Olmesartan improves left ventricular function in pressure-overload hypertrophied rat heart by blocking angiotensin II receptor with synergic effects of upregulation of angiotensin converting enzyme 2

Abstract

It is not clear how the blocking effect of angiotensin II receptors by olmesartan affects the functional recovery of pressure-overload hypertrophied heart. Hypertrophied heart was created by abdominal aortic banding above the celiac artery in Wistar rats at the age of eight weeks. Hypertrophied heart was excised and studied at 10 and 16 weeks after the operation (HT groups). For the last four weeks before the experiment, olmesartan (0.2 mg/kg per day) was administered subcutaneously by osmotic minipumps (Olm groups). Left ventricular function was measured by Langendorff perfusion. The levels of mRNA for angiotensin-converting enzyme (ACE), ACE2 and extracellular signal-regulated kinases (ERKs) in myocardium were analyzed by RT-PCR. Left ventricular systolic (+dP/dt_max, left ventricular systolic pressure) and diastolic functions (-dP/dt_max, tau) were impaired in HT groups, while in Olm groups they were significantly improved. The left ventricle to body weight (LV/BW) ratio increased significantly in HT groups, but in Olm groups the LV/BW ratio decreased significantly in comparison with HT groups. The ACE2 mRNA level was significantly higher in Olm groups as compared with HT groups. Plasma angiotensin II and the ERK mRNA level in HT groups increased significantly, but decreased in Olm groups in comparison with HT groups significantly. Olmesartan improved left ventricular function and hypertrophy through the increase of the ACE2 mRNA and decrease of both angiotensin II and ERK mRNA in pressure-overload rat heart.

Keywords

olmesartan hypertrophy angiotensin II type 1 receptor blockers angiotensin converting enzyme 2.

References

Agata, J. , Ura, N. , Yoshida, H. , Shinshi, Y. , Sasaki, H. , Hyakkoku, M. et al. (2006) Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme. Hypertens Res 29: 865-874.

Baker, K.M. , Booz, G.W. and Dostal, D.E. (1992) Cardiac actions of angiotensin II: Role of an intracardiac renin-angiotensin system. Annu Rev Physiol 54: 227-241.

Crackower, M.A. , Sarao, R. , Oudit, G.Y. , Yagil, C. , Kozieradzki, I. , Scanga, S.E. et al. (2002) Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417: 822-828.

Danilczyk, U. and Penninger, J.M. (2006) Angiotensin-converting enzyme II in the heart and the kidney. Circ Res 98: 463-471.

De Mello, W.C. and Jan Danser, A.H. (2000) Angiotensin II and the heart: On the intracrine renin-angiotensin system. Hypertension 35: 1183-1188.

Donoghue, M. , Hsieh, F. , Baronas, E. , Godbout, K. , Gosselin, M. , Stagliano, N. et al. (2000) A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 87: e1-e9.

Fogari, R. , Preti, P. , Derosa, G. , Marasi, G. , Zoppi, A. , Rinaldi, A. et al. (2002) Effect of antihypertensive treatment with valsartan or atenolol on sexual activity and plasma testosterone in hypertensive men. Eur J Clin Pharmacol 58: 177-180.

Gallagher, P.E. , Chappell, M.C. , Ferrario, C.M. and Tallant, E.A. (2006) Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes. Am J Physiol Cell Physiol 290: C420-426.

Ichikawa, S. and Takayama, Y. (2001) Long-term effects of olmesartan, an Ang II receptor antagonist, on blood pressure and the renin-angiotensin-aldosterone system in hypertensive patients. Hypertens Res 24: 641-646.

10.

Igase, M. , Strawn, W.B. , Gallagher, P.E. , Geary, R.L. and Ferrario, C.M. (2005) Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1-7) expression in the aorta of spontaneously hypertensive rats . Am J Physio Heart Circ Physio 289: H1013-H1019.

11.

Igase, M. , Kohara, K. , Nagai, T. , Miki, T. and Ferrario, C.M. (2008) Increased expression of angiotensin converting enzyme 2 in conjunction with reduction of neointima by angiotensin II type 1 receptor blockade. Hypertens Res 31: 553-559.

12.

Ishiyama, Y. , Gallagher, P.E. , Averill, D.B. , Tallant, E.A. , Brosnihan, K.B. and Ferrario, C.M. (2004) Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 43: 970-976.

13.

Ito, H. , Hirata, Y. , Hiroe, M. , Tsujino, M. , Adachi, S. , Takamoto, T. et al. (1991) Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes . Circ Res 69: 209-215.

