Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Beneficial effects of SPM-5185, a cysteine-containing NO donor in myocardial ischemia-reperfusion. 141 1

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.
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PMID:Endothelial and myocardial cell protection by a cysteine-containing nitric oxide donor after myocardial ischemia and reperfusion. 750 67

Hearts exposed to global myocardial ischemia associated with cardiac surgery often suffer postischemic endothelial and contractile dysfunction related to antecedent regional or global ischemia. Our studies tested the hypothesis that supplementing blood cardioplegia and reperfusion with the nitric oxide (NO) precursor L-arginine or the NO donor SPM-5185 would preserve endothelial function, reduce infarct size, and reverse postcardioplegia regional contractile dysfunction or global dysfunction. In the first study involving 23 anesthetized dogs undergoing regional ischemia, supplementation of blood cardioplegia with L-arginine: (1) reduced infarct size; (2) improved postischemic regional segmental work and diastolic stiffness; (3) attenuated neutrophil accumulation in the area at risk; and (4) improved postischemic depressed coronary artery endothelial function. The NO synthase inhibitor N-nitro-L-arginine (L-NA) reversed these protective effects. In another experiment involving 18 anesthetized dogs undergoing normothermic global ischemia, hearts treated with blood cardioplegia supplemented with the NO donor SPM-5185 demonstrated better postischemic coronary artery endothelial function, lowered myeloperoxidase activity in the ischemic-reperfused myocardium, and significantly improved global ventricular function in the group receiving high-dose SPM-5185. We conclude that the inclusion of L-arginine or high-dose NO donor SPM-5185 in blood cardioplegia improves postischemic ventricular performance and endothelial function in ischemically injured hearts, possibly by inhibition of neutrophil-mediated damage via the L-arginine-NO pathway.
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PMID:Augmentation of microvascular nitric oxide improves myocardial performance following global ischemia. 757 37