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


BACKGROUND
The AT(1)-ant is as effective as angiotensin-converting enzyme inhibitors in treating HF, but the mechanisms whereby AT(1)-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) AT(1)-ant (L158809, Merck, Rahway, New Jersey); 3) AT(1)-ant + AT(2)-ant (PD-123319, Parke Davis, Ann Arbor, Michigan); or 4) AT(1)-ant + kinin B(2) receptor antagonist (B(2)-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 AT(1)-ant reduced LVW and MCSA and the AT(2)-ant blocked these effects in BN rats, but the B(2)-ant did not. The AT(1)-ant reduced LVW and MCSA in BNK rats, and this effect was reversed by the AT(2)-ant. In BN rats, ICF was reduced and LVEF increased by AT(1)-ant, and both AT(2)-ant and B(2)-ant reversed these effects. In BNK rats, the AT(1)-ant failed to reduce ICF, and its therapeutic effect on LVEF was significantly blunted.


CONCLUSIONS
In HF, the AT(2) receptor plays an important role in the therapeutic effects of AT(1)-ant, and this effect may be mediated partly through kinins; however, kinins appear to play a lesser role in the antihypertrophic effect of AT(1)-ant.
Liu
Yun-He
YH
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Yang
Xiao-Ping
XP
Shesely
Edward G
EG
Sankey
Steadman S
SS
Carretero
Oscar A
OA
D058672:Adrenergic beta-2 Receptor Antagonists; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D006334:Heart Function Tests; D007705:Kinins / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D051381:Rats; D011914:Rats, Inbred BN; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000378:metabolism*
D058672:Adrenergic beta-2 Receptor Antagonists; D057911:Angiotensin Receptor Antagonists; D007705:Kinins; D018343:Receptors, Adrenergic, beta-2; D011945:Receptors, Angiotensin