缺血-再灌注损伤发病机制的研究进展.ppt

overproduction of superoxide anions by postischaemic endothelial cells underlying these remote vascular responses to reperfusion, superoxide dismutase and other antioxidants can restore this response in postischaemica rterioles Mice that are genetically de?cient in leukocyte (CD11/CD18) or endothelial cell adhesion molecules (P-selectin, ICAM-1), unlike wild-type (control) mice, do not exhibit an impaired endothelium dependent vasodilation after I/R, The pH paradox refers to the paradoxical worsening of cell injury when pH is returned from acidotic to normal during reperfusion. This change of pH rather than reoxygenation precipitates lethal cell injury after reperfusion. Significantly, lethal cell injury caused by the pH paradox can be prevented by inhibition of Na+/H+ exchange in the plasma membrane. For example, acidosis can initially depress the Ca2+i transient that triggers contraction, but later on it can profoundly enhance the transient. Much of this latter effect forms the basis of the so-called “pH-paradox” that occurs during post ischaemic reperfusion of the heart.? The scenario is that intracellular acid overload leads to intracellular Ca2+ overload and the appearance of triggered arrhythmias. A major part of the effect is mediated through overdrive of the acid extrusion proteins NHE and NBC, as inhibiting the transporters pharmacologically prevents much of the Ca2+overload and suppresses the arrhythmia. Selective inhibition of these transporters appears to be cardioprotective during post ischaemic reperfusion. Several selective inhibitors have been developed by the pharmaceutical industry as potential therapeutic agents for treatment of ischaemic disorders of the heart.? In the calcium paradox, Ca -free incubation produces Na loading of cardiac myocytes largely mediated by Na influx via L-type Ca channels. Subsequent exposure to normal extracellular Ca activates sarcolemmal Na /Ca exchanger. Ca exchange operating in the reverse mode. As a consequen