TY - JOUR
T1 - Comparative effects of different modes of renin angiotensin system inhibition on hypercholesterolaemia-induced atherosclerosis
AU - Lu, Hong
AU - Balakrishnan, Anju
AU - Howatt, Deborah A.
AU - Wu, Congqing
AU - Charnigo, Richard
AU - Liau, Gene
AU - Cassis, Lisa A.
AU - Daugherty, Alan
PY - 2012/3
Y1 - 2012/3
N2 - 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.
AB - 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.
KW - aliskiren
KW - atherosclerosis
KW - enalapril
KW - losartan
KW - renin angiotensin system
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U2 - 10.1111/j.1476-5381.2011.01712.x
DO - 10.1111/j.1476-5381.2011.01712.x
M3 - Article
C2 - 22014125
AN - SCOPUS:84863180525
SN - 0007-1188
VL - 165
SP - 2000
EP - 2008
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 6
ER -