Effectiveness of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker on atrial natriuretic peptide.

The aim of this study was to evaluate the effectiveness of an angiotensin-converting enzyne inhibitor (ACEI, quinapril) or angiotensin II receptor blocker (ARB, candesartan) on atrial natriuretic peptide (ANP) activity in rats with hypertension induced by nitric oxide (NO) inhibition. ACEI and ARB have a number of pharmacologic effects, including blood pressure reduction, myocardial preservation, and an unknown effect in the circulation. The changes in ANP in NO inhibitor-induced hypertensive rats were evaluated in order to elucidate the interaction between ANP and NO in the regulation of blood pressure. Thirty-six rats were divided into 4 groups and administered the experimental agents for 8 weeks: group Control was given regular food (n=9), group N(G)-nitro-L-arginine (L-NNA) was administered L-NNA (25 mg. kg(-1). day(-1), n=9), group ACEI was administered L-NNA and quinapril (10 mg. kg(-1). day(-1), n=9), and group ARB was administered L-NNA and candesartan (10 mg. kg(-1). day(-1), n=9). Blood pressure, plasma ANP, atrial ANP, ANP mRNA, and ANP granules were measured. A significant elevation in blood pressure was observed in group L-NNA. However, there were no increases in plasma ANP (L-NNA: 138.8+/-64.4, Control: 86.7+/-36.4), ANP mRNA (L-NNA: 2.2+/-1.0, Control: 1.7+/-0.5) or ANP granules (L-NNA: 61.1+/-10.2, Control: 64.5+/-8.5). No increase in blood pressure was seen in groups ACEI and ARB. However, plasma ANP (ACEI: 1,392.3+/-1,034.4, ARB: 1,142.8+/-667.3), ANP mRNA (ACEI: 52.8+/-29.1, ARB: 42.9+/-21.2), and ANP granules (ACEI: 122.5+/-23.4, ARB: 136.3+/-33.2) increased significantly. NO inhibitor-induced hypertension caused no changes in ANP concentrations. However, the ACEI and ARB had a direct effect on the induction of ANP secretion. The findings suggest that ANP secretion is directly effected by ACEI and ARB, which seems to play a key role in lowering blood pressure, relieving heart failure symptoms, and preserving the myocardium.     

Rationale for the use of combination angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapy in heart failure.

BACKGROUND: The present multicenter study investigated whether the combination of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) is more beneficial for preventing left ventricular remodeling and suppressing neurohumoral factors than either ACEI or ARB alone. METHODS AND RESULTS: One hundred and six patients with mild-to-moderate congestive heart failure treated in 26 Japanese institutes were randomly assigned to the combination therapy or monotherapy. Changes in physical activity (New York Heart Association functional classes, Specific Activity Scale (SAS)), concentrations of neurohumoral factors (plasma renin activity, angiotensin II, aldosterone, and brain natriuretic peptide (BNP)), and cardiac function for 6 months were compared between the 2 groups. It was found that the combination therapy, which was administered at doses standard in Japan, increased the SAS score (4.5 +/- 1.5 to 4.9 +/- 1.5, p<0.05) and decreased the plasma BNP concentration (183 +/- 163 to 135 +/- 118 pg/ml, p<0.05). In contrast, there were no changes in SAS score (4.5 +/- 1.4 to 4.6 +/- 1.4, NS) or BNP concentration (156 +/- 157 to 151 +/- 185 pg/ml, NS) in the patients receiving monotherapy. CONCLUSIONS: The results of the study demonstrate that the combination therapy, even at the standard doses for Japan, improves physical activity and plasma BNP concentration more than the monotherapy. A larger study is required to assess the effects of the combination therapy on major clinical outcomes.     

Olmesartan medoxomil, an angiotensin II receptor blocker ameliorates insulin resistance and decreases triglyceride production in fructose-fed rats.

Although angiotensin II receptor blockers (ARBs) have been recommended as a first line of anti-hypertensive agents in patients with diabetes, it remains unclear whether ARBs have a favorable effect on insulin action and triglyceride (TG) metabolism, both of which are impaired in type 2 diabetes. In this study we addressed this issue by investigating how a newly developed ARB, olmesartan medoxomil, influenced insulin sensitivity and TG metabolism in fructose-fed rats, a representative animal model of insulin resistance. Olmesartan was administrated as a 0.01% drinking solution ad libitum to rats either fed normal chow or fructose-enriched chow (60%) for 21 days. Olmesartan treatment markedly decreased both systolic and diastolic blood pressure in both chow-fed and fructose-fed animals. The area under the curve of insulin (AUCI) was substantially greater in fructose-fed rats in the intravenous glucose tolerance test, and olmesartan treatment significantly reduced the AUCI. Olmesartan significantly improved the insulin sensitivity index in fructose-fed rats assessed by Bergman's minimal model without affecting insulin-independent glucose disposal. Olmesartan significantly decreased plasma TG and non-esterified fatty acid levels in fructose-fed rats without affecting lipoprotein lipase mass. The TG secretion rate determined by the triton WR1339 technique was two-fold higher in fructose-fed rats, but olmesartan restored the TG secretion to a normal rate. Olmesartan did not affect plasma parameters, insulin sensitivity or TG metabolism in chow-fed rats. Olmesartan ameliorates insulin resistance and overproduction of TG in fructose-fed rats, and these effects appear to be independent of its hypotensive action.     

Effects of angiotensin-converting enzyme inhibitors or an angiotensin receptor blocker in combination with aspirin and cilostazol on in-stent restenosis

It remains to be determined whether adding an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to antiplatelet therapy has a therapeutic benefit on in-stent restenosis. After successful coronary stenting, 165 patients (167 lesions) were randomly assigned to a basal (aspirin 162 mg + cilostazol 200 mg/day), ACEI (basal treatment + quinapril 10 mg or perindopril 4 mg/day), or ARB (basal treatment + losartan 50 mg/day) treatment group. Quantitative coronary angiography was performed before, immediately following, and 6 months after stenting. Follow-up coronary angiography was completed in 126 patients (128 lesions). Restenosis rates tended to be higher (12, 26, and 12% for the basal, ACEI, and ARB groups, respectively), and target lesion revascularization rates were higher in the ACEI group than in the other groups (9, 23,* and 5%, respectively, *P < 0.05 versus basal group). Moreover, late lumen loss was higher in the ACEI group than in the basal group (0.60 +/- 0.55, 0.98 +/- 0.61* and 0.73 +/- 0.64 mm in the basal, ACEI, and ARB groups, respectively). The combinations of an ACEI or ARB with aspirin and cilostazol are ineffective for the prevention of in-stent restenosis, and an ACEI may even promote intimal proliferation after stent implantation.     

Lack of effect on coronary atherosclerotic disease biomarkers with modest dosing of an angiotensin-converting enzyme inhibitor, angiotensin II type-1 receptor blocker, and the combination

BACKGROUND: Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, used alone or in combination, have been shown to improve outcomes in certain populations, primarily when administered in high doses. For stable coronary atherosclerotic disease, however, the relative physiologic effect of these therapies is unclear. Furthermore, because of the notorious subtarget dosing of such agents in clinical practice, we explored the influence of a modest dosing of an angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blockers, and the combination on common biologic markers of coronary atherosclerotic disease. METHODS: This randomized, cross-over study enrolled stable coronary atherosclerotic disease patients (n=20), each receiving three treatments: candesartan 16 mg daily, ramipril 5 mg daily, and candesartan 8 mg plus ramipril 2.5 mg daily. Treatments were administered for 2 weeks with a 2-week washout. Blood samples were collected before and after each treatment. Markers of endothelial function, fibrinolytic balance, and vascular inflammation were measured. RESULTS: No significant differences were observed in the pretreatment concentrations of angiotensin-converting enzyme or of any measured biologic marker. Relative to pretreatment levels, candesartan alone was the only therapy to exhibit an action on any measured biomarker--a trend toward increased nitric oxide concentrations (P=0.054). Otherwise, no effects on biologic markers were observed with the treatments. CONCLUSION: This study of various methods of the renin-angiotensin system inhibition in stable coronary atherosclerotic disease patients demonstrates negligible effects of a modest dosing of ramipril and the combination of ramipril plus candesartan on common biologic markers of coronary atherosclerotic disease. Candesartan at modest doses may favorably influence endothelial function. Overall, however, the results indicate that the commonly practiced subtarget dosing of such treatments provides little, if any, benefit pertaining to key physiologic components of coronary atherosclerotic disease.     

Rationale for the use of combination angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy in heart failure

BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality in the United States. The renin-angiotensin system (RAS) plays a major role in its pathophysiology, and angiotensin-converting enzyme (ACE) inhibitors are the cornerstone of therapy. However, HF continues to progress despite this therapy, perhaps because of production of angiotensin II by alternative pathways, which lead to direct stimulation of the angiotensin II receptor. Angiotensin II receptor blocker (ARB) therapy alone or in combination with the ACE inhibitor is a promising approach to block the RAS and slow HF progression more completely. METHODS: The current medical literature on the pathophysiology of HF and the use of ACE inhibitors and ARBs was extensively reviewed. RESULTS: Evidence from basic science, experimental animals, and clinical trials provides data on the safety and efficacy of RAS inhibition with ACE inhibitors and ARBs as monotherapy and in combination. Data from the Evaluation of Losartan in the Elderly (ELITE) II trial indicate that ARBs alone do not appear to be more effective than ACE inhibitors in HF, but studies evaluating their use in combination are currently ongoing. CONCLUSIONS: The addition of an ARB offers more complete angiotensin II receptor blockade of the RAS than can be obtained by ACE inhibitors alone. Combination therapy preserves the benefits of bradykinin potentiation offered by ACE inhibitors while providing potential antitrophic influences of AT(2) receptor stimulation and may play an increased role in the treatment of chronic HF in the future.     

Effect of renin-angiotensin-aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker.

Although dual blockade of the renin-angiotensin-aldosterone system (RAAS) with the combination of an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) is generally well-established as a treatment for nephropathy, this treatment is not fully effective in some patients. Based on the recent evidence implicating aldosterone in renal disease progression, this study was conducted to examine the efficacy of blockade with three different mechanisms by adding an aldosterone blocker in patients who do not respond adequately to the dual blockade. A 1-year randomized, open-label, multicenter, prospective controlled study was conducted, in which 32 non-diabetic nephropathy patients with proteinuria exceeding 0.5 g/day were enrolled after more than 12 weeks of ACE-I (5 mg enalapril) and ARB (50 mg losartan) combination treatment. These patients were allocated into two groups of 16 patients each: a triple blockade group in which 25 mg of spironolactone daily was added to the ACE-I and ARB combination treatment, and a control group in which 1 mg of trichlormethiazide or 20 mg of furosemide was added to the combination treatment instead of spironolactone depending upon the creatinine level. After 1 year of treatment, the urinary protein level decreased by 58% (p<0.05) with the triple blockade but was unchanged in the controls. Furthermore, urinary type IV collagen level decreased by 40% (p<0.05) with the triple blockade but was unchanged in the controls. The decreases in urinary protein and urinary type IV collagen were not accompanied by a decrease in blood pressure. Mean serum creatinine, potassium and blood pressure did not change significantly by either treatment. In conclusion, triple blockade of the RAAS was effective for the treatment of proteinuria in patients with non-diabetic nephropathy whose increased urinary protein had not responded sufficiently to a dual blockade.     

Familial hypertrophic cardiomyopathy. Insertion-deletion polymorphism of angiotensin-converting enzyme and angiotensin II receptor

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic-based disease. Several gene mutations leading to HCM development have been described. AIM: Detailed examination of phenotype and genotype of a family with HCM. METHODS: Clinical and genetic examinations were performed in a family with HCM, in which 3 sick persons with different disease phenotype were found. RESULTS: In all sick persons the same molecular substitution G->A (AGG->AAG) was noticed. It led to substitution Arg780-Lys in exon 21 beta-myosin heavy chain gene, which was responsible for the development of the disease. Insertion- deletion polymorphism analysis in ACE gene revealed D/D (deletion/deletion) genotype in proband and D/I (deletion/ insertion) phenotype in his mother and sister, who were heterozygous. Polymorphism A1166C analysis in AT1 gene revealed the presence of genotype A/A in proband and A/C in his mother and sister. In proband and his sister a very similar phenotype was observed, whereas they had different polymorphism for ACE gene and angiotensin 1 receptor gene. In sick proband's mother, who had phenotype different to her children, the same polymorphism as in his daughter was noticed. CONCLUSIONS: In the described family with HCM, different phenotype and polymorphism of ACE and AT1 genes were found.     

Reporting on sex-based analysis in clinical trials of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker efficacy

BACKGROUND:

Clinical practice recommendations for hypertension do not make recommendations specific to men or women. However, the sex hormones appear to modulate differently the renin-angiotensin system (RAS), which plays a central role in the regulation of blood pressure. Today, little is known about the effects of sex on the efficacy of therapies that antagonize the RAS, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).

OBJECTIVE:

To identify randomized controlled trials evaluating the efficacy of ACEIs and ARBs in preventing major cardiovascular outcomes, determine what proportion of the trial participants were female, and evaluate whether there was any evidence of a sex difference in the efficacy of these agents.

METHODS:

A systematic review of the literature was conducted to identify randomized controlled trials that used either ACEIs or ARBs for the treatment of hypertension.

RESULTS:

Thirteen ACEI trials and nine ARB trials were identified. Sex-specific outcome data were available in six of the ACEI trials and three of the ARB trials. These trials enrolled 74,105 patients; 39.1% were women. Seven of the nine trials indicated that ACEIs or ARBs may be slightly more beneficial in men. The magnitude of these differences, in most trials, was small.

CONCLUSIONS:

Sex-specific data are reported in 43% of large hypertension clinical trials. Review of the trials reporting sex-specific effect sizes indicates that ACEIs and ARBs may be more effective in men.     

Aldosterone escape with diuretic or angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy in patients with mild to moderate hypertension

Renin-angiotensin-aldosterone system (RAAS) hyperactivity is implicated in the development of hypertension and progressive damage in target organs. Chronic inhibition of the RAAS or use of thiazide-type diuretics may trigger an aldoster-one escape. The aim of this study was to assess this phenomenon in hypertensive patients treated with thiazide-type diuretics (hydrochlorothiazide [HCTZ]) or single or double blockade of the RAAS (irbesartan [IRBE], quinapril [QUIN], and IRBE+QUIN). Blood pressure levels were obtained by 24-hour ambulatory blood pressure monitoring. Plasma renin activity and aldosterone levels were determined by immunoradiometric assay. Blood pressure level was normalized in the 4 treatment groups; the HCTZ and IRBE+QUIN groups showed an increased plasma aldosterone level after 12 weeks (9.1+/-2.2 to 14.1+/-1.4 and 6.9+/-1.9 to 12.9+/-2.3 ng/dL, respectively; P<.05), whereas plasma renin activity was increased only in the HCTZ group (0.9+/-0.2-1.7+/-0.2 ng/mL/h; P<.05). The increase in plasma aldosterone level after 12 weeks of HCTZ and IRBE+QUIN therapy suggests early aldosterone escape.     

Combination angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy: its role in clinical practice

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are commonly prescribed for the management of hypertension. In addition, each of these drug classes has been shown to be effective in the treatment of congestive heart failure, proteinuric chronic kidney disease, and most recently the high-cardiac-risk profile patient. The individual success of each of these drug classes has fueled the theory that given together, the overall biologic effect of both would surpass that of either given alone. The foundation of this premise, although biologically plausible, has yet to be proven in a compelling enough fashion to support the everyday use of these two drug classes in combination. Additional clarifying studies are required to establish whether specific patient subsets exist that might benefit from such combination therapy.     

Successful treatment of severe hypertension with the combination of angiotensin converting enzyme inhibitor and angiotensin II receptor blocker.

Three patients who suffered from congestive heart failure caused by severe hypertension were treated with a combination therapy consisting of angiotensin converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Before initiation of treatment, all three patients showed elevations of serum creatinine concentration (sCr), plasma renin activity (PRA), and plasma aldosterone concentration (PAC), which indicated insufficient blood supply to the kidney during exacerbation of hypertension. All three cases successfully recovered from hypertensive heart failure with the combination therapy. sCr gradually decreased during continuation of the therapy, although one patient showed an increase in sCr at an early stage of the combination therapy. Blockade of the renin-angiotensin-aldosterone system (RAAS) by the combination of ACEI and ARB was well tolerated in patients with severe hypertension with renal damage and showed a beneficial effect in protecting against further renal damage. This result suggests that combination therapy with ACEI and ARB should be considered as a candidate treatment in cases of severe hypertension.     

Effects of aliskiren on the fibrinolytic system in patients with coronary artery disease receiving angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor blocker

Aliskiren is a novel blood pressure-lowering agent acting as an oral direct renin inhibitor. We evaluated the effects of aliskiren on the fibrinolytic system in patients with coronary artery disease who were receiving angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs). We studied 17 patients with coronary artery disease whose systolic blood pressure was more than 130 mmHg despite treatment with ACEIs or ARBs. Aliskiren (150 mg) was added to ACEIs or ARBs, and was continued for 6 weeks. Aliskiren significantly decreased systolic blood pressure (140 ± 6–128 ± 8 mmHg, P < 0.001) and plasma renin activity (1.8 ± 2.3–0.6 ± 0.9 ng/ml/h, P < 0.01) after 6 weeks. However, it did not affect plasminogen activator inhibitor-1 (28.8 ± 14.5–30.6 ± 13.6 ng/ml, P = 0.84), fibrinogen (305 ± 72 vs 301 ± 71 mg/dl, P = 0.33), or D-dimer (0.49 ± 0.24–0.51 ± 0.28 μg/ml, P = 0.70) levels. Our data suggested that patients receiving ACEIs or ARBs would not be expected to have any changes in biomarkers of the fibrinolytic system with additional pharmacologic inhibition of the renin–angiotensin–aldosterone system.     

Comparative effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on plasma fibrinolytic balance in humans.

Angiotensin-converting enzyme (ACE) inhibition significantly decreases plasminogen activator inhibitor-1 (PAI-1) without altering tissue plasminogen activator (tPA) during activation of the renin-angiotensin-aldosterone system in humans. Because ACE inhibitors and angiotensin II type 1 (AT(1)) receptor antagonists differ in their effects on angiotensin II formation and bradykinin degradation, the present study compared the effect of equivalent hypotensive doses of an ACE inhibitor and AT(1) antagonist on fibrinolytic balance. Plasma PAI-1 antigen, tPA antigen, plasma renin activity, and aldosterone were measured in 25 normotensive subjects (19 white, 6 black; 14 men, 11 women; mean age 38.5+/-1.8 years; mean body mass index 25.3+/-0.7 kg/m(2)) during low salt intake alone (10 mmol Na/d), low salt intake + quinapril (40 mg PO bid), and low salt intake + losartan (50 mg PO bid). Compared with low salt alone (systolic blood pressure [BP] 118.8+/-2.2 mm Hg), both quinapril (106.3+/-2.5 mm Hg, P<0.001) and losartan (105.4+/-2. 8 mm Hg, P<0.001) reduced BP. No statistical difference was found between quinapril and losartan in their BP lowering effect. Losartan (P=0.009), but not quinapril, lowered heart rate. Both drugs significantly lowered aldosterone (P<0.001 versus low salt alone for each); however, this effect was significantly greater for quinapril than for losartan (P<0.001 for quinapril versus losartan). Treatment with quinapril, but not with losartan, was associated with a decrease in both PAI-1 antigen (P=0.03) and activity (P=0.018). PAI-1 activity was lower during treatment with quinapril than with losartan (P=0.015). The average PAI-1 antigen concentration was 13. 0+/-2.0 ng/mL during low salt alone, 10.5+/-1.6 ng/mL during quinapril treatment, and 12.3+/-2.1 ng/mL during losartan treatment. In contrast, plasma tPA antigen concentrations were reduced during treatment with losartan (P=0.03) but not with quinapril. This study provides the first evidence that ACE inhibitors and AT(1) antagonists differ in their effects on fibrinolytic balance under conditions of activation of the renin-angiotensin-aldosterone system. Further studies are needed to address the mechanism for the contrasting effects of these 2 classes of drugs on fibrinolysis and to define the clinical significance of these differences.     

Use of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy to reduce cardiovascular events in high-risk patients: Part 1

Cardiovascular disease is understood as a continuum; risk factors induce a pathophysiologic cascade that culminates in end-organ failure. The renin-angiotensin system (RAS) influences multiple aspects of the pathophysiology via hemodynamic and nonhemodynamic effects. Many long-term clinical trials provide overwhelming evidence of benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) across the cardiovascular continuum, including benefits regarding hypertension, myocardial infarction, stroke, renal disease, and heart failure. Trials also indicate additive or synergistic effects of combination therapy in renal disease and heart failure, a possibility supported by the basic biochemistry of the agents. Discussion of these trials is included in part 1 of this 2-part review. Part 2 of the review will discuss the extensive interaction of the RAS with the cellular and molecular pathophysiology of cardiovascular disease and the cross-continuum effects of ARBs and ACE inhibitors, which raise the possibility that RAS inhibition can offer protection in high-risk patients who do not have symptoms. The benefits of combined ACE inhibitor/ARB therapy in high-risk patients await confirmation; ongoing clinical research in this area will be discussed.