(Circulation. 2001;103:148.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Effects of Combination of ACE Inhibitor and Angiotensin Receptor Blocker on Cardiac Remodeling, Cardiac Function, and Survival in Rat Heart Failure
From the Department of Pharmacology (S.K., Y.I., H.K., M.K., Y.Z., H.I.) and Department of Medicine, Division of Cardiology (M.Y.), Osaka City University Medical School, Osaka, Japan.
Correspondence to Shokei Kim, MD, PhD, Department of Pharmacology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. E-mail kims{at}med.osaka-cu.ac.jp
Background—The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats.
Methods and Results—DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy.
Conclusions—The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.
Key Words: heart failure • angiotensin • survival
This article has been cited by other articles:
 |
|
 |
|
  R. Choudhary, A. Palm-Leis, R. C. Scott III, R. S. Guleria, E. Rachut, K. M. Baker, and J. Pan All-trans retinoic acid prevents development of cardiac remodeling in aortic banded rats by inhibiting the renin-angiotensin system Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H633 - H644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Yamamoto, K. Kataoka, H. Shintaku, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Novel Mechanism and Role of Angiotensin II Induced Vascular Endothelial Injury in Hypertensive Diastolic Heart Failure Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2569 - 2575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Role of Xanthine Oxidoreductase in the Reversal of Diastolic Heart Failure by Candesartan in the Salt-Sensitive Hypertensive Rat Hypertension, October 1, 2007; 50(4): 657 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Okura, Y. Nakashima, H. Tojo, E. Tashiro, and K. Saku Valsartan, an Angiotensin II Type-I Receptor Blocker, and Left Ventricular Diastolic Function: A Case Report Angiology, July 1, 2005; 56(4): 467 - 473. [Abstract] [PDF]
|
|
|
|
|
|
A. Pourdjabbar, T. G. Parker, Q. T. Nguyen, J.-F. Desjardins, N. Lapointe, J. N. Tsoporis, and J.-L. Rouleau Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1997 - H2005. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Okada, Y. Watanabe, T. Kikuta, T. Kobayashi, Y. Kanno, T. Sugaya, and H. Suzuki Bradykinin Decreases Plasminogen Activator Inhibitor-1 Expression and Facilitates Matrix Degradation in the Renal Tubulointerstitium under Angiotensin-Converting Enzyme Blockade J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2404 - 2413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rosenkranz TGF-{beta}1 and angiotensin networking in cardiac remodeling Cardiovasc Res, August 15, 2004; 63(3): 423 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Azizi and J. Menard Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists Circulation, June 1, 2004; 109(21): 2492 - 2499. [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-H. Liu, X.-P. Yang, E. G. Shesely, S. S. Sankey, and O. A. Carretero Role of angiotensin II type 2 receptors and kinins in the cardioprotective effect of angiotensin II type 1 receptor antagonists in rats with heart failure J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1473 - 1480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Yoshida, K. Yamamoto, T. Mano, Y. Sakata, N. Nishikawa, M. Nishio, T. Ohtani, T. Miwa, M. Hori, and T. Masuyama AT1 Receptor Blocker Added to ACE Inhibitor Provides Benefits at Advanced Stage of Hypertensive Diastolic Heart Failure Hypertension, March 1, 2004; 43(3): 686 - 691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O. Boluyt, K. Converso, H. S. Hwang, A. Mikkor, and M. W. Russell Echocardiographic assessment of age-associated changes in systolic and diastolic function of the female F344 rat heart J Appl Physiol, February 1, 2004; 96(2): 822 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Jin, S. Takai, M. Yamada, M. Sakaguchi, K. Kamoshita, K. Ishida, Y. Sukenaga, and M. Miyazaki Impact of chymase inhibitor on cardiac function and survival after myocardial infarction Cardiovasc Res, November 1, 2003; 60(2): 413 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nishikimi, F. Yoshihara, S. Horinaka, N. Kobayashi, Y. Mori, K. Tadokoro, K. Akimoto, N. Minamino, K. Kangawa, and H. Matsuoka Chronic Administration of Adrenomedullin Attenuates Transition From Left Ventricular Hypertrophy to Heart Failure in Rats Hypertension, November 1, 2003; 42(5): 1034 - 1041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Sato, H. Yaoita, K. Maehara, and Y. Maruyama Attenuation of heart failure due to coronary stenosis by ACE inhibitor and angiotensin receptor blocker Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H359 - H368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sugie, Y. Kagaya, M. Takeda, H. Yahagi, C. Takahashi, J. Takahashi, M. Ninomiya, J. Watanabe, R. Ichinohasama, F. Tezuka, et al. Should increasing the dose or adding an AT1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction? Cardiovasc Res, June 1, 2003; 58(3): 611 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sakata, K. Yamamoto, T. Mano, N. Nishikawa, J. Yoshida, T. Miwa, M. Hori, and T. Masuyama Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction Cardiovasc Res, March 1, 2003; 57(3): 757 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nakamura, M. Yoshiyama, T. Omura, K. Yoshida, Y. Izumi, K. Takeuchi, S. Kim, H. Iwao, and J. Yoshikawa Beneficial effects of combination of ACE inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction Cardiovasc Res, January 1, 2003; 57(1): 48 - 54. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kim, Y. Izumi, Y. Izumiya, Y. Zhan, M. Taniguchi, and H. Iwao Beneficial Effects of Combined Blockade of ACE and AT1 Receptor on Intimal Hyperplasia in Balloon-Injured Rat Artery Arterioscler. Thromb. Vasc. Biol., August 1, 2002; 22(8): 1299 - 1304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhang Old and new tools to dissect calcineurin's role in pressure-overload cardiac hypertrophy Cardiovasc Res, February 1, 2002; 53(2): 294 - 303. [Abstract] [Full Text] [PDF]
|
|