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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

Yun-He Liu, MD^*, Xiao-Ping Yang, MD^*, Edward G. Shesely, PhD^*, Steadman S. Sankey, PhD and Oscar A. Carretero, MD^*,*

^* Hypertension and Vascular Research Division, Department of Internal Medicine, Detroit, Michigan, USA
Division of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, Michigan, USA

View larger version (31K): [in a new window]   Figure 1 Left ventricular weight (LVW), myocyte cross-sectional area (MCSA), interstitial collagen fraction (ICF), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular ejection fraction (LVEF) four months after sham or coronary artery ligation in Brown Norway (BN) and Brown Norway Katholiek (BNK) rats. ***p < 0.001. HF = heart failure.

View larger version (48K): [in a new window]   Figure 2 Effect of the AT1-ant L158809 (AT1a) alone and combined with the AT2-ant PD123319 (AT2a) on LVW, MCSA, ICF, LVEDV, LVESV, and LVEF in BN and BNK rats with HF after myocardial infarction. *p < 0.05; **p < 0.01; ***p < 0.001. Abbreviations as in Figure 1.

View larger version (32K): [in a new window]   Figure 3 Effect of the AT1-ant L158809 (AT1a) alone and combined with the kinin B2-ant icatibant (B2) on LVW, MCSA, and ICF. Right panels show the difference in the response to AT1-ant ( from HF vehicle) between BN and BNK rats with HF after myocardial infarction. *p < 0.05; **p < 0.01; ***p < 0.001. Abbreviations as in Figure 1.

View larger version (33K): [in a new window]   Figure 4 Effect of the AT1a alone and combined with the kinin B2ant on LVEDV, LVESV, and LVEF. Right panels show the difference in the response to AT1-ant ( from HF vehicle) in BN and BNK rats with HF after myocardial infarction. *p < 0.05; **p < 0.01; ***p < 0.001. Abbreviations as in Figure 1.

View larger version (30K): [in a new window]   Figure 5 Hypothetical mechanism of action of AT1-ant in heart failure: 1) AT1-ant prevent the effect of angiotensin II on the AT1 receptor, leading to cardioprotection (preventing cardiac hypertrophy, fibrosis, and remodeling and improving function); 2) angiotensin II activates the AT2 receptors, which act via release of kinins, and B2 and/or B1 receptors, which act via release of nitric oxide, thereby leading to anticardiac fibrosis, preventing remodeling and improving function; a) in BN rats with HF, B2-ant only blocks the B2 receptor; the B1 receptors may be activated and prevent cardiac hypertrophy; and b) in BNK rats neither B1 nor B2 receptors are activated; as circulating kinins are absent in this strain, and AT2 receptors may act directly via nitric oxide to prevent cardiac hypertrophy. Rectangular callouts (AT1-ant, AT2-ant or B2-ant) point to the receptor blockade site, and oval callouts point to two strains (BN and BNK). Abbreviations as in Figure 1.