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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

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 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.

Hans R BrunnerLausanne University, Lausanne and Medizinische Poliklik, Universitaetsspital, Basel, SwitzerlandAbstract: 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. The drug was well tolerated with a similar adverse event profile to placebo. In patients with type 2 diabetes, olmesartan medoxomil reduced renal vascular resistance, increased renal perfusion, and reduced oxidative stress. In several large, randomized, double-blind trials, olmesartan medoxomil 20 mg has been shown to be significantly more effective, in terms of primary endpoints, than recommended doses of losartan, valsartan, irbesartan, or candesartan cilexetil, and to provide better 24 h BP protection. Olmesartan medoxomil was at least as effective as amlodipine, felodipine and atenolol, and significantly more effective than captopril. The efficacy of olmesartan medoxomil in reducing cardiovascular risk beyond BP reduction is currently being investigated in trials involving patients at high risk due to atherosclerosis or type 2 diabetes. Keywords: olmesartan medoxomil, hypertension, angiotensin receptor antagonist

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.

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.

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.

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

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.

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.

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.

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.

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

The acute effects of various vasopressor agents on the diameter of the common carotid artery were studied in halothane-anesthetized normotensive rats. The animals were infused intravenously for 60 min with equipressor doses of angiotensin II (10 ng/min), the alpha1-stimulant methoxamine (5 microg/min), lysine vasopressin (5 mU/min), or vehicle. The arterial diameter was measured by using a high-resolution ultrasonic echo-tracking device. The three vasoconstrictors increased the carotid artery diameter, but this effect was significantly more pronounced with lysine vasopressin. Even a nonpressor dose of lysine vasopressin (1 mU/min) caused a significant increase in the arterial diameter. The lysine vasopressin-induced vasodilatation could be prevented by the administration of d(CH2)5Tyr(Me)AVP (10 microg, i.v.), a selective V1-vasopressinergic receptor antagonist. These data therefore suggest that a short-term increase in blood pressure induces in rats a distention of the carotid artery. The increase in arterial diameter seems to involve an active mechanism with lysine vasopressin caused by the stimulation of V1-vasopressinergic receptors.

Objective To compare the acute and sustained renal hemodynamic effects on hypertensive patients of 100 mg irbesartan and 20 mg enalapril each once daily. Patients Twenty patients (aged 35-70 years) with uncomplicated, mild-to-moderate essential hypertension and normal serum creatinine levels completed this study. Study design After random allocation to treatment (n=10 per group), administration schedule (morning or evening) was determined by further random allocation, with crossover of schedules after 6 weeks' therapy. Treatment and administration assignments were double-blind. Twenty-four-hour ambulatory blood pressure was monitored before and after 6 and 12 weeks of therapy. Renal hemodynamics were determined on the first day of drug administration and 12 and 24 h after the last dose during chronic treatment. Results Administration of each antihypertensive agent induced a renal vasodilatation with no significant change in glomerular filtration rate. However, the time course appeared to differ: irbesartan had no significant acute effect 4 h after the first dose, but during chronic administration a renal vasodilatory response was found 12 and 24 h after the dose; enalapril was effective acutely and 12 h after administration, but no residual effect was found 24 h after the dose. Both antihypertensive agents lowered mean ambulatory blood pressure effectively, with no significant difference between treatments or between administration schedules (morning versus evening). Conclusions Irbesartan and enalapril have comparable effects on blood pressure and renal hemodynamics in hypertensive patients with normal renal functioning. However, the time profiles of the renal effects appear to differ, which might be important for long-term renoprotective effects.

