Angiotensin-converting enzyme inhibitors (ACEi) protect the heart against
ischemia/reperfusion injury. Part of this cardioprotective effect may be mediated through
kinins. Because
kinins are also metabolized by
neutral endopeptidase (NEP) 24.11 in vivo, we hypothesized that (a) inhibition of NEP-24.11 would afford cardioprotection similar to that of ACEi and potentiate the effect of ACEi; and (b) these effects are mediated by
kinins or
atrial natriuretic peptide (
ANP) or both. In Lewis inbred rats, the left anterior descending coronary artery (LAD) was occluded for 30 min, followed by 120-min reperfusion. Immediately before reperfusion rats received vehicle, the ACEi
ramiprilat, the NEP-24.11 inhibitor (NEPi)
CGS24592, or both. To test whether the effect of NEPi could be suppressed by blocking
kinins or
ANP, the
kinin-receptor antagonist
icatibant or
ANP antagonist
HS-142-1 was administered before LAD occlusion. In controls,
infarct size/risk area was 69 +/- 4%; NEPi reduced this to 24 +/- 4% (p < 0.001) and
ramiprilat to 20 +/- 3% (P < 0.001). NEPi did not potentiate the effect of
ramiprilat (
infarct size/risk area, 18 +/- 4%). The protective effect of NEPi was blocked by
icatibant;
infarct size/risk area, 61 +/-4%, significantly larger than NEPi along (p < 0.001) but no different from controls. The effect of NEPi was slightly diminished by the
ANP antagonist
HS-142-1 (
infarct size/risk area, 35 +/- 3%; NS vs. NEPi alone). Thus NEP-24.11 participates in catabolism of
kinins in the heart; inhibition of NEP-24.11 may increases cardiac
kinins, which are responsible for the cardioprotective effect of NEPi.