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Biomedical subjects

M Azizi

Publications and source records attributed to M Azizi.

At least 37 records · Page 2Linked to original sources
PubMed2000

Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans.

The aim of this study was to assess the antihypertensive activity of fasidotril, a dual inhibitor of neprilysin (NEP) and angiotensin I-converting enzyme (ACE), in various models of hypertension in rats (spontaneously hypertensive rats [SHR]; renovascular Goldblatt 2-kidney, 1-clip rats; and deoxycorticosterone acetate [DOCA]-salt hypertensive rats) and in patients with mild-to-moderate essential hypertension. Fasidotril treatment (100 mg/kg PO twice daily for 3 weeks) resulted in a progressive and sustained decrease in systolic blood pressure (-20 to -30 mm Hg) in SHR and Goldblatt rats compared with vehicle-treated rats and prevented the progressive rise in blood pressure in DOCA-salt hypertensive rats. After a 4-week placebo run-in period, 57 patients with essential hypertension were included in a randomized double-blind, placebo-controlled, parallel-group study and received orally either fasidotril (100 mg twice daily) or placebo for 6 weeks. Blood pressure was measured during the 6 hours after the first intake and then at trough (12 hours after the last intake) on days 7, 28, and 42. The first dose of fasidotril had no significant effect on blood pressure. After 42 days, compared with placebo, fasidotril lowered supine systolic and diastolic blood pressures by 7.4/5.4 mm Hg and standing blood pressure by 7.6/6.8 mm Hg. Fasidotril, a dual NEP/ACE inhibitor, was an effective oral antihypertensive agent during chronic treatment in high-renin renovascular rats, normal-renin SHR, and low-renin DOCA-salt hypertensive rats and in patients with essential hypertension.

Alanine↗
PubMed2000

In vitro and in vivo inhibition of the 2 active sites of ACE by omapatrilat, a vasopeptidase inhibitor.

The vasopeptidase inhibitor omapatrilat inhibits both neutral endopeptidase and angiotensin-converting enzyme (ACE). The in vitro and in vivo inhibitory potency of omapatrilat and the specific ACE inhibitor fosinopril toward the 2 active sites of ACE (called N- and C-domains) was investigated with the use of 3 substrates: angiotensin I, which is equally cleaved by the 2 ACE domains; hippuryl-histidyl-leucine, specific synthetic substrate of the C-domain in high- salt conditions; and a newly synthesized specific substrate of the N-domain designed by acetylating the lysine residue of AcSDKP. In vitro, omapatrilat was 5 times more potent than fosinoprilat in inhibiting angiotensin I hydrolysis. Omapatrilat inhibited similarly both N- and C-domain hydrolysis, whereas fosinoprilat was slightly more specific for the N-domain. The in vivo selective inhibitory potency of single oral doses of 10 mg omapatrilat and 20 mg fosinopril were investigated in a double-blind, placebo-controlled, cross-over study in 9 mildly sodium-depleted normotensive subjects. In accordance with the in vitro results, fosinopril appeared to be more specific for the N-domain than the C-domain in vivo, since plasma and urine AcSDKP concentrations were significantly higher than those observed with omapatrilat. This study shows that it is possible to assess separately in vitro and in vivo the selectivity of ACE or ACE/neutral endopeptidase inhibitors. A differential selectivity may explain some peculiar properties observed with some ACE inhibitors.

Adolescent↗
PubMed2000

Influence of the M235T polymorphism of human angiotensinogen (AGT) on plasma AGT and renin concentrations after ethinylestradiol administration.

The T235 allele of the angiotensinogen (AGT) gene is associated with plasma AGT concentration and pregnancy-induced hypertension. The aim of this study was to compare changes in the circulating renin-angiotensin system after short-term (2 days) and repeated (7 days) administration of 50 microg ethinylestradiol (EE) in homozygous normotensive men (TT and MM). After repeated EE administration, renin stimulation was induced by a single oral dose of 40 mg furosemide, followed by 50 mg captopril, 12 h later. The short-term administration of EE did not induce a significant differential genotype-dependent increase in AGT concentration. In the 7-day study, TT subjects had higher peak plasma AGT concentrations than MM subjects. The more pronounced AGT increase in TT subjects resulted in similar plasma renin activity at a lower plasma active renin concentration, with a higher plasma renin activity/active renin ratio. The difference between genotypes in renin secretion resulted in readjustment of angiotensins production. In conclusion, the T235 allele of the AGT gene is associated with greater stimulation of AGT secretion in plasma after EE administration. In the short-term, complete readjustment of the circulating renin-angiotensin system occurs, through a decrease in renin release, which blunts the effects of the increase in AGT concentration.

Adolescent↗
PubMed2000

Dehydroepiandrosterone replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects.

Dehydroepiandrosterone (DHEA; 50 and 25 mg) and placebo tablets were orally administered daily to 24 healthy aging men and women (67.8 +/- 4.3 yr) for 8 days according to a balanced incomplete block design. Nine blood tests on both the first and eighth days allowed the measurement of DHEA, its sulfate DHEAS, and metabolites: testosterone, 5alpha-androstan-3alpha,17beta-diol glucuronide, estradiol, and estrone. Relatively low background levels of DHEA(S) were observed, and with the reestablishment of "young" levels, four important results were obtained. 1) Blood DHEA had an apparent terminal half-life of more than 20 h, the same order of magnitude as that of blood DHEAS, a result explainable by back-hydrolysis of the large amount of DHEAS formed after oral administration of DHEA, a mechanism providing long-lived unconjugated DHEA and metabolites. 2) The metabolic conversion of DHEAS to DHEA was significantly greater in women than in men. 3) No accumulation of steroids was observed. 4) No worrying transformation to androgen and estrogen was recorded; indeed, the limited increased estradiol in aged women could be predicted to be beneficial. These results suggested that daily oral administration of DHEA (25/50 mg) is safe in elderly subjects. The 50-mg dose was chosen for a 1 yr, double blind, placebo-controlled trial of daily oral administration of DHEA in 60- to 80-yr-old individuals (DHEAge).

Aged↗
PubMed2000

[Can the degree of renal artery stenosis be automatically quantified?].

The objective of the reported study is to validate a computer system, QUASAR, dedicated to the quantification of renal artery stenoses. This system estimates automatically the reference diameter and calculates the minimum diameter to compute a degree of stenosis. A hundred and eighty images of atheromatous stenoses between 10% and 80% were collected from two French independent protocols. For the 49 images of the EMMA protocol, the results from QUASAR were compared with the visual estimation of an initial investigator and with the results from a reference method based on a panel of fixe experienced experts. For the 131 images of the ASTARTE protocol, the results from QUASAR were compared with those from a semi-automatic quantification system and with those from a system based on densitometric analysis. The present work validates QUASAR in a population of narrow atheromatous stenoses (> 50%). In the context of the EMMA protocol, QUASAR is not significantly different from the mean of the fixe experts. It is unbiased and more precise than the estimation of a single investigator. In the context of the ASTARTE protocol, there is no significant difference between the three methods for the stenoses higher than 50%, however, globally, QUASAR surestimates significantly (up to 10%) the degree of stenosis.

Aged↗
PubMed1999

A solid-phase immobilized epitope immunoassay (SPIE-IA) permitting very sensitive and specific measurement of angiotensin II in plasma.

We have developed a new enzyme immunometric assay for angiotensin II (AII) based on SPIE-IA technology (solid-phase immobilized epitope-immunoassay). A monoclonal antibody with optimal properties (mAb3 131) was selected from a series of 19 anti-AII mAbs. The mAb had to be purified from ascitic fluid in a specific manner in order to remove endogenous AII from the antibody-binding sites. We established a sensitive (minimum detectable concentration 0.5 pg/ml) and precise (CV below 15% in the 2-100 pg/ml range) SPIE-IA. Using different AII-related peptides, we observed that this new assay has a specificity profile that compares favourably with the corresponding competitive immunoassay. We have used the assay to measure AII in 42 plasma samples, and demonstrated a good correlation with values obtained using a commercial radioimmunoassay. Assay specificity was supported by HPLC fractionation experiments, confirming the absence of interference induced by endogenous AII-related products.

Acetylcholinesterase↗
PubMed1999

Pharmacodynamic effects of dual neutral endopeptidase-angiotensin-converting enzyme inhibition versus angiotensin-converting enzyme inhibition in humans.