MDL 100,240, a dual inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), was administered intravenously to two panels of four healthy males in a four-period, dose-increasing (0, 1.56, 6.25, and 25 mg, and 0, 3.13, 12.5, and 50 mg, respectively) double-blind, placebo-controlled study. Plasma ACE activity and blood-pressure response to exogenous angiotensin I and angiotensin II i.v. challenges and safety and tolerance were assessed over a 24-h period. MDL 100,240 induced a rapid, dose-related, and sustained inhibition of ACE (>70% over 24 h at doses > or =12.5 mg). The time integral of ACE inhibition was related to the dose but with near-maximal values already attained at doses > or =12.5 mg. Systolic and diastolic blood-pressure responses to exogenous angiotensin I challenges were inhibited in a dose-dependent fashion, whereas the effects of angiotensin II remained unaffected. Mean supine blood pressure decreased transiently (3 h) at doses > or =3.125 mg and < or =24 h with the 25- and 50-mg doses, but not significantly. MDL 100,240 was well tolerated. In healthy subjects, MDL 100,240 exerts a dose-dependent and long-lasting ACE-blocking activity, also expressed by the inhibition of the pressor responses to exogenous angiotensin I challenges. The baroreceptor reflex, assessed by the response to exogenous angiotensin II challenge, remains unaltered.

This article reviews the pharmacokinetics and pharmacodynamics of angiotensin II (AII) receptor antagonists (AIIRA), with particular focus on the novel compound irbesartan. Irbesartan has the highest oral bioavailability in its class (60% to 80%) and, unlike valsartan, its absorption is not affected by food. Irbesartan displays linear, dose related pharmacokinetics and, with the exception of tasosartan's active metabolite, has the longest elimination half-life of the AIIRA (11 to 15 h). Irbesartan exhibits the lowest amount of protein binding, limiting its potential for drug interactions. No drug interactions with irbesartan have been identified. Unlike losartan, candesartan, and tasosartan, irbesartan does not require biotransformation for AII blockade. The pharmacokinetics of irbesartan are not altered in renally or hepatically impaired patients, probably owing to excretion characteristic by both biliary and renal routes, or by differences in gender or age. Within its therapeutic dose range (150 to 300 mg), irbesartan shows sustained, dose related blockade 24 h after dosing. Irbesartan lowers blood pressure in a dose related manner up to 300 mg daily. Some clear differences in pharmacokinetics and pharmacodynamics exist among the AIIRA, which may have clinical implications.

The pharmacokinetic and pharmacodynamic properties of nonpeptide angiotensin antagonists in humans are reviewed in this paper. Representatives of this new therapeutic class share common features: lipophilia, intermediate bioavailability, high affinity for plasma proteins and liver metabolism; some have active metabolites. Angiotensin II antagonists block the blood pressure response to exogenous angiotensin II in healthy volunteers, decrease baseline blood pressure in both normal and hypertensive patients, produce a marked rise in plasma renin activity and endogenous angiotensin II and increase renal blood flow without altering glomerular filtration rate. These effects are dose-dependent, but their time course varies between the drugs owing to pharmacokinetic and pharmacodynamic differences. Additionally, the extent of blood pressure reduction is dependent on physiological factors such as sodium and water balance. The characterisation of their pharmacokinetic-pharmacodynamic relationships deserves further refinement for designing optimal therapeutic regimens and proposing dosage adaptations in specific conditions.

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. On the basis of their chemical structures, ARBs use different binding pockets in the receptor, which are associated with differences in dissociation times and, in most cases, apparently insurmountable antagonism. The physicochemical differences between ARBs also manifest in different tissue penetration, including passage through the blood-brain barrier. Differences in binding mode and tissue penetration are also associated with differences in pharmacokinetic profile, particularly duration of action. Although generally highly specific for angiotensin II type 1 receptors, some ARBs, particularly telmisartan, are partial agonists at peroxisome proliferator-activated receptor-γ. All of these properties are comprehensively reviewed in this article. Although there is general consensus that a continuous receptor blockade over a 24-hour period is desirable, the clinical relevance of other pharmacological differences between individual ARBs remains to be assessed.

SUMMARY 1 The availability of orally active specific angiotensin receptor antagonists (AT1 antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin-angiotensin system in the pathogenesis of cardiovascular disease. 2 The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin-converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin-angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs. 3 The most common side effect of ACE inhibitors, dry cough, does not occur with AT1 antagonists, which confirms the long-held view that this untoward effect of the ACE inhibitors is due to renin-angiotensin-independent mechanisms. 4 Long-term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic armamentarium.

The renin-angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. Antagonizing angiotensin (Ang) II at the receptor site may produce fewer side effects than inhibition of the promiscuous converting enzyme. The present study was designed to assess in healthy human subjects the effect of LRB081, a new orally active AT1-receptor antagonist, on the pressor action of exogenous Ang II. At the same time, plasma hormones and drug levels were monitored. At 1-week intervals and in a double-blind randomized fashion, 8 male volunteers received three doses of LRB081 (10, 40, and 80 mg) and placebo. Blood pressure (BP) was measured at a finger by photoplethysmograph. The peak BP response to intravenous injection of a standard dose of Ang II was determined before and for < or = 24 h after administration of an oral dose of LRB081 or placebo. After drug administration, the blood BP response to Ang II was expressed in percent of the response before drug administration. At the same time, plasma renin activity (PRA), Ang II, aldosterone, catecholamine (radioassays), and drug levels (by high-performance liquid chromatography) were monitored. After LRB081 administration, a dose dependent inhibition of the BP response to Ang II was observed. Maximal inhibition of the systolic BP response was 54 +/- 3 (mean +/- SEM), 63 +/- 2, and 93 +/- 1% with 10, 40, and 80 mg LRB081, respectively. The time to peak was 3 h for 6 subjects and 4 and 6 h for 2 others. Preliminary plasma half-life (t1/2) was calculated at 2 h. With the highest dose, the inhibition remained significant for 24 h (31 +/- 5%, p < 0.05). Maximal BP-blocking effect and maximal plasma drug level coincided, suggesting that the unmetabolized LRB081 is responsible for the antagonistic effect. PRA and Ang II increased dose dependently after LRB081 intake. Aldosterone, epinephrine, and norepinephrine concentrations remained unchanged. No clinically significant adverse reaction was observed during the study. LRB081 is a well-tolerated, orally active, potent, and long-acting Ang II receptor antagonist. Unlike in the case of losartan, no active metabolite of LRB081 has been shown to be responsible for the main effects.

Renal effects of angiotensin II receptor blockade in normotensive subjects. Several new non-peptide, orally active, angiotensin II receptor antagonists have recently been developed which enable to block the renin-angiotensin system at the AT 1 receptor site. In contrast to angiotensin converting enzyme (ACE) inhibitors, these antagonists do not interfere with the metabolism of kinins. The effect of these agents on renal function may thus potentialy differ from those of ACE inhibitors. Therefore, the renal pharmacology of various angiotensin II receptor antagonists has been examined in normotensive subjects. In normotensive subjects, losartan and irbesartan have been shown to have no effect on glomerular filtration rate and to induce either no change or a modest increase in renal blood flow. These results were confirmed thereafter in hypertensive patients where losartan produced a renal vasodilation with no change in glomerular filtration. In healthy subjects, both losartan and irbesartan induce an acute increase in urinary sodium excretion. The natriuretic response to losartan is proportionally more important during salt-depletion. In contrast to other angiotensin II receptor antagonists, losartan has a unique property to increase uric acid excretion. In this paper we show that this property is due to the potent inhibitory effect of the parent compound of losartan on the urate/anion transport in the human renal proximal tubule.

