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PRECLINICAL STUDIES

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

Manuscript received August 21, 2003; revised manuscript received November 13, 2003, accepted November 25, 2003.

^* Reprint requests and correspondence: Dr. Oscar A. Carretero, Division Head, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202-2689, USA.
ocarret1{at}hfhs.org

OBJECTIVES: We studied the role of angiotensin II type 2 (AT₂) receptors and kinins in the cardioprotective effect of angiotensin II type 1 antagonists (AT₁-ant) in rats with heart failure (HF) after myocardial infarction.

BACKGROUND: The AT₁-ant is as effective as angiotensin-converting enzyme inhibitors in treating HF, but the mechanisms whereby AT₁-ant exert their benefits on HF in vivo are more complex than previously understood.

METHODS: Brown Norway Katholiek rats (BNK), which are deficient in kinins because of a mutation in the kininogen gene, and their wild-type control (Brown Norway [BN]) underwent myocardial infarction. Two months later, they were treated for two months with: 1) vehicle; 2) AT₁-ant (L158809, Merck, Rahway, New Jersey); 3) AT₁-ant + AT₂-ant (PD-123319, Parke Davis, Ann Arbor, Michigan); or 4) AT₁-ant + kinin B₂ receptor antagonist (B₂-ant) (icatibant) (only BN). We measured left ventricular weight (LVW) gravimetrically, myocyte cross-sectional area (MCSA) and interstitial collagen fraction (ICF) histologically, and ejection fraction by ventriculography.

RESULTS: Development of HF was comparable in BN and BNK rats. The AT₁-ant reduced LVW and MCSA and the AT₂-ant blocked these effects in BN rats, but the B₂-ant did not. The AT₁-ant reduced LVW and MCSA in BNK rats, and this effect was reversed by the AT₂-ant. In BN rats, ICF was reduced and LVEF increased by AT₁-ant, and both AT₂-ant and B₂-ant reversed these effects. In BNK rats, the AT₁-ant failed to reduce ICF, and its therapeutic effect on LVEF was significantly blunted.

CONCLUSIONS: In HF, the AT₂ receptor plays an important role in the therapeutic effects of AT₁-ant, and this effect may be mediated partly through kinins; however, kinins appear to play a lesser role in the antihypertrophic effect of AT₁-ant.

Abbreviations and Acronyms   Ang II = angiotensin II   AT1 = angiotensin II type 1   AT1-ant = angiotensin II type 1 antagonist   AT2 = angiotensin II type 2   B2-ant = kinin B2 receptor antagonist   B2-KO = B2 kinin receptor knockout   BN = Brown Norway   BNK = Brown Norway Katholiek   EDV = end-diastolic volume   EF = ejection fraction   ESV = end-systolic volume   HF = heart failure   ICF = interstitial collagen fraction   LV = left ventricular/ventricle   LVW = left ventricular weight   MBP = mean blood pressure   MCSA = myocyte cross-sectional area   MI = myocardial infarction   NO = nitric oxide

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