Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure - Role of kinins and angiotensin II type 2 receptors

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT(1)-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT(1)-ant may block the RAS at the level of the AT(1) receptor and activate the angiotensin II type 2 (AT(2)) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT(1)-ant has a similar effect and whether these effects are partly due to activation of the AT(2) receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B-2 receptor antagonist icatibant (B-2-ant); or (c) an AT(1)-ant with and without an AT(2)-antagonist (AT(2)-ant) or B-2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT(1)-ant. The B-2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT(1)-ant was blocked by the AT(2)-ant. The decreases in LVEDV and LVESV caused by the AT(1)-ant were also partially blocked by the B-2-ant. We concluded that (a) in HF both ACEi and AT(1)-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT(1)-ant is triggered by activation of the AT(2) receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT(1) receptors increases both renin and angiotensins; these angiotensins stimulate the AT(2) receptor, which in turn may play an important role in the therapeutic effect of the AT(1)-ant via kinins and other autacoids.