Vol. 287, Issue 2, 527-537, November 1998

SP/W-5186, A Cysteine-Containing Nitric Oxide Donor, Attenuates Postischemic Myocardial Injury

Gao-Lin Liu, Theodore A. Christopher, Bernard L. Lopez, Feng Gao, Yaping Guo, Erhe Gao, Karlheinz Knuettel , Martin Feelisch¹ and Xin L. Ma

Division of Emergency Medicine, Thomas Jefferson University; Pharmacia AG, Monheim, Germany (G.-L.L., T.A.C., B.L.L., F.G., Y.G., E.G., M.F., X.L.M.); The Wolfoson Institute for Biomedical Research, University College London, London, UK (K.K., M.F.); and Schwarz Pharma AG, Monheim, Germany (K.K.)

The effects of SP/W-5186, a cysteine-containing nitric oxide (·NO) donor, on myocardial reperfusion injury were studied in a rabbit ischemia (45 min) and reperfusion (180 min) model. Five min before reperfusion, either low-dose (0.3 µmol/kg) or high-dose (1 µmol/kg) SP/W-5186 was given intravenously as a bolus. Administration of 0.3 µmol/kg SP/W-5186 did not change mean arterial blood pressure, heart rate or pressure-rate index. However, administration of low-dose SP/W-5186 exerted marked cardioprotective effects as evidenced by improved cardiac functional recovery (P < .05 vs. vehicle), decreased plasma creatine kinase concentration (P < .01) and reduced infarct size (P < .01). Moreover, administration of SP/W-5186 significantly decreased platelet aggregation (P < .01 vs. vehicle), attenuated polymorphonuclear leukocyte (PMN) accumulation in myocardial tissue, inhibited PMN adhesion to endothelial cells and preserved endothelial function. Administration of high-dose SP/W-5186 resulted in a transient but significant decrease in mean arterial blood pressure and exerted more cardiac protection compared with low-dose treatment. However, the effects on platelet aggregation, PMN accumulation and PMN adhesion did not differ significantly between the two SP/W-5186 groups. Furthermore, administration of SP/W-6373, an analogue of SP/W-5186 that lacks the NO moiety, failed to exert any protective effects. These results demonstrate that NO released from SP/W-5186 significantly protected myocardial tissue from reperfusion injury. The primary mechanisms of the observed cardioprotection by SP/W-5186 involve inhibition of platelet aggregation, attenuation of PMN-endothelium interaction and preservation of endothelial function.