BACKGROUND: There is currently no clear evidence that dual neutral endopeptidase-angiotensin-converting enzyme inhibitors have effects on angiotensin-converting enzyme, renin, or blood pressure that are different from specific angiotensin-converting enzyme inhibitors in humans. METHODS AND RESULTS: In a double-blind, placebo-controlled crossover study, single oral doses of the dual neutral endopeptidase-angiotensin-converting enzyme inhibitor, 10 mg BMS-186716 and the angiotensin-converting enzyme inhibitor fosinopril (20 mg) were administered to 9 normotensive subjects with induced mild sodium depletion. Values for area under the time curve from 0 to 24 hours [AUC(0-24)] for the plasma angiotensin II/angiotensin I ratio and for angiotensin II were similar for 10 mg BMS-186716 and 20 mg fosinopril. Plasma atrial natriuretic peptide decreased significantly after 20 mg fosinopril (9+/-3 pg/mL; P < .05 versus 10 mg BMS-186716 and placebo) compared with 10 mg BMS-186716 (16+/-5 pg/mL) and placebo (16+/-5 pg/mL). BMS-186716, 10 mg, significantly increased urinary atrial natriuretic peptide from baseline by 2+/-1.3-fold (P < .05 versus placebo and 20 mg fosinopril). AUC(0-24) of plasma active renin did not differ significantly between 10 mg BMS-186716 (3898+/-333 pg x h x mL(-1)) and 20 mg fosinopril (4383+/-302 pg x h x mL(-1); difference not significant). Both drugs decreased blood pressure, but the AUC(0-24) of the changes in mean blood pressure differed significantly from placebo (79+/-84 mm Hg x h) only for 20 mg fosinopril (181+/-6 mm Hg x h; P < .05) but not for 10 mg BMS-186716 (118+/-7 mmHg x h). CONCLUSIONS: In this model, single oral doses of 10 mg BMS-186716 and 20 mg fosinopril induced similar 24-hour in vivo angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, increased urinary atrial natriuretic peptide and blunted the expected decrease in plasma atrial natriuretic peptide caused by angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, did not inhibit plasma active renin rise compared with 20 mg fosinopril. A single oral dose of 10 mg BMS-186716 had a shorter blood pressure-lowering effect than 20 mg fosinopril.

Administration, Oral↗
PubMed1999

A retrospective study of Angle Class I malocclusions treated orthodontically without extractions using two palatal expansion methods.

The correction and relapse of mandibular anterior crowding was evaluated in a population of 58 patients with Angle Class I malocclusion who were treated orthodontically without extraction of permanent teeth. The subjects were retrospectively evaluated from records taken before treatment, posttreatment, and postretention. The postretention period averaged 8 years (minimum of 4 and maximum of 20 years). All cases in Groups A and B were given orthopedic treatment to develop the maxillary apical base in the transverse and anteroposterior planes. Group A was treated with expansion of the inner bow of the face bow appliance (Kloehn), and Group B was treated with the Haas palatal expansion appliance. Both groups were then treated orthodontically with tandem mechanics. The response variables measured were: overbite, overjet, intercanine distance, intermolar distance, and irregularity index. Study groups A and B were not significantly different for subject age, retention, or postretention time. Moreover, the groups did not show significant difference for any of the response variables before treatment. However, there was a statistically significant difference in the treatment times (P =.0133). A statistically significant treatment effect was observed for most response variables in the groups. Overbite, overjet, and irregularity index were significantly reduced, intermolar distance was significantly increased, and intercanine distance showed no significant change in Groups A and B. In the postretention period, there was a tendency for variables to change slightly toward their before treatment values but no compromise of orthodontic correction was noted. The irregularity index in Group A was corrected from 4.8 to 1.1 mm and remained at 1.1 mm in the postretention period. The irregularity index in Group B was corrected from 5.1 to 1.2 mm (P =.0001) and changed slightly from 1. 2 to 1.7 mm (P =.0540) in the postretention period. We concluded that mandibular incisors tended to become more crowded postretention. However, in contrast to previous reports, we calculate this relapse to be small. Neither before treatment nor posttreatment variables were predictive of relapse.

