Beneficial effects of SPM-5185, a cysteine-containing NO donor in myocardial ischemia-reperfusion.
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.
Siegfried
M R
MR
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Carey
C
C
Ma
X L
XL
Lefer
A M
AM
D000818:Animals; D002415:Cats; D003327:Coronary Disease / Q000503:physiopathology*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides; D004562:Electrocardiography; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009336:Necrosis; D009504:Neutrophils / Q000502:physiology; D009569:Nitric Oxide / Q000032:analysis*; D012307:Risk Factors
D004151:Dipeptides; C076992:N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester; C076993:pivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester; D009569:Nitric Oxide; D003545:Cysteine