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


METHODS
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.


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.


CONCLUSIONS
Drugs that inhibit the RAS, irrespective of their mode of inhibition, profoundly affect atherosclerotic lesion development in a dose-dependent manner.
Saha Cardiovascular Research CenterGraduate Center for Nutritional SciencesDepartment of Statistics, University of Kentucky, Lexington, KY, USANovartis Institutes for Biomedical Research, Cambridge, MA, USA.
Hong
H
Lu
Saha Cardiovascular Research CenterGraduate Center for Nutritional SciencesDepartment of Statistics, University of Kentucky, Lexington, KY, USANovartis Institutes for Biomedical Research, Cambridge, MA, USA.
Anju
A
Balakrishnan
Saha Cardiovascular Research CenterGraduate Center for Nutritional SciencesDepartment of Statistics, University of Kentucky, Lexington, KY, USANovartis Institutes for Biomedical Research, Cambridge, MA, USA.
Deborah A
DA
Howatt
Saha Cardiovascular Research CenterGraduate Center for Nutritional SciencesDepartment of Statistics, University of Kentucky, Lexington, KY, USANovartis Institutes for Biomedical Research, Cambridge, MA, USA.
Congqing
C
Wu
Saha Cardiovascular Research CenterGraduate Center for Nutritional SciencesDepartment of Statistics, University of Kentucky, Lexington, KY, USANovartis Institutes for Biomedical Research, Cambridge, MA, USA.
Richard
R
Charnigo
Saha Cardiovascular Research CenterGraduate Center for Nutritional SciencesDepartment of Statistics, University of Kentucky, Lexington, KY, USANovartis Institutes for Biomedical Research, Cambridge, MA, USA.
Gene
G
Liau
Saha Cardiovascular Research CenterGraduate Center for Nutritional SciencesDepartment of Statistics, University of Kentucky, Lexington, KY, USANovartis Institutes for Biomedical Research, Cambridge, MA, USA.
Lisa A
LA
Cassis
Saha Cardiovascular Research CenterGraduate Center for Nutritional SciencesDepartment of Statistics, University of Kentucky, Lexington, KY, USANovartis Institutes for Biomedical Research, Cambridge, MA, USA.
Alan
A
Daugherty
D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D000092502:Renin Inhibitors
D000577:Amides; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D002784:Cholesterol; D004656:Enalapril; D005650:Fumarates; D019808:Losartan; D044140:Receptor, Angiotensin, Type 1; D011973:Receptors, LDL; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren