n-nitratopivaloyl-s-(n--acetylalanyl)-cysteine-ethyl-ester and Myocardial-Ischemia

Coronary artery ischemia initiated by occlusion or thrombus formation produces myocardial ischemia that can ultimately result in myocardial cell injury and necrosis of the myocardium. Current clinical strategies for the treatment of acute myocardial ischemia include coronary angioplasty, directional coronary atherectomy, and the administration of thrombolytic agents to restore blood flow to the ischemic myocardium. While coronary reperfusion can salvage ischemic tissue, it may in itself also contribute to coronary vascular and myocardial cell injury (1-4). Myocardial reperfusion after coronary artery ischemia accelerates the necrosis of reversibly injured cardiac myocytes by enhancing cell swelling, the disruption of cell ultrastructure, formation of contraction bands, and the influx of calcium and other ions (2, 3). Recent experimental evidence strongly suggests that coronary artery endothelial dysfunction may be an early trigger for neutrophil-mediated myocardial reperfusion injury (4-7). Nitric oxide (NO.) release by the coronary vasculature is impaired within 5 mins after reperfusion of ischemic myocardium and results in a profound loss of vascular homeostasis (7). Polymorphonuclear neutrophils (PMN) begin to accumulate within the ischemic-reperfusion myocardium as a result of diminished coronary NO. release; activated PMNs then mediate myocardial cell injury and necrosis (6, 7). Novel therapeutic strategies aimed at the preservation or replenishment of coronary NO. concentrations may prove beneficial in the treatment of myocardial reperfusion injury in the future.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dipeptides; Heart; Humans; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Nitric Oxide; Sydnones

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