Endothelial and myocardial cell protection by a cysteine-containing nitric oxide donor after myocardial ischemia and reperfusion.
The cardioprotective actions of SPM-5185, a novel cysteine-containing nitric oxide (NO) donor, were investigated in two models of myocardial ischemia-reperfusion (MI-R) injury. In the first study, dogs were subjected to 60 min of left anterior descending (LAD) coronary artery occlusion followed by 270 min of reperfusion. During reperfusion, animals were randomly assigned to receive intracoronary SPM-5185 (500 nM) or the NO-deficient analogue of SPM-5185, SPM-5267 (500 nM). Transmural myocardial blood flow to the ischemic zone was not different between the SPM-5185 group of dogs and the SPM-5267 group (0.04 +/- 0.01 and 0.03 +/- 0.01 ml/min/g, respectively). Similarly, the area of left ventricular myocardium placed at risk by LAD coronary artery occlusion was equivalent in dogs receiving SPM-5185 (33.6 +/- 3%) and SPM-5267 (30.4 +/- 2%). However, the necrotic area, expressed as a percentage of the area at risk, was reduced by 70% in the SPM-5185-treated dogs (14.5 +/- 4 vs. 47.5 +/- 9%; p < 0.001). Furthermore, cardiac myeloperoxidase activity indicated that fewer neutrophils accumulated in the necrotic zone of the SPM-5185-treated dogs. In the second study, dogs were subjected to 30 min of global myocardial ischemia followed by 1 h of cardioplegic arrest and 1 h of reperfusion. SPM-5185 (10 microM) added to the blood cardioplegia solution resulted in a 95 +/- 14% post-ischemic recovery of contractile function compared with 36 +/- 8% (p < 0.05) in vehicle-treated dogs. Additionally, SPM-5185 treatment completely preserved coronary arterial vasorelaxation to acetylcholine after ischemia and reperfusion and resulted in a 62% reduction in cardiac tissue myeloperoxidase activity (p < 0.05). We conclude that (a) SPM-5185 exerts significant cardioprotection from MI-R injury after regional or global ischemia, and (b) this cardioprotection appears to be related to the inhibition of neutrophil-mediated injury.
Lefer
D J
DJ
Department of Cardiothoracic Surgery, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27157-1096.
Nakanishi
K
K
Vinten-Johansen
J
J
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004151:Dipeptides / Q000627:therapeutic use*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D012977:Sodium Nitrite / Q000494:pharmacology
D004151:Dipeptides; C076992:N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester; C076993:pivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester; D009195:Peroxidase; D012977:Sodium Nitrite; D000109:Acetylcholine