ACE-inhibition attenuates cardiac cell damage and preserves release of NO in the postischemic heart

Abstract

Cardioprotective effects of angiotensin-converting enzyme (ACE) inhibition have been demonstrated in postischemic reperfusion. This occurred via bradykinin and indirect evidence suggested mediation by nitric oxide (NO), which probably acts as a radical scavenger. To test this hypothesis, we measured release of lactate dehydrogenase (LDH) from isolated guinea pig hearts (constant flow perfusion, 37°C) as a marker of cellular damage, before and after global ischemia (15 min), and we investigated the release of NO during reperfusion, both, without and with ACE inhibition. The main catabolites of NO, nitrate and nitrite, were also quantified. Coronary perfusion pressure (CPP) indicated coronary resistance changes. Cilazaprilat (CIL, 10 μM) was used for inhibition of ACE. Marked and protracted cellular damage occurred during reperfusion in the control group, myocardial LDH release rising nearly 10-fold from 1.5 mU/ml (basal level) to 14 mU/ml during acute reperfusion, then declining to 7 mU/ml after 5 min. ACE inhibition mitigated the acute rise of LDH (9 mU/ml), and reduced its release to preischemic values already after 3 min of reperfusion. Postischemic NO release in the 2nd min of reperfusion was about 40% of the preischemic value (approx. 200 nM) in untreated hearts, while there was 70% recovery after ACE inhibition. After 25 min, NO had recovered to 69% in controls vs. 100% with CIL. Coronary venous nitrate+nitrite was not infringed during early reperfusion (2nd min). After 25 min, nitrate+nitrite had decreased in controls (about 75% of preischemic values), but increased to 110% with CIL. In control hearts, CPP rose continuously from the 10th to the 25th min of reperfusion (from 39 to 55 mmHg), indicating progressive vasoconstriction. CIL significantly attenuated this effect. The results suggest that NO might be consumed during early reperfusion in the act of detoxifying radicals. In control hearts, “endothelial stunning” takes place. Concerning NO production and vasodilatory tone, ACE-inhibition augments postischemic NO release and mitigates disturbances caused by ischemia and reperfusion.