Adaptation to ischemia with special emphasis on nitric oxide

Abstract: Nitric oxide (NO) may play an essential role for maintenance of cardiac function and perfusion. Endothelial dysfunction of atherosclerotic vessels may aggravate cardiac ischemia/reperfusion injury. Adaptation to ischemia may be induced by short episodes of ischemia and reperfusion before sustained ischemia, which may be performed on the heart itself or another organ to protect the heart. NO has been suggested to be a signal molecule initiating this adaptation, while inducible nitric oxide synthase (iNOS) has been suggested as a mediator of delayed preconditioning of the heart. The protection afforded by preconditioning may potentially be associated with changes of vessel tone. Most investigations of the role of cardiac nitric oxide and ischemic preconditioning in ischemia/reperfusion injury has been conducted in animals with normal vessels. With the development of recombinant DNA technology, animal models of atherosclerosis have emerged. One of these models is the apolipoprotein E and LDL receptor double knockout (ApoE/LDLr KO) mouse, which develops atherosclerosis with a distribution pattern of lesions similar to humans. In the present studies, we demonstrate endothelial dysfunction in ApoE/LDLrKO mice and that the tolerance of their hearts to ischemia was decreased (Langendorff model). A NO donor attenuated the decreased ischemic tolerance of ApoE/LDLrKO mice hearts, while the same concentration of the donor was detrimental in normal hearts, probably due to NO-overproduction and peroxynitrate formation. We also demonstrated several kinds of adaptation to ischemia by preconditioning. Classic ischemic preconditioning could protect not only normal mice hearts bit also atherosclerotic mice hearts. Exposure to hyperoxia exerted a similar protection as ischemic preconditioning in atherosclerotic mice. Spontaneous heart infarctions in vivo adapted the heart of atherosclerotic mice to induced ischemia ex vivo analogous to delayed ischemic preconditioning. Spontaneous ischemic events in the brain also protected the hearts of atherosclerotic mice, and this effect could be mimicked by inducing brain ischemia by bilateral internal carotid artery ligation in normal mice. Spontaneous and induced brain ischemia attenuated vessel contractility in vitro, increased vessel dilatation, and upregulated iNOS in the vessel wall as well as in the heart. Pharmacological and genetical inhibition of iNOS abolished the protective effects and changed vessel