Dataset Information

Comparative effects of different modes of renin angiotensin system inhibition on hypercholesterolaemia-induced atherosclerosis.

ABSTRACT:

Background and purpose

Inhibition of the renin angiotensin system (RAS) has been consistently demonstrated to reduce atherosclerosis. However, there has been no direct comparison among the three available pharmacological modes of inhibiting the RAS, which are inhibitors of renin, ACE and angiotensin II type 1 receptor. The purpose of this study was to determine the relative effects of these three modes of pharmacological RAS inhibition in reducing atherosclerosis by determining the dose-response relationships.

Experimental approach

Male LDL receptor -/- mice were administered either vehicle or any of three doses of aliskiren, enalapril or losartan through s.c. infusion for 12 weeks. All mice were fed a saturated fat-enriched diet during drug infusions. Systolic and diastolic BPs were measured during the study using a non-invasive tail-cuff system. Plasma cholesterol and renin concentrations, atherosclerotic lesions, and renal angiotensin II concentrations were determined at the termination of the study.

Key results

Plasma renin concentrations were increased by all three drugs. None of the drugs changed plasma cholesterol concentrations. All drugs produced a dose-related decrease in BP. All three drugs also profoundly reduced atherosclerosis in a dose-dependent manner. The highest dose of each drug markedly attenuated lesion size, with no significant differences between the different drugs. The highest dose of each drug also similarly reduced renal angiotensin II concentrations.

Conclusion and implications

Drugs that inhibit the RAS, irrespective of their mode of inhibition, profoundly affect atherosclerotic lesion development in a dose-dependent manner.

SUBMITTER: Lu H

PROVIDER: S-EPMC3372847 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Publications

Comparative effects of different modes of renin angiotensin system inhibition on hypercholesterolaemia-induced atherosclerosis.

Lu Hong H Balakrishnan Anju A Howatt Deborah A DA Wu Congqing C Charnigo Richard R Liau Gene G Cassis Lisa A LA Daugherty Alan A

British journal of pharmacology 20120301 6

<h4>Background and purpose</h4>Inhibition of the renin angiotensin system (RAS) has been consistently demonstrated to reduce atherosclerosis. However, there has been no direct comparison among the three available pharmacological modes of inhibiting the RAS, which are inhibitors of renin, ACE and angiotensin II type 1 receptor. The purpose of this study was to determine the relative effects of these three modes of pharmacological RAS inhibition in reducing atherosclerosis by determining the dose- ...[more]

PMID: 22014125

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Project description:BackgroundHigh glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control.ObjectivesWe investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts.MethodsWe evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis.ResultsGlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression.ConclusionPoor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition.Trial registrationhttps://clinicaltrials.gov/ NCT03546062.

Project description:Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation.In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models.Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P<0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P<0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study.Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal potassium homeostasis contributes to hyperkalemia in these patients. A better understanding of extrarenal potassium homeostasis will provide an opportunity to use this drug more safely in patients with diabetic nephropathy as well as other patient populations.

Project description:Background Previous data suggest that using renin-angiotensin-aldosterone system inhibitors (RAASIs) improves survival in patients with cardiovascular diseases. We sought to investigate the association of different patterns of use of RAASIs on perioperative and 1-year outcomes following carotid revascularization. Methods and Results We investigated patients undergoing carotid revascularization, either with carotid endarterectomy or transfemoral carotid artery stenting, in the VQI (Vascular Quality Initiative) VISION (Vascular Implant Surveillance and Interventional Outcomes Network) data set between 2003 and 2018. We divided our cohort into 3 groups: (1) no history of RAASI intake, (2) preoperative intake only, and (3) continuous pre- and postoperative intake. The final cohort included 73 174 patients; 44.4% had no intake, 50% had continuous intake, and 5.6% had only preoperative intake. Compared with continuous intake, preoperative and no intake were associated with higher odds of postoperative stroke (odds ratio [OR], 1.7 [95% CI, 1.5-1.9]; P<0.001; OR, 1.1 [95% CI, 1.03-1.2]; P=0.010); death (OR, 4.8 [95% CI, 3.8-6.1]; P<0.001; OR, 1.9 [95% CI, 1.6-2.2]; P<0.001); and stroke/death (OR, 2.05 [95% CI, 1.8-2.3]; P<0.001; OR, 1.2 [95% CI, 1.1-1.3]; P<0.001), respectively. At 1 year, preoperative and no intake were associated with higher odds of stroke (hazard ratio [HR], 1.4 [95% CI, 1.3-1.6]; P<0.001; HR, 1.15, [95% CI, 1.08-1.2]; P<0.001); death (HR, 1.7 [95% CI, 1.5-1.9]; P<0.001; HR, 1.3 [95% CI, 1.2-1.4]; P<0.001); and stroke/death (HR, 1.5 [95% CI, 1.4-1.7]; P<0.001; HR, 1.2 [95% CI, 1.17-1.3]; P<0.001), respectively. Conclusions Compared with subjects discontinuing or never starting RAASIs, use of RAASIs before and after carotid revascularization was associated with a short-term stroke and mortality benefit. Future clinical trials examining prescribing patterns of RAASIs should aim to clarify the timing and potential to maximize the protective effects of RAASIs in high-risk vascular patients.

Dataset Information

Comparative effects of different modes of renin angiotensin system inhibition on hypercholesterolaemia-induced atherosclerosis.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Comparative effects of different modes of renin angiotensin system inhibition on hypercholesterolaemia-induced atherosclerosis.

Similar Datasets

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