Adolescent↗
PubMed1999

Premarital sexual, child rearing, and family attitudes of Iranian men and women in the United States and in Iran.

Sexual, child rearing, and family attitudes of 160 Iranian immigrants in the United States (61 men, 99 women) and 97 Iranians (55 men, 42 women) in Iran were compared. Iranians in the United States in general, and women in particular, compared with their counterparts in Iran, expressed more permissive attitudes toward premarital sex and sex education, more tolerance toward homosexuality, and a greater acceptance of marital dissolution. Iranians in both countries assigned a high value to the maternal role and to family loyalty but did not endorse unrestricted freedom for youngsters. Influences of attitudinal disparity on interpersonal and family relationships are discussed, and implications for marriage counseling and family therapy are suggested.

Acculturation↗
PubMed1999

Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and losartan.

BACKGROUND: The variability of the blood pressure response to blockade of the angiotensin II type 1 receptor is influenced by renin status and pharmacokinetics and pharmacokinetic-pharmacodynamic interactions. OBJECTIVE: To compare the pharmacokinetic-pharmacodynamic interactions of two doses of an ester prodrug of a noncompetitive angiotensin II type 1 receptor antagonist, candesartan cilexetil, at 8 and 16 mg, with those of the reference angiotenisn II type 1 receptor blocker, losartan, at the standard dose (50 mg), in a human model that controls renin status. DESIGN AND METHODS: In a double-blind placebo-controlled crossover study, we compared the effects on renin and mean blood pressure over 24 h of single oral doses of candesartan cilexetil at 8 and 16 mg and losartan at 50 mg in 16 sodium-depleted normotensive subjects. RESULTS: The area under the curve (0-24 h) for plasma active renin did not differ significantly between 8 mg candesartan cilexetil and 50 mg losartan, but was significantly higher for 16 than for 8 mg candesartan cilexetil or for 50 mg losartan. The area under the curve (0-24 h) for the fall in mean blood pressure with 16 mg candesartan cilexetil (-197 +/- 96 mmHg/h) was significantly greater than that for placebo (-112 +/- 81 mmHg/h; P< 0.05) but the difference was not statistically significant compared with either 8 mg candesartan cilexetil (-158 +/- 95 mmHg/h) or 50 mg losartan (-144 +/- 66 mmHg/h). The area under the curve (0-24 h) for the fall in mean blood pressure did not significantly differ between 8 mg candesartan cilexetil, 50 mg losartan and placebo. The area under the curve (0-24 h) for plasma active renin was significantly correlated to that for plasma levels of the active metabolite of losartan, EXP 3174 (r = 0.65, n = 16, P< 0.01). No such correlation was detected for each single dose of candesartan cilexetil but a dose-response relationship was present when both doses were combined. CONCLUSIONS: The pharmacodynamic effects of a single oral dose of 16 mg candesartan cilexetil are greater than those of 50 mg losartan and 8 mg candesartan cilexetil. The variability in the pharmacokinetic-pharmacodynamic interaction is less pronounced for candesartan than for EXP 3174, which could result in reduced variability of the blood pressure effects in patients.

Administration, Oral↗
PubMed1999

Renal and metabolic clearance of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) during angiotensin-converting enzyme inhibition in humans.

We investigated the contributions of angiotensin-converting enzyme (ACE) and glomerular filtration to creating the new metabolic balance of the hemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) that occurs during acute and chronic ACE inhibition in healthy subjects. We also studied the effect of chronic renal failure on the plasma concentration of AcSDKP during long-term ACE inhibitor (ACEI) treatment or in its absence. In healthy subjects, a single oral dose of 50 mg captopril (n=32) and a 7-day administration of 50 mg captopril BID (n=10) resulted in a respective 42-fold (range, 18- to 265-fold) and 34-fold (range, 24-fold to 45-fold) increase in the ratio of urinary AcSDKP to creatinine accompanied by a 4-fold (range, 2- to 6.8-fold) and 4.8-fold (range, 2.6- to 11.8-fold) increase in plasma AcSDKP levels. Changes in plasma AcSDKP and in vitro ACE activity over time showed an intermittent reactivation of ACE between each captopril dose. In subjects with chronic renal failure (creatinine clearance<60 mL/min per 1.73 m2), plasma AcSDKP levels were 22 times higher (95% confidence interval, 15 to 33) in the ACEI group (n=35) than the control group (n=23); in subjects with normal renal function, they were only 4.1 times higher (95% confidence interval, 3.2 to 5.3) in the ACEI group (n=19) than the non-ACEI group (n=21). Renal failure itself led to a slight increase in plasma AcSDKP concentration. In conclusion, intermittent reactivation of ACE between doses of an ACEI is the major mechanism accounting for the lack of major AcSDKP accumulation during chronic ACE inhibition in subjects with normal renal function.