Abstract We undertook this cross-sectional study to compare the mechanical behavior and postischemic response of the radial artery of 15 newly diagnosed hypercholesterolemic patients with those of 15 age- and sex-matched normocholesterolemic control subjects and 21 hypercholesterolemic patients treated for 2 years with an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (simvastatin, 10 to 20 mg/d). At the time of the study total cholesterol levels were at 7.9±0.2, 4.9±0.2, and 6.0±0.3 mmol/L in the three groups, respectively (mean±SEM, P P

This study was undertaken to assess in conscious normotensive rats the effects of beta-adrenoceptor stimulation on plasma neuropeptide Y (NPY) levels. Wistar rats were subjected to adrenal demedullation on the right side and were either adrenalectomized or sham-operated on the left side. Eleven days later, the conscious rats were infused i.v. for 30 min with either isoproterenol (10 ng/min) or its vehicle. Plasma NPY levels were significantly lower (23.8 +/- 2.6 pM, means +/- S.E.M., n = 12, P0.01) in vehicle-treated medullectomized rats than in corresponding sham-operated controls (36.7 +/- 4.1 pM, n = 12). The medullectomized rats infused with isoproterenol showed plasma NPY levels (36.7 +/- 3.3 pM, n = 11) comparable to those of sham-operated rats having received the vehicle. These data therefore demonstrate that plasma NPY levels are lower in rats without adrenal medulla and that in these animals isoproterenol increases NPY release, most likely by activating pre-synaptic beta-adrenoceptors.

Introduction: The evaluation of a new drug in normotensive volunteers provides important pharmacodynamic and pharmacokinetic information as long as the compound has a specific mechanism of action which can be evaluated in healthy subjects as well as in patients. The purpose of the present paper is to discuss the results that have been obtained in normal volunteers with the specific angiotensin II receptor antagonist, losartan potassium Dose-finding: Over the last few years, studies in normotensive subjects have demonstrated that the minimal dose of losartan that produces maximal efficacy is 40-80 mg. Losartan has a long duration of action and its ability to produce a sustained blockade of the renin–angiotensin system is due almost exclusively to the active metabolite E3174 Hormonal effects: Angiotensin II receptor blockade with losartan induces an expected increase in plasma renin activity and plasma angiotensin II levels. A decrease in plasma aldosterone levels has been found only with a high dose of losartan (120 mg) Renal and blood pressure effects: In normotensive subjects, losartan has little or no effect on blood pressure unless the subjects are markedly salt-depleted. Losartan causes no change in the glomerular filtration rate and either no modification or only a slight increase in renal blood flow. Losartan significantly increases urinary sodium excretion, however, and surprisingly produces a transient rise in urinary potassium excretion. Finally, losartan increases uric acid excretion and lowers plasma uric acid levels Conclusions: These results suggest that losartan is an effective angiotensin II receptor antagonist in normal subjects. Its safety and clinical efficacy in hypertensive patients will be addressed in large clinical trials

Transient inhibition of angiotensinogen production in transgenic mice bearing an antisense angiotensinogen gene. Angiotensinogen is the precursor of the biologically active hormone angiotensin II. Enzyme kinetic parameters suggest that concentrations of plasma angiotensinogen are rate limiting in the renin reaction. It is therefore assumed that a decrease in angiotensinogen synthesis in vivo would result in a decrease in angiotensin II plasma levels and then of blood pressure. To test this hypothesis, we generated a transgenic mouse line that carries an inducible antisense angiotensinogen gene. Transient inhibition of angiotensinogen synthesis could be demonstrated in these transgenic animals. However, the amounts of liver angiotensinogen message and plasma angiotensinogen concentrations were rapidly back to levels observed in control animals.

