Protection of ischemia-reperfusion injury by sydnonimine NO donors via inhibition of neutrophil-endothelium interaction.
Ischemia of a vascular bed followed by reestablishment of blood flow results in an accelerated and severe form of tissue injury known as "reperfusion injury." We have investigated reperfusion injury in cats subjected to either myocardial ischemia-reperfusion or splanchnic ischemia-reperfusion. In both cases, a critical early event after reperfusion is endothelial dysfunction characterized by reduced release of endothelium-derived relaxing factor now known to be nitric oxide (NO). Endothelial dysfunction leads to adherence of polymorphonuclear (PMN) leukocytes to the dysfunctional endothelium. Infusion of a sydnonimine NO donor (C87-3754), but not a similar compound lacking the NO moiety (C88-3934), just before reperfusion protected in both forms of ischemia-reperfusion. In the first case, C87-3754, but not C88-3934, attenuated myocardial necrosis, and in the second case, the NO donor improved survival and moderated the indices of shock. In both cases, C87-3754 preserved the endothelium of the ischemic-reperfused vasculature and exerted anti-PMN effects (i.e., reduced PMN adherence to the endothelium or attenuated PMN release of superoxide radicals). Thus, an NO donor infused at a rate calculated to replace the lost NO from the vascular endothelium of the ischemic region exerts significant protective effects on reperfusion of that ischemic vascular bed.
Lefer
A M
AM
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799.
Siegfried
M R
MR
Ma
X L
XL
D000818:Animals; D002415:Cats; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D013558:Sydnones / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D013558:Sydnones; D014665:Vasodilator Agents; C072857:3-(cis-2,6-dimethylpiperidino)sydnonimine; D009569:Nitric Oxide