Adult↗
PubMed1999

[Combined blockade of the renin-angiotensin system].

In view of the internal counter-regulation mechanisms of the renin-angiotensin system (RAS), complete blockade would not seem to be possible if only one of its components is targeted. Instead of increasing the dosage of an angiotensin converting enzyme (ACE) inhibitor or that of an angiotensin II antagonist (AA), blockade of the system at two different levels by neutralising the internal counter-regulation mechanism could provide more effective blockade and, therefore, more pronounced biological effects. For this reason, the authors undertook two studies in a model of mild salt depletion of a normotensive subject, which showed additive effects on the lowering of the blood pressure and renin secretion during combined administration of captopril and losartan, then enalapril and losartan. There was no additive effect on plasma aldosterone levels. The administration of the ACE inhibitor neutralised the expected increases in plasma Angiotensin II values due to the losartan. All combinations of ACE inhibitor and AA were tested in spontaneous hypertensive rats using a dosage scale from 1 to 30, the results of which showed the beneficial effects of combined blockade on left ventricular mass and the deleterious effects on renal function when blockade of the RAS is too complete. Based on the results obtained in normotensive subjects and homogeneous groups of hypertensive animals, the authors conclude that low doses of an AA and of an ACE inhibitor is more effective in lowering the blood pressure than higher doses of each drug administered separately. How can these results be applied clinically in hypertension and cardiac failure? The choice between increasing the dose of each of the two drugs or the association of low doses of both drugs will depend more on the tolerance of each therapeutic strategy than on the efficacy. The choice between the two strategies will also depend on the demonstration of consequences specific to each modality of inhibition of the system, especially with respect to the effects of accumulation of bradykinin and to stimulation of type 2 receptors. The additive effects of a combined treatment should be validated by repeated administration in hypertensive patients.

Angiotensin II↗
PubMed1999

[Audit of the treatment of arterial hypertension in specialized consultation].

The objective of the study was to estimate the control of elevated blood pressure (BP) among patients regularly followed-up and to analyse physicians attitudes in patients having uncontrolled BP. Two hundred and fifty-eight consecutive patients (mean age 56 years, 58% of males) with essential hypertension attending the outpatient department of a specialised hypertension clinic, having at least a 6-month follow-up at the clinic and at least 3 prior visits, were included in the study. Twelve different physicians were in charge of these patients. Data were collected [1] from the structured computerised record called ARTEMIS and [2] from a structured questionnaire filled up by the physician after each visit, where he/she explained the reasons for his/her decisions. BP was measured by a nurse using an automatic device (oscillometric method) and then by a physician using a mercury sphygmomanometer. During follow-up, mean physician's BP fell from 179/107 to 148/91 mmHg and mean nurse BP fell from 164/96 to 143/83 mmHg. Percentages of patients having a controlled hypertension (BP < 140/90 mmHg) were 27% (physician's BP) and 45% (nurse BP). Physicians did not modify treatment in 59% of patients among whom they measured a BP > or = 140/90 mmHg. The 3 main reasons given by physicians for not modifying treatment were: BP controlled when using other BP measurement methods (nurse, home or ambulatory BP), 44%; BP control considered as satisfactory, 29%; systolic hypertension in the elderly, 8%. The person (physician or nurse) who measures BP and the measurement method have dramatic consequences on BP control level. Reasons for not modifying treatment in uncontrolled patients (physician's BP > or = 140/90 mmHg) were based on opinions rather than evidence, for example when isolated systolic hypertension in the elderly is concerned.

Adult↗
PubMed1999

Effect of angiotensin-converting enzyme inhibition on plasma, urine, and tissue concentrations of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro in rats.

The hemoregulatory peptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP) has been reported to accumulate in plasma and urine after the oral administration of angiotensin-converting enzyme (ACE) inhibitors in humans. It is unknown whether such an accumulation also occurs in tissues. We administered captopril (3, 10, or 30 mg/kg) orally for 2 weeks to Wistar rats. In a second experiment, captopril (10 mg/kg) was administered for 9 days and was followed by a 1-h i.v. infusion of either AcSDKP (0.1 or 2 mg/kg) or saline on day 9. Captopril alone dose-dependently increased plasma AcSDKP by a factor of 3 to 5 and urine AcSDKP by a factor of 3. It slightly increased renal and pulmonary AcSDKP concentrations but did not affect AcSDKP concentrations in bone marrow and spleen. The combination of AcSDKP (2 mg/kg) and captopril gave very high AcSDKP concentrations in plasma and urine and increases in AcSDKP concentration by factors of 27 in kidney, 5.5 in lung, and 6.9 in the extracellular fraction of bone marrow. In contrast, no change was observed in the AcSDKP concentration in spleen and in the intracellular fraction of bone marrow. In conclusion, during chronic ACE inhibition in rats, AcSDKP levels slightly increased in organs with high ACE contents. No such increase occurred in hematopoietic organs. AcSDKP had to be combined with captopril to significantly increase its concentration in tissues other than the spleen. The possibility of pharmacologically increasing AcSDKP levels in the extracellular fraction of bone marrow may be of value for protecting hematopoietic cells from the toxicity of cancer chemotherapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

The hemoregulatory peptide N-acetyl-ser-asp-lys-pro impairs angiotensin I-induced contractions in rat aorta.

The hemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is degraded by ACE. This study was designed to examine the effect of Ac-SDKP on the contractions to angiotensin I. Experiments were performed on rat aortic rings with endothelium exposed to nitro-L-arginine. Ac-SDKP (10 and 100 microM) significantly augmented angiotensin I ED20 (from 2.0+/-0.4 to 4.2+/-1.0 and 5.0+/-0.9 nM) and ED50 (from 4.3+/-0.7 to 8.6+/-1.0 and 10.7+/-1.3 nM, respectively), but did not alter its maximal response. The contractions to angiotensin II were not affected by Ac-SDKP. No degradation of exogenous Ac-SDKP nor detectable release of endogenous Ac-SDKP were observed in the incubation medium. These results suggest that Ac-SDKP impairs angiotensin I response by inhibiting ACE and subsequent angiotensin II formation.

Angiotensin I↗
PubMed1997

Synergistic effects of ACE inhibition and Ang II antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats.

BACKGROUND: Blockade of type 1 angiotensin (Ang) II receptors combined with ACE inhibition may amplify the efficacy of the renin-angiotensin system blockade because ACE inhibitors do not completely and permanently suppress Ang II production. METHODS AND RESULTS: Enalapril or losartan (1, 3, 10, and 30 mg/kg) or their combination was administered for 2 to 4 weeks to spontaneously hypertensive rats. The combination of low doses of each agent induced greater reductions in blood pressure (BP) and left ventricular weight/body weight (LVW/ BW) ratio than monotherapy with the same or higher doses. When approximately equipotent regimens of enalapril, losartan, and their combination, as judged by BP fall, were compared, there were similar increases in plasma and renal renin and in plasma Ang-(1-7) and Ang I and similar reductions in plasma angiotensinogen. Enalapril alone reduced plasma Ang II levels, and losartan alone increased Ang II levels. The combination of enalapril with losartan prevented or reduced the increase in Ang II levels observed with losartan alone. CONCLUSIONS: These findings show that the synergistic interaction between the effects of low doses of enalapril and losartan on BP and LVW/BW ratio is due to more effective inhibition of the renin-angiotensin system by their combination than by either agent alone. When both drugs are given together, the ACE inhibitor-induced fall in plasma Ang II results in modulation of the Ang II antagonist-induced reactive rise in Ang II, thereby lowering the plasma Ang II concentration, which competes with the antagonist for the Ang II receptors.

Angiotensin Receptor Antagonists↗