Abstract We investigated the short-term and sustained hormonal and renal effects of angiotensin II (Ang II) receptor blockade in normotensive healthy volunteers. Twenty-four subjects maintained on a fixed sodium diet were randomized to receive for 8 days a placebo or 10 or 50 mg doses of the Ang II antagonist irbesartan (SR 47436, BMS 186295) according to a double-blind, parallel group design. Plasma renin activity, plasma immunoreactive Ang II and aldosterone levels, blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 8 hours after the first and eighth administration of each dose of irbesartan or placebo. Ang II receptor blockade with irbesartan induced a dose-dependent compensatory increase in plasma renin activity and plasma angiotensin levels and a significant decrease in plasma aldosterone levels. The compensatory rise in plasma renin activity and Ang II levels was more pronounced on day 8, reflecting a long duration of the blocking effect of irbesartan. Irbesartan induced small changes in blood pressure and did not significantly modify renal blood flow and glomerular filtration rate. However, a significant decrease in filtration fraction was observed during receptor blockade on days 1 and 8. The tubular effects of irbesartan were characterized by a dose-dependent increase in sodium and chloride excretions. Interestingly, the cumulative natriuretic response to Ang II receptor blockade was similar on days 1 and 8, suggesting that in these subjects, renal Ang II receptors are not blocked over 24 hours during repeated administration even though this antagonist has a long duration of action (t 1/2 of 15 to 17 hours). Irbesartan had no significant effect on urinary potassium and uric acid excretions on days 1 and 8. Together, these results demonstrate that in healthy subjects the Ang II receptor antagonist irbesartan decreases filtration fraction and promotes urinary sodium excretion without affecting urinary uric acid excretion and that these renal hemodynamic and tubular effects are maintained during a repeated 8-day administration.

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. The HR was assessed from electrocardiographic recordings obtained annually throughout the study period. The primary end point was the interval to cardiac events. After adjustment for confounders, the hazard ratio of the composite cardiac primary end point for a 10-beats/min of the baseline HR increment was 1.16 (95% confidence interval 1.12 to 1.20). Compared to the lowest HR quintile, the adjusted hazard ratio in the highest quintile was 1.73 (95% confidence interval 1.46 to 2.04). Compared to the pooled lower quintiles of baseline HR, the annual incidence of primary end point in the top baseline quintile was greater in each of the 5 study years (all p

1. In patients treated with angiotensin-converting enzyme inhibitors, kinin-related effects have been postulated repeatedly, but information on changes in plasma kinin levels in these patients is sparse. Difficulties in the measurement of plasma kinins account for this, at least in part. 2. The main purpose of the present study was to investigate, in normal human subjects, the effect of the angiotensin-converting enzyme inhibitor quinapril on plasma kinins. 3. High-affinity antisera (Kd 4. After an oral quinapril dose of 20 mg, we found, in nine healthy men, an increase in plasma kinin levels from 16.1 ± 1.9 pmol/1 (mean ± SEM) to 22.4 ± 2.8, 23.9 ± 23, 29.1 ± 4.7 (P < 0.05) and 203 ± 4.2 pmol/1 at 2, 4, 8 and 24 h after drug intake, respectively. 5. Thus, in normal subjects treated with angiotensin-converting enzyme inhibitor plasma levels of B2-receptor stimulating kinins increase.

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide and, therefore, a defective endothelial function could be involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure. To investigate endothelial function in humans in vivo, agents such as acetylcholine, a short-acting stimulator of the release of endothelium-derived nitric oxide, has been used. Conversely, N -mono-methyl- l -arginine, a specific inhibitor of nitric oxide synthesis from l -arginine, has recently been shown to decrease blood flow during infusion into the brachial artery of healthy volunteers (control subjects) by inhibiting the basal release of nitric oxide. Consistent with experimental studies, the blood flow response to acetylcholine is blunted in patients with chronic heart failure compared with healthy age-matched volunteers. In contrast, the decrease in blood flow induced by N -mono-methyl- l -arginine appears to be exaggerated in congestive heart failure. The blood flow response to nitroglycerin or sodium nitroprusside, endothelium-independent vasodilators, is usually preserved in patients with chronic, nonedematous heart failure, indicating a normal response of the vascular smooth muscle of resistance vessels to exogenous nitric oxide. In contrast, the dilator response of the radial artery diameter to nitroglycerin and flow-dependent dilation is impaired in patients with chronic heart failure, indicating that the abnormal flow-mediated relaxation of large arteries may be caused by both endothelial and structural abnormalities. Thus impaired endothelium-dependent dilation of peripheral resistance vessels emerges in chronic heart failure, suggesting a reduced release of nitric oxide on stimulation; the latter (defective) mechanism may be involved in the impaired vasodilator capacity in the peripheral circulation (e.g., during exercise). In contrast, the basal release of nitric oxide from endothelium of resistance vessels appears to be preserved or may even be enhanced and may play an important compensatory role in chronic heart failure during resting conditions by antagonizing neurohumoral vasoconstrictor forces.

