Amlodipine Ameliorates Up-Regulation of ET-1 in Left Ventricle of Hypercholesterolemia Rabbits

Document Type: Original Article


1 Department of Physiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

2 Biotechnology Research Center & Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

3 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

4 Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran


In addition to antihypertensive effects, amlodipine may exhibit cardiovascular protective effects in heart tissue. The aim of this study was to evaluate the effects of amlodipine and/or high cholesterol diet on blood, heart tissue concentration and mRNA expression of endothelin-1 (ET-1) in male New Zealand white rabbits.
Materials and Methods
A total of 40 male New Zealand rabbits were divided into four groups: the normal control group, normal group receiving amlodipine, high-cholesterol diet group and high-cholesterol diet with amlodipine group. After 8 weeks, all the animals anesthetized and blood or tissues samples were collected.
After 8 weeks of a high cholesterol diet, the group with such a diet had a significantly higher ratio of left ventricle (LV) weight to body weight than the control group (P= 0.0001). After treatment with amlodipine for 8 weeks, ET-1 level was reduced considerably in comparison with the control (P= 0.01) and high- cholesterol diet groupes (P= 0.01). Amlodipine consumption caused significant reduction (P= 0.01) in the level of ET-1 in heart tissues of high-cholesterol diet group but it had no remarkable effect on the reduction of heart tissue ET-1 in amlodipine group compared with the control group.
The present study demonstrates that ventricular prepro-ET-1 mRNA quantitatively increases in the high- cholesterol diet rabbits which results in development of ventricular hypertrophy. It seems that the treatment with amlodipine retards the progression of LV hypertrophy through attenuation of ET-1 levels independent of lipid changes.


1.James PT, Rigby N, Leach R. International obesity task Force. The obesity epidemic, metabolic syndrome and future prevention strategies. Eur J Cardiovasc Prev Rehabil 2004; 11:3-8.

2.Alpert MA. Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome. Am J Med Sci 2001; 321:225-236.

3.Hubert HB, Feinleib M, McNamara PM, Casteelii WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983; 67:9 68-77.

4.Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, et al. Obesity and the risk of heart failure. N Engl J Med 2002; 347:305-313.

5.Sadoshima J, Izumo S. The cellular andmolecular response of cardiac myocytes to mechanical stress. Annu Rev Physiol 1997; 59:551-571.

6.Castelli WP, Anderson K. A population at risk: prevalence of high cholesterol levels in hypertensive patients of the Framingham Study. Am J Med 1986; 23-32.

7.Bohn F, Johansson B, Hedin U, Alving K, Pernow J. Enhanced vasoconstrictor effect of big endothelin-1 patients with athrosclerosis : relation to conversion to endothelin - 1 .Atherosclerosis 2002; 160:215-222.

8.Lerman A, Webster MW, Chesebro JH, Edwards WD, Wei CM, Fuster V, et al. Circulating and tissue endothelin immnoreactivity in hypercholesterolemic pigs. Circulation 1993; 88:2923-2928.

9.Haak T, Marz W, Jungmann E, Hausser S, Siekmeier R, Gross W, et al. Elevated endothelin levels in patients with hyperlipidemia. Clin Investig 1994; 72:580-584.

10.Yue TL, Gu JL, Wang C, Reith AD, Lee JC, Mirabile RC, et al. Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. J Biol Chem 2000; 275:37895-378901.

11.Davenport AP,Maguire JJ. Of mice and men: advances in endothelin research and first antagonist gains FDA approval. Trends Pharmacol Sci 2002; 23:155-157.

12.Waters D, Lesperance J, Francetich M, Causey D, Theroux P, Chiang YK, et al. A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis. Circulation 1990; 82:1940-1953.

13.Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, Miller ME, et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation 2000; 102:1503-1510.

14.Jukema JW, Zwinderman AH, van Boven AJ, Reiber JH, Van der Laarse A, Lie KI, et al. Evidence for a synergistic effect of calcium channel blockers with lipid-lowering therapy in retarding progression of coronary atherosclerosis in symptomatic patients with normal to moderately raised cholesterol levels. The REGRESS Study Group. Arterioscler Thromb Vasc Biol 1996; 16:425-430.

15.Catapano AL. Calcium antagonists and atherosclerosis. Experimental evidence. Eur Heart J 1997; 18:A80-86.

16.Bellosta S, Bernini F. Lipophilic Calcium Antagonists in Antiatherosclerotic Therapy. Current Atherosclerosis Reports 2000; 2:76-81.

17.Mitani H, Takimoto M, Bandoh T, Kimura M. Increases of vascular endothelin-converting enzyme activity and endothelin-1 level on atherosclerotic lesions in hyperlipidemic rabbits. Eur J Pharmacol 2000; 387:313-319.

18.Sugden PH. Signaling pathways activated by vasoactive peptides in the cardiac myocyte and their role in myocardial pathologies. J Card Fail 2002; S359-369.

19.Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, et al.Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 1993; 92:398-403.

20.Ishiye M, Umemura K, Uematsu T, Nakashima M. Angiotensin AT1 receptor-mediated attenuation of cardiac hypertrophy due to volume overload: involvement of endothelin. Eur J Pharmacol 1995; 280:11-7.

21.Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, et al. Increased NADH-oxidase- mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin- angiotensin system. Circulation 1999; 99:2027-2033.

22.Hu CT, Chang HR, Hsu YH, Liu CJ, Chen HI. Ventricular hypertrophy and arterial hemodynamics following deprivation of nitric oxide in rats. Life Sci 2005; 78:164-173.

23.Castro GJ, Bhatnagar A. Effect of extracellular ions and modulators of calcium transport on survival of tert- butyl hydroperoxide exposed cardiac myocytes. Cardiovasc Res 1993; 27:1873-1881.

24.Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 2001; 108:1429-1437.

25.Lee TM, Chou TF, Tsai CH. Association of pravastatin and left ventricular mass in hypercholesterolemic patients: role of 8-iso-prostaglandin f2alpha formation. J Cardiovasc Pharmacol 2002; 40:868-874.