14.

Komuro, I. , Kaida, T. , Shibazaki, Y. , Kurabayashi, Y. , Katoh, Y. , Hoh, E. et al. (1990) Stretching cardiac myocytes stimulates protooncogene expression. J Biol Chem 265: 3595-3598.

15.

Komuro, I. and Yazaki, Y. (1993) Control of cardiac gene expression by mechanical stress. Annu Rev Physiol 55: 55-75.

16.

Liu, Y. , Leri, A. , Li, B. , Wang, X. , Cheng, W. , Kajstura, J. et al. (1998) Angiotensin II stimulation in vitro induces hypertrophy of normal and postinfarcted ventricular myocytes. Circ Res 82: 1145-1159.

17.

Mann, D.L. , Kent, R.L. and Cooper, 4th G. (1989) Load regulation of the properties of adult feline cardiocytes: growth induction by cellular deformation. Circ Res 64: 1079-1090.

18.

Mendes, A.C.R. , Ferreira, A.J. , Pinheiro, S.V.B. and Santos, R.A.S. (2005) Chronic infusion of angiotensin-(1-7) reduces heart angiotensin II levels in rats. Regul Pept 125: 29-34.

19.

Minakawa, M. , Takeuchi, K. , Ito, K. , Tsushima, T. , Fukui, K. , Takaya, S. et al. (2003) Restoration of sarcoplasmic reticulum protein level by thyroid hormone contributes to partial improvement of myocardial function, but not to glucose metabolism in an early failing heart. Eur J Cardio-Thorac Surg 24: 493-501.

20.

National Institutes of Health (1985) Guide for the Care and Use of Laboratory Animals. NIH Publication : USA No. 86-23.

21.

National Society for Medical Research (1967 ) Principles of Laboratory Animal Care, USA.

22.

Parker, T.G. and Schneider, M.D. (1991) Growth factors, proto-oncogenes, and plasticity of the cardiac phenotype. Annu Rev Physiol 53: 179-200.

23.

Pool, J.L. , Glazer, R. , Chiang, Y.T. and Gatlin, M. (1999) Dose-response efficacy of valsartan, a new angiotensin II receptor blocker. J Hum Hypertens 13: 275-281.

24.

Tipnis, S.R. , Hooper, N.M. , Hyde, R. , Karran, E. , Christie, G. , Turner, A.J. et al. (2000) A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase . J Biol Chem 275: 33238-33243.

25.

Tom, B. , de Vries, R. , Saxena, P.R. and Danser, A.H.J. (2001) Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade. Hypertension 38: 95-99.

26.

Turner, A.J. and Hooper, N.M. (2002) The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 23: 177-183.

27.

Turner, A.J. , Tipnis, S.R. , Guy, J.L. , Rice, G. and Hooper, N.M. (2002) ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors . Can J Physiol Pharmacol 80: 346-353.

28.

Vickers, C. , Hales, P. , Kaushik, V. , Dick, L. , Gavin, J. , Tang, J. et al. (2002) Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 277: 14838-14843.

29.

Widdop, R.E. , Sampey, D.B. and Jarrott, B. (1999) Cardiovascular effects of angiotensin-(1-7) in conscious spontaneously hypertensive rats. Hypertension 34: 964-968.

30.

Yamakado, T. and Nakano, T. (1990) Left ventricular systolic and diastolic function in the hypertrophied ventricle. Jpn Circ J 54: 554-562.

31.

Yamamuro, M. , Yoshimura, M. , Nakayama, M. , Abe, K. , Sumida, H. , Sugiyama, S. et al. (2008) Aldosterone, but not angiotensin II, reduces angiotensin converting enzyme 2 gene expression levels in cultured neonatal rat cardiomyocytes. Circ J 72: 1346-1350.

32.

Yamazaki, T. , Komuro, I. , Kudoh, S. , Zou, Y. , Shiojima, I. , Mizuno, T. et al. (1995) Angiotensin II partly mediates mechanical stress-induced cardiac hypertrophy. Circ Res 77: 258-265.

33.

Zou, Y. , Komuro, I. , Yamazaki, T. , Aikawa, R. , Kudoh, S. , Shiojima, I. et al. (1996) Protein kinase C, but not tyrosine kinases or Ras, plays a critical role in angiotensin II-induced activation of Raf-1 kinase and extracellular signal-regulated protein kinases in cardiac myocytes . J Biol Chem 271: 33592-33597.