Nitric Oxide Accounts for Postischemic Cardioprotection Resulting from Angiotensin-Converting Enzyme Inhibition

Abstract

Summary The cardioprotective effect of angiotensin-converting enzyme (ACE) inhibitors in cardiac ischemia/reperfusion damage is assumed to result largely from inhibition of the enzymatic breakdown of endogenous bradykinin (BK). We assessed the role of nitric oxide (NO) in mediating the beneficial actions of BK and the possible mechanism of the effect of NO. We experimentally infringed myocardial function in a working guinea pig heart preparation by ischemia (15 min) and reperfusion. The parameter external heart work (EHW), determined before and after ischemia, served as criterion for quantitation of recovery. We assessed oxidative stress during reperfusion by measuring glutathione release in coronary venous effluent; lactate release was used as a measure of ischemie challenge. The principal ability of NO to scavenge oxygen radicals was separately investigated in a chemiluminescence (CL) assay with the NO-donor sodium nitroprusside (SNP) and lucigenin. The ACE inhibitor ramiprilat (RT 25 μM) improved postischemic function significantly (55% recovery of EHW vs. 29% for controls). BK 1 nM was even more cardioprotective (71% recovery). The NO-synthase inhibitor N^g-nitro-L-arginine (NOLAG 10 μM) inhibited the effects of RT and BK (18% recovery each). SNP (0.3 μM) improved recovery to 57%. the prostacyclin analogue iloprost (ILO, 0.1 and 3 nM) had no beneficial effect (21 and 20% recovery, respectively). With 8-bromo-cyclicGMP, a membrane-permeable cGMP analogue, function was not better than control (30% recovery). Release of glutathione during reperfusion was decreased by the three compounds known to increase NO concentration in the heart; lactate release was the same in all groups. In the CL studies, SNP concentration-dependently extinguished the light signal elicited by reactive oxygen species generated by hypoxanthine-xanthine oxidase or by hypochlorous acid (HOCI). Thus, NO was responsible for the BK-mediated cardioprotective action of RT in our model, presumably by acting directly as an oxygen radical scavenger during reperfusion.