n-nitratopivaloyl-s-(n--acetylalanyl)-cysteine-ethyl-ester and Necrosis

It has recently been demonstrated that myocardial ischemia and reperfusion results in a marked decrease in the release of nitric oxide (NO) by the coronary endothelium. NO may possess cardioprotective properties, possibly related to inhibition of neutrophil-related activities. We tested the hypothesis that a cysteine-containing nitric oxide donor compound, SPM-5185, would reduce infarct size and inhibit neutrophil-related activities (adherence to coronary vascular endothelium, accumulation).. The effects of intracoronary infusion of SPM-5185 were investigated in a 5.5-hour model of myocardial ischemia (1 hour) and reperfusion (4.5 hours) (MI-R) in anesthetized, open-chest dogs. SPM-5185 (500 nmol/L) or saline vehicle was infused for 4.5 hours into the left anterior descending coronary artery (LAD) at the time of reperfusion after 1 hour of LAD occlusion. MI-R in dogs receiving saline vehicle resulted in severe myocardial injury characterized by dyskinesis, a profound elevation of plasma creatine kinase, marked myocardial necrosis, and high cardiac myeloperoxidase (MPO) activity in the ischemic and necrotic zones. In contrast, treatment with SPM-5185 resulted in a modest restoration of regional function, a reduction of myocardial necrosis expressed as a percentage of the area at risk (12.5 +/- 3.2% versus 41.7 +/- 5.4%, P < .001), and significant reductions of MPO activity in the ischemic zone (0.8 +/- 0.1 versus 2.5 +/- 0.7 U/100 mg tissue, P < .05) and the necrotic zone (1.6 +/- 0.2 versus 3.3 +/- 0.6 U/100 mg tissue, P < .05). In additional studies, SPM-5185 (500 nmol/L) significantly (P < .001) attenuated the adherence of LTB4-stimulated canine neutrophils to autologous segments of coronary artery and attenuated the neutrophil-induced contraction of isolated coronary arterial rings.. SPM-5185 reduces myocardial necrosis and neutrophil accumulation in an acute model of canine myocardial ischemia and reperfusion. This reduction in myocardial cell injury may be partially related to the inhibitory actions of this novel NO donor on neutrophil adherence to the coronary endothelium.

Topics: Animals; Cell Adhesion; Coronary Circulation; Creatine Kinase; Dipeptides; Dogs; Endothelium, Vascular; Female; Heart; Hemodynamics; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Necrosis; Neutrophils; Nitric Oxide; Peroxidase

Intravenous administration of SPM-5185 [N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester], a cysteine-containing nitric oxide (NO) donor, or SPM-5267 [pivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester], an analogue of SPM-5185 that lacks the NO moiety, was studied in a feline myocardial ischemia-reperfusion model. Administration of SPM-5185 (1 mg/kg), followed by a 2-mg.kg-1.h-1 infusion starting 10 min before reperfusion, resulted in significant protection 4.5 h postreperfusion. In the myocardial ischemia (MI)+SPM-5267 group, 38 +/- 4% of the area at risk was necrotic, whereas the necrotic area/area at risk was only 7 +/- 2% in the MI+SPM-5185 group (P less than 0.01). Moreover, SPM-5185 treatment markedly attenuated the endothelial dysfunction observed in the left anterior descending coronary artery after reperfusion by 50%. These beneficial effects occurred despite the absence of a significant change in myocardial oxygen demand, as measured by the pressure-rate index. In vitro experiments demonstrated that SMP-5185, but not SPM-5267, decreased adherence of neutrophils to the coronary vascular endothelium and decreased production of superoxide radicals. Therefore, a likely mechanism of the observed cardioprotection by SPM-5185 involves attenuation of polymorphonuclear leukocyte-induced endothelial dysfunction.

Topics: Animals; Cats; Coronary Disease; Cysteine; Dipeptides; Electrocardiography; Hemodynamics; Male; Myocardial Reperfusion; Myocardial Reperfusion Injury; Necrosis; Neutrophils; Nitric Oxide; Risk Factors