NITRIC-OXIDE ACCOUNTS FOR POSTISCHEMIC CARDIOPROTECTION RESULTING FROM ANGIOTENSIN-CONVERTING ENZYME-INHIBITION - INDIRECT EVIDENCE FOR A RADICAL SCAVENGER EFFECT IN ISOLATED GUINEA-PIG HEART

The cardioprotective effect of angiotensin-converting enzyme (ACE) inh ibitors in cardiac ischemia/reperfusion damage is assumed to result la rgely from inhibition of the enzymatic breakdown of endogenous bradyki nin (BK). We assessed the role of nitric oxide (NO) in mediating the b eneficial 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 parame ter external heart work (EHW), determined before and after ischemia, s erved as criterion for quantitation of recovery. We assessed oxidative stress during reperfusion by measuring glutathione release in coronar y venous effluent; lactate release was used as a measure of ischemic c hallenge. 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 rami prilat (RT 25 mu M) improved postischemic function significantly (55% recovery of EHW vs. 29% for controls). BK 1 nM was even more cardiopro tective (71% recovery). The NO-synthase inhibitor N-g-nitro-L-arginine (NOLAG 10 mu M) inhibited the effects of RT and BK (18% recovery each ). SNP (0.3 mu M) improved recovery to 57%, the prostacyclin analogue iloprost (ILO, 0.1 and 3 nM) had no beneficial effect (21 and 20% reco very, respectively). With 8-bromo-cyclicGMP, a membrane-permeable cGMP analogue, function was not better than control (30% recovery). Releas e of glutathione during reperfusion was decreased by the three compoun ds known to increase NO concentration in the heart; lactate release wa s the same in all groups. In the CL studies, SNP concentration-depende ntly extinguished the light signal elicited by reactive oxygen species generated by hypoxanthine-xanthine oxidase or by hypochlorous acid (H OCl). Thus, NO was responsible for the BK-mediated cardioprotective ac tion of RT in our model, presumably by acting directly as an oxygen ra dical scavenger during reperfusion.