trandolapril and Arteriosclerosis

Even minor reduction in glomerular filtration rate accelerates atherogenesis and increases cardiovascular risk. The current study on the apolipoprotein E -/- mouse was designed to investigate whether nephron reduction by uninephrectomy causes cardiac remodeling and whether this is prevented by antioxidative treatment.. We randomized apolipoprotein E -/- mice to undergo uninephrectomy or sham operation and subsequent treatment with either Tempol, Ebselen, Trandolapril, or a combination of Tempol and Trandolapril. After 12 weeks, the experiment was terminated by perfusion fixation under anesthesia. The myocardium was analyzed by morphometry. Additionally, the expression of endothelial nitric oxide synthase, transforming growth factor-beta1, vascular endothelial growth factor, flt-1, collagen I and presence of nitrotyrosine were assessed using immunohistochemistry or western blotting.. Untreated uninephrectomized animals had lower capillary length density and higher volume fraction of interstitial tissue in the myocardium and bigger plaques in aorta compared with those who underwent sham operation. These changes did not develop in uninephrectomized animals treated with Tempol, Ebselen, Trandolapril, or Tempol + Trandolapril. In untreated uninephrectomized mice, the presence of nitrotyrosine and the expression of transforming growth factor-beta1, vascular endothelial growth factor, and collagen I were more marked. This was ameliorated by Tempol, Ebselen, Trandolapril, and Tempol + Trandolapril.. We conclude that in the apolipoprotein E -/- mouse, even minor reduction in renal function, for example, by uninephrectomy, causes remodeling of the heart. This was ameliorated to a similar extent by antioxidants and angiotensin-converting enzyme inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Apolipoproteins E; Arteriosclerosis; Cyclic N-Oxides; Disease Models, Animal; Drug Therapy, Combination; Gene Silencing; Heart Ventricles; Indoles; Male; Mice; Mice, Knockout; Myocardium; Nephrectomy; Oxidative Stress; Spin Labels; Ventricular Dysfunction, Left; Ventricular Remodeling

1. We investigated the relationship between angiotensin II formation and the development of atherosclerotic lesions in the aorta of monkeys (Macaca fascicularis) fed a high-cholesterol (4% cholesterol and 6% corn oil) diet for 6 months, and studied the effects of an angiotensin converting enzyme (ACE) inhibitor, trandolapril (10 mg kg-1 per day, p.o.), and an angiotensin II type 1 receptor antagonist, 2-butyl-4-(methylthio)-1-[[2'[[[(propylamino)carbonyl]amino]sulfonyl] (1,1'-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR 720; 20 mg kg-1 per day, p.o.). 2. The level of low-density lipoprotein was significantly increased by the cholesterol diet, whereas that of high-density lipoprotein was significantly decreased. The relative areas of the atherosclerotic lesions in the thoracic aorta in the normal and cholesterol-diet groups were 1.3+/-0.3 and 64+/-10%, respectively. 3. Plasma renin and ACE activities showed no differences between the normal and cholesterol-diet groups. ACE activity and the concentration of angiotensin II were significantly increased in the aorta of the cholesterol-fed monkeys. 4. Trandolapril and HR 720 decreased significantly the area of the atherosclerotic lesions in the thoracic aorta of cholesterol-fed monkeys, but not the mean blood pressure and the levels of low-density and high-density lipoproteins. 5. In plasma and aorta, trandolapril, but not HR 720, decreased significantly the ACE activities in the cholesterol-fed monkeys, while both of these drugs decreased significantly the angiotensin II levels. 6. In conclusion, blockade of angiotensin II function in vascular tissues by trandolapril or HR 720 may play an important role in preventing the development of atherosclerotic lesions.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arteriosclerosis; Biphenyl Compounds; Cholesterol, Dietary; Female; Imidazoles; Indoles; Macaca fascicularis; Male; Peptidyl-Dipeptidase A

This study was undertaken to determine whether low doses of the angiotensin-converting enzyme (ACE) inhibitor trandolapril affected atherosclerosis in the Watanabe heritable hyperlipidemic (WHHL) rabbit. Trandolapril (10 micrograms/kg body weight per 48 hours) was begun at 3 months of age and continued for 9 months. The selected dose reduced serum ACE activity but did not influence blood pressure. Both serum and aortic ACE activity were reduced by more than 80% in the trandolapril-treated compared with control WHHL rabbits, similar to the suppression achieved with the 25-fold-higher dose that in our previous studies induced marked inhibition of aortic atherosclerotic lesions in the WHHL rabbit. In contrast to these prior findings, low-dose trandolapril had no effect on aortic surface involvement by atherosclerosis, aortic cholesterol content, or aortic morphology. The data suggest that the antiatherosclerotic action of ACE inhibitors in the WHHL rabbit may not be related directly to arterial enzyme inhibition.

Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arteriosclerosis; Blood Pressure; Cholesterol; Hyperlipidemias; Indoles; Molecular Sequence Data; Peptidyl-Dipeptidase A; Rabbits

The effects of trandolapril (0.25 mg/kg body wt per 48 hours) on aortic atherosclerosis were examined in the Watanabe heritable hyperlipidemic rabbit treated from 3 to 12 months of age. Trandolapril caused a significant decrease in atherosclerotic involvement of the intimal surface of total aorta from 56.3 +/- 5.0% in control Watanabe rabbits to 35.0 +/- 4.1% with treatment (p less than 0.01). The largest reductions were observed in descending thoracic aorta where 21.8 +/- 5.7% of intimal surface was involved in the trandolapril-treated animals versus 54.4 +/- 7.7% in the control group (p less than 0.01). Significant decreases also occurred in ascending aorta/arch and abdominal aortic segments. Cholesterol content of descending thoracic aorta was also significantly reduced in the trandolapril-treated rabbits. The atherosclerotic plaques in aorta from trandolapril-treated rabbits appeared to contain less foam cells and relatively greater amounts of connective tissue than those from control animals. These studies indicate that trandolapril inhibits aortic atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. The similarity in results between the current study and that using captopril suggests that the antiatherosclerotic action of trandolapril and captopril represents a class effect related to angiotensin converting enzyme inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Diseases; Arteriosclerosis; Blood Pressure; Body Weight; Cholesterol; Female; Indoles; Male; Rabbits; Time Factors