This series of studies was designed to assess in normal volunteers the relationships between various doses (5, 10, 20, 40, 80, and 120 mg) of the orally active angiotensin II antagonist losartan (DuP 753, MK-954) and their inhibitory effect on the pressure response to a given bolus of angiotensin I or II. It was found that the maximal inhibitory effect was reached with a dose of 80 mg. The minimal dose necessary for maximal efficacy would therefore be expected to be between 40 and 80 mg. The effect lasted for more than 24 h and was related almost exclusively to the circulating levels of the active metabolite EXP3174. It remains to be demonstrated in hypertensive patients that the same dose relationship holds for the antihypertensive effect, but preliminary data already suggest that this is the case. Am J Hypertens 1992;5:243S-246S

METHODOLOGY: A new non-invasive ultrasonic device was developed to characterize the biomechanical properties of medium and large peripheral arteries. Simultaneous recordings of internal diameter and blood pressure over the whole cardiac cycle are used to establish compliance-pressure curves. Since blood pressure, which is an inherent co-determinant of arterial compliance, is taken into account, the comparison of arteries from patients with markedly different blood pressures has become possible. In a first study, the effects of three different antihypertensive drugs (20 mg lisinopril, 100 mg atenolol, 20 mg nitrendipine administered once a day) on arterial compliance and distensibility were investigated in young healthy volunteers. RESULTS: After 8 days of treatment, lisinopril induced a significant increase in arterial compliance. Subsequently, we compared the mechanical behaviour of arteries from newly diagnosed hypertensive patients (radial artery) or the carotid artery from spontaneously hypertensive rats (SHR) with that of corresponding arteries in normotensive counterparts. No decrease in arterial distensibility was found in the hypertensive groups over the measured blood pressure range. This result is not totally consistent with previous in vitro or in situ localized studies. Methodological differences, the absence of blood flow and/or denervation may partly explain these contradictory results. Finally, we tested the effects of hydralazine (5 mg/day) and captopril (25 mg/day), administered for 6 weeks in drinking water, on the behaviour of the carotid arteries of 16-week-old SHR. The two drugs effectively reduced blood pressure while shifting the distensibility-pressure curves upward in comparison to the placebo-treated animals, suggesting an improvement in arterial compliance. CONCLUSIONS: While hypertension does not itself appear to alter the elastic behaviour of large peripheral arteries, antihypertensive treatment may increase the compliance of these blood vessels.

The aim of this study was to investigate the relationships between plasma concentrations of losartan, an orally active angiotensin II inhibitor, its active metabolite EXP3174, and angiotensin II blockade. Six healthy subjects received single oral doses of 40, 80, or 120 mg losartan and placebo at 1-week intervals in a crossover study. Angiotensin II blockade was assessed by the blood pressure response to exogenous angiotensin II before and after losartan administration. EXP3174 reached higher plasma concentrations and was eliminated more slowly than its parent compound; its levels paralleled the profile of angiotensin II blockade closer than losartan. Inhibition of the pressure response was dose dependent. The Hill-shaped relationship between response and EXP3174 concentration (or time-integrated variables) approached a plateau with 80 mg. The dose-dependent increase in plasma renin and angiotensin II exhibited a considerable individual scatter. We conclude that losartan produces a dose-dependent, effective angiotensin II blockade that is largely determined by the active metabolite EXP3174. Clinical Pharmacology and Therapeutics (1992) 51, 513–521; doi:10.1038/clpt.1992.56

The study of vasoactive agents in man often requires accurate measurement of short-lasting changes in blood pressure. Using a noninvasive photoplethysmographic device (Finapres), the authors investigated in normotensive subjects whether rapid increases in blood pressure can be assessed precisely by monitoring finger blood pressure continuously. Six volunteers were studied on two consecutive days. On the first day, increasing doses of angiotensin I were injected intravenously with the aim to find a test dose which raised systolic blood pressure by 25 to 40 mm Hg. After oral administration of a placebo, the same test dose was injected repeatedly over the next 24 hours. On the second day, the subjects took either 6.25 (n = 3) or 25 mg (n = 3) captopril PO and the serial administration of the test dose of angiotensin I was continued for the next 4 hours. After placebo intake there was a good reproducibility of the blood pressure response to angiotensin I with a coefficient of variation of 15 +/- 4.5% (Mean +/- SD, n = 6). Captopril caused a dose-dependent inhibition of the pressor effect of angiotensin I. These data indicate that noninvasive blood pressure monitoring at the finger represents a useful tool to study short-lasting blood pressure changes produced by vasoactive agents in man.

Cet article porte sur l'utilite clinique des dosages immunologiques en matiere de diagnostique des maladies cardiovasculaires. Pour cela des dosages de substances vasoactives telles que renines, angiotensine, aldosterone, vasopressine sont effectues

The present study was undertaken to assess in unanesthetized rats the effect of a kinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg-trifluoroacetic acid) on blood pressure, heart rate, and splanchnic nerve activity. The antagonist infused intra-arterially (50 micrograms/min) for 10 min had no blood pressure effect in control rats. It did, however, cause a significant increase in blood pressure in animals preinfused with a nonpressor dose of angiotensin II (1 ng/min i.v.) for 70 min. The antagonist-induced blood pressure rise was not associated with an increase in splanchnic nerve activity. Acute angiotensin-converting enzyme (ACE) inhibition with captopril (2.5 mg i.v.) had no influence on the pressor response to the kinin antagonist in angiotensin II-treated rats. These results obtained in conscious normotensive rats suggest that endogenous kinins participate in the control of blood pressure by attenuating the vasoconstrictor effect of angiotensin II. The involvement of kinin does not seem to be enhanced by acute ACE inhibition.

To compare the antihypertensive efficacy of olmesartan medoxomil with that of candesartan cilexetil after 1, 2 and 8 weeks of treatment.Randomised, double-blind, parallel-group study conducted at 44 centres in Germany, Poland and the Czech Republic.643 patients (aged 19-86 years) with mainly mild-to-moderate essential hypertension received active double-blind treatment.Following a 2-week placebo run-in, eligible patients were randomly assigned to receive olmesartan medoxomil 20mg (n = 319) or candesartan cilexetil 8mg (n = 324) once daily for 8 weeks.Changes from baseline in daytime, 24-hour and night-time diastolic (DBP) and systolic (SBP) blood pressures assessed by ambulatory blood pressure monitoring (ABPM), and changes from baseline in sitting cuff DBP and SBP.Mean decreases from baseline in daytime DBP by ABPM at weeks 1, 2 and 8 were 6.7, 8.4 and 9.3mm Hg, respectively, in the olmesartan medoxomil group compared with 5.3, 6.0 and 7.8mm Hg, respectively, in the candesartan cilexetil group. The between-group differences were significantly in favour of olmesartan medoxomil at all three timepoints (p/= 0.0126). Significant differences in favour of olmesartan medoxomil were also observed for mean 24-hour DBP and for mean daytime and 24-hour SBP by ABPM. Decreases from baseline in sitting cuff BP at trough were similar in the two groups (15-16mm Hg for DBP and 21mm Hg for SBP). Both treatments were well tolerated.Olmesartan medoxomil reduced daytime and 24-hour DBP and SBP, assessed by ABPM, more effectively than candesartan cilexetil at the doses tested. The majority of the treatment effect in both groups was seen after only 1 or 2 weeks of dosing, when the between-group differences were already statistically significant.