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.

Figure 1

Comparison of different modes of RAS inhibition on changes in plasma renin concentrations. Plasma renin concentrations were measured using a radioimmunoassay kit (n = 7 per group). Histograms represent means and bars represent SEM. *P < 0.0001 versus the vehicle, and ^#P < 0.0001 versus enalapril 0.25 mg·kg⁻¹·day⁻¹. (A) Effects of aliskiren; (B) enalapril and (C) losartan.

Figure 2

Comparison of different modes of RAS inhibition on changes in systolic BP. Changes in systolic BP were compared in LDL receptor -/- mice between 1 week before pump implantation (baseline) and at 12 weeks after drug administration at the indicated doses (n = 8–14 per group). Histograms represent means and bars represent SEM. *P < 0.0001 versus the vehicle, and ^#P < 0.0001 versus the two lower doses of losartan (2.5 and 12.5 mg·kg⁻¹·day⁻¹). (A) Effects of aliskiren; (B) enalapril and (C) losartan.

Figure 3

Comparison of different modes of RAS inhibition on changes of diastolic BP. Changes in diastolic BP were compared in LDL receptor -/- mice between 1 week before pump implantation (baseline) and at 12 weeks after drug administration at the indicated doses (n = 8–14 per group). Histograms represent means and bars represent SEM. *P < 0.0001 versus the vehicle, and ^#P < 0.0001 versus the two lower doses of losartan (2.5 and 12.5 mg·kg⁻¹·day⁻¹). (A) Effects of aliskiren; (B) enalapril and (C) losartan.

Figure 4

Comparison of different modes of RAS inhibition on atherosclerotic lesion size in aortic arches. The lesion area (as a % of whole area) was measured on the intimal surface of aortic arches (n = 8–14 per group). Triangles represent the values for individual mice, diamonds represent means, and bars are SEM. *P < 0.001 versus the vehicle. (A) Effects of aliskiren; (B) enalapril and (C) losartan.