and depletion differed in the two protocols. Acutely, subjects appeared to regulate sodium balance mainly by the distal nephron, with little contribution of the proximal tubule. In contrast, in the chronic protocol, changes in sodium reabsorption could be measured both in the proximal and distal nephrons. Acute water loading was an important confounding factor which increased sodium excretion by reducing proximal sodium reabsorption. This interference of water was particularly marked in salt-depleted subjects. CONCLUSION: Acute and chronic salt loading/salt depletion protocols investigate different renal mechanisms of control of sodium balance. The endogenous lithium clearance technique is a reliable method to assess proximal sodium reabsorption in humans. However, to investigate sodium handling in diseases such as hypertension, lithium should be measured preferably on 24 h or overnight urine collections to avoid the confounding influence of water.

Background —Local pulse pressure (PP) is an independent determinant of carotid artery wall thickness, stronger than mean blood pressure (BP). The present study was designed to assess whether a β-adrenoceptor antagonist–based or an ACE inhibitor–based treatment was able to reduce carotid artery wall hypertrophy through a reduction in carotid PP rather than by lowering mean BP and whether the influence of local PP reduction could also be detected at the site of a muscular artery, the radial artery. Methods and Results —Ninety-eight essential hypertensive patients were randomized to 9 months of double-blind treatment with either celiprolol or enalapril. Arterial parameters were determined with high-resolution echo-tracking systems. PP was measured locally with applanation tonometry and independently of mean BP. After 9 months of treatment, mean BP, carotid PP, and intimal-medial thickness (IMT) decreased significantly, with no difference between the 2 groups. The reduction in carotid PP but not in mean BP was a major independent determinant of the reduction in carotid IMT. Radial artery IMT and PP decreased significantly with both treatments. However, the reduction in radial artery IMT was not related to the changes in radial artery PP. Conclusions —The regression of carotid artery wall hypertrophy during long-term antihypertensive treatment was dependent on the reduction in local PP rather than on the lowering of mean BP. The effect of PP lowering on IMT reduction was observed at the site of an elastic artery but not at the site of a muscular artery.

The objective of this study was to determine whether cardiac hypertrophy in hypertensive rats could be reduced and normalized by intermittent reduction of blood pressure, and to determine whether left ventricular hypertrophy was related to 24 h workload or peak blood pressure responses.Hypertension was created by the application of a 0.20 mm clip to the left renal artery. Blood pressure response was monitored using a telemetry system (Data Science International). Blood pressure was reduced for varying periods of the day by giving different doses of captopril in the drinking water or by intra-peritoneal administration. Cardiac size was measured by weighing the ventricles and factoring by the body weight to obtain a cardiac index.Captopril 75 mg/kg per day and 25 mg/kg per day in the drinking water administered between 1800 and 2000 h lowered the 24 h blood pressure more than captopril 15 mg/kg per day or 5 mg/kg per day intra-peritoneally given at 0800 h. Captopril 75 mg/kg per day and captopril 15 mg/kg per day (intra-peritoneal) caused regression of cardiac hypertrophy whereas the other doses had no effect The best predictor of the cardiac hypertrophy response was the blood pressure between 0800 and 1200 h (i.e. the sleeping blood pressure). Twenty-four hour cardiac work did not correlate with the response.Cardiac hypertrophy can be reduced by intermittent treatment of elevated blood pressure. It is also caused by intermittent elevation of blood pressure. It appears that the crucial factor is when these alterations in blood pressure take place. An elevated blood pressure during the sleeping hours causes left ventricular hypertrophy, whereas a normal blood pressure during the sleeping hours allows reduction. It is suggested that acute wall stress is the signal to initiate the events that lead to cardiac hypertrophy but this only occurs if the hormonal milieu is appropriate.

Atherosclerotic plaques preferentially develop in regions exposed to a low mean shear stress and cyclic reversal of flow direction (oscillatory flow). This contrasts with plaque-free zones where endothelial cells are exposed to unidirectional flow. Previous works from our laboratory using a unique experimental flow system demonstrated the existence of a differential regulation of endothelial nitric oxide synthase (NOS III) gene expression by unidirectional and oscillatory flow patterns. We further studied the possible mechanisms responsible for selective unresponsiveness of NOS III gene regulation to oscillatory flow. The results obtained demonstrate that (i) induction of the activity of the 1600-base-pair NOS III gene promoter by unidirectional and oscillatory shear stress is modulated by similar mechanisms that involve NF-κB activation, but do not involve Ras-dependent MAP kinase activation, and (ii) the lack of induction of NOS III gene regulation by oscillatory shear stress can be attributed to the activation of a yet unidentified negative cis -acting element present in the NOS III gene.

Low adherence of hypertensive patients to prescribed antihypertensive medications is a major cause of unsatisfactory blood pressure control. Several factors might have a negative influence on long-term adherence with treatment, for example a poor patient-doctor relationship and the presence of drug-induced side-effects. Various strategies are recommended in order to improve patient compliance, including educational programmes, self-measurement of blood pressure and monitoring of compliance. All methods may be helpful to encourage the patient to take the prescribed medication(s) regularly. It is also important to find a drug regimen which is at the same time simple, efficacious and well tolerated. Finally it should be pointed out that the motivation of the patient to follow the treatment requires the doctor to be equally motivated.

Aims The performance of the experimental paradigm of angiotensin challenges with continuous non-invasive blood pressure measurement was evaluated. Angiotensin dose–response relationships were characterized, along with the influence of clinical covariates. The stability of angiotensin-induced peaks and the variability of the angiotensin doses were assessed. Finally, the predictive value of studies based on angiotensin challenges to determine drug doses effective in therapeutics was evaluated. Methods The data were gathered from 13 clinical studies on nine angiotensin II receptor antagonists, one ACE inhibitor and one dual ACE-NEP inhibitor, using Finapres® for measuring the response to exogenous angiotensin challenges. Modelling of angiotensin dose–response curves and determination of the inter and intrasubject variability were performed by nonlinear regression (NONMEM). The different sources of variations in angiotensin I and II doses and angiotensin-induced peaks were evaluated by analyses of variance. The dose of ACE inhibitors and angiotensin II receptor antagonists inhibiting blood pressure increase by at least 75%, as measured by this method, was chosen for comparison with the labelled starting dose. Results Angiotensin challenges exhibited a clear dose–response relationship which can be characterized both by an Emax or a log linear model. The log linear model gave an average systolic/diastolic response of 24±6/20±5 mmHg for a unit dose of 1 μg of angiotensin II equivalents, and an increase of 6/6 mmHg for each doubling of the dose. The angiotensin ED50 calculated values were 0.67 μg for systolic and 0.84 μg for diastolic blood pressure. The angiotensin doses for eliciting a given response and the angiotensin induced peaks were fairly constant between period and subject, but vary significantly between studies. Based on an inhibition of blood pressure by 75%, the agreement was good between the doses of ACE inhibitors and angiotensin receptor antagonists predicted from studies using the methodology of angiotensin challenges and the doses shown to be clinically efficacious, in spite of high intersubject and intrasubject variabilities. Conclusions This experimental method represents a valid surrogate for the therapeutic target and a useful tool for the pharmacokinetic and pharmacodynamic profiling of drugs acting on the renin-angiotensin system.

Non-invasive ambulatory blood pressure monitoring (ABPM) is particularly useful for assessing the efficacy of antihypertensive drugs. It provides a large number of blood pressure readings during daytime as well as night-time, which results in a more precise assessment of prevailing blood pressure than can be obtained from sporadic measurements taken by a doctor. Because of this greater precision ABPM reduces the number of patients required in clinical trials to demonstrate differences. It also allows one to define precisely the profile of the blood-pressure-lowering effect of a given drug. Placebo has little effect on ABPM. Thus, a placebo phase is not absolutely necessary. ABPM makes it possible to evaluate the efficacy of an antihypertensive medication by analysing data for patients with a placebo effect separately from data for true responders to the medication. In everyday practice ABPM helps one to detect among patients with hypertension refractory to treatment those who exhibit controlled blood pressures outside the medical environment, thus permitting one to avoid an unnecessary step-up of treatment. In addition ABPM can also help one to identify symptoms occurring during antihypertensive treatment that are related to excessive drug-induced changes in blood pressure.

The aim of this study was to assess the relationship between the plaque burden of nonstenotic coronary artery segments and the wall thickness of peripheral arteries using intracoronary and transcutaneous ultrasound imaging, respectively. Intracoronary ultrasound (CVIS, 3.5 Fr) was performed in 27 patients undergoing percutaneous transluminal coronary angioplasty. Carotid arteries were imaged by B-mode ultrasound with semiautomatic edge detection and radial arteries by high resolution A-mode echotracking (NIUS 2). Quantitative measurements included coronary artery intima-media cross-sectional area (IM(CSA)) and cross-sectional narrowing (CSN), as well as intima-media thickness (IMT) and lumen radius (r) of the common carotid and the radial arteries. Intima-media thickness was increased in coronary, carotid, and radial arteries. Coronary arteries had an IM(CSA) of 7.7 +/- 2.5 mm(2) and a CSN of 24% +/- 8%. Despite this moderate plaque burden, lumen area was preserved (12.3 +/- 4.2 mm(2)) because of compensatory enlargement of coronary arteries. Right and left carotid and right radial arteries had an IMT of 575 +/- 78 microm, 570 +/- 129 microm, and 328 +/- 61 microm, respectively. There was no correlation between coronary IM(CSA) and carotid IMT (r = 0.07) or radial IMT (r = 0.02), and there was no correlation between coronary CSN and carotid IMT/r (r = 0.12), or radial IMT/r (r = 0.25). In conclusion, in these patients with symptomatic ischemic disease no relationship between IMT of the coronary arteries and IMT of carotid or radial arteries was found. Although increasingly popular, IMT of peripheral arteries may be of limited value as surrogate marker for the severity of coronary artery disease. Cathet. Cardiovasc. Intervent. 48:12-17, 1999.

Abstract —Connexin43 (Cx43), the predominant gap junction protein in vessels and heart, is involved in the control of cell-to-cell communication and is thought to modulate the contractility of the vascular wall and the electrical coupling of cardiac myocytes. We have investigated the effects of arterial hypertension induced by inhibition of nitric oxide synthase on the expression of Cx43 in aorta and heart as well as on the distensibility of the carotid artery. Administration of 0.4 g/L N G -nitro- l -arginine methyl ester (L-NAME) to rats in their drinking water for 4 weeks increased intra-arterial mean blood pressure, wall thickness of aorta and carotid artery (25%), and heart weight (17%). Analysis of heart mRNA demonstrated increased expression of the fetal skeletal α-actin and of atrial natriuretic peptide but not of Cx43. In contrast, Cx43 mRNA and protein were decreased by 50% in the aortas of L-NAME–treated rats that did not show increased carotid distensibility. Because these data contrasted with those obtained in the 2-kidney, 1 clip model of rat hypertension, which is characterized by increased arterial distensibility and Cx43 expression in aorta, we investigated by Western blot analysis the posttranslational modifications of Cx43. We found that Cx43 was more phosphorylated in the aorta of 2-kidney, 1 clip rats than in that of L-NAME or control rats, which indicated a differential regulation of Cx43 in different models of hypertension. The data suggest that the cell-to-cell communication mediated by Cx43 channels may help regulate the elasticity of the vascular wall.

Abstract —The purpose of this study was to determine the effect of dietary Mg deficiency (80 mg/kg versus control diet: 960 mg/kg) on blood pressure and mechanical properties of the rat common carotid artery. The internal diameter and intra-arterial pressure of carotid artery were measured continuously with an echo-tracking device. At 19 weeks, systolic, diastolic, and mean blood pressures were higher in Mg-deficient rats. Histological examination showed an increase in cross-sectional area, intima-media thickness, and media-to-lumen ratio in carotid artery of Mg-deficient rats. Mg deficiency did not modify the arterial distensibility–blood pressure curve. At mean blood pressure, arterial distensibility was significantly less in 19-week-old rats than in 5-week-old rats of both control and Mg-deficient groups. A significant interaction between age and Mg-deficient diet on arterial distensibility ( P

Abstract —Use of angiotensin (Ang) II AT 1 receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II–induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% ( P

Professor Hans Rudolf BrunnerBorn 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. He has been involved in the development of drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. He was among the first medical practitioners to introduce the use of angiotensin-converting enzyme inhibitors in the treatment of hypertension and congestive heart failure. Professor Brunner has been a medical advisor to Speedel since 1999.