enalapril and Aortic-Diseases

Uremia accelerates atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. We examined whether this effect may be preventable by pharmacological blockade of the renin-angiotensin system (RAS).. Uremia was induced in apoE-/- mice by 5/6 nephrectomy (NX). Treatment with the angiotensin converting enzyme inhibitor enalapril (2 or 12 mg/kg/d) from week 4 to 36 after NX reduced the aortic plaque area fraction from 0.23+/-0.02 (n=20) in untreated mice to 0.11+/-0.01 (n=21) and 0.08+/-0.01 (n=23), respectively (P<0.0001); the aortic plaque area fraction was 0.09+/-0.01 (n=22) in sham-operated controls. Enalapril from week 20 to 44 after NX also retarded the progression of atherosclerosis. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) and concentrations of IgM antibodies against oxidized low density lipoprotein (OxLDL) increased after NX (P<0.01). Enalapril (12 mg/kg/d) attenuated these increases (P<0.05) and reduced aortic expression of vascular cell adhesion molecule (VCAM)-1 mRNA (P<0.05). Atherosclerosis in NX mice was also reduced by losartan (an angiotensin II receptor-blocker), but not when blood pressure was lowered with hydralazine (a non-RAS-dependent vasodilator).. The results suggest that inhibition of RAS abolishes the proatherogenic effect of uremia independent of its blood pressure-lowering effect, possibly because of antiinflammatory and antioxidative mechanisms.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Anti-Idiotypic; Aorta, Thoracic; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Blood Pressure; Disease Models, Animal; Disease Progression; Drosophila Proteins; Enalapril; Follow-Up Studies; Gene Expression; Immunoglobulin G; Immunoglobulin M; Intercellular Adhesion Molecule-1; Lipoproteins, LDL; Losartan; Mice; Nephrectomy; Oxidation-Reduction; Peptidyl-Dipeptidase A; Prognosis; Receptors, Cell Surface; Renin-Angiotensin System; RNA, Messenger; Uremia; Vascular Cell Adhesion Molecule-1

Role of tissue angiotensin-converting enzyme (ACE) in the development of pressure-overload cardiovascular hypertrophy was examined in rats by comparing the inhibitory effect of trandolapril (high efficiency on tissue ACE) with that of enalapril (low efficiency) at equally antihypertensive doses. Rats with abdominal aorta banded or sham-operated were orally treated with trandolapril (0.5 mg/kg per day), enalapril (20 mg/kg per day) or vehicle for 8 weeks after the surgical maneuvers. In vehicle-treated rats, the banding raised the intra-aortic systolic pressure by 58%, diastolic pressure by 31%, maximum velocity of pressure rise by 65%, left ventricular (LV) weight by 41%, LV hydroxyproline concentration by 56%, aortic mass by 46%, LV ACE activity by 45%, and aortic ACE activity by 265%. Although both drugs equally reduced the aortic systolic pressure to approx. 70% and diastolic pressure to approx. 80% that of banded rats receiving vehicle, trandolapril partially prevented the LV hypertrophy, whereas enalapril yielded nonsignificant suppression. Trandolapril completely prevented the LV increments in hydroxyproline and ACE activity, whereas enalapril partially inhibited the LV hydroxyproline increase with little inhibition of LV ACE activity. In contrast, both inhibitors almost completely prevented the aortic hypertrophy, with the ACE activity of the aorta being potently inhibited. These results suggest that tissue ACE is the principal factor for pressure-induced aortic hypertrophy and an important yet non-essential factor for LV hypertrophy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Aortic Diseases; Blood Pressure; Cardiomegaly; Enalapril; Heart Ventricles; Hydroxyproline; Indoles; Male; Organ Size; Rats; Rats, Wistar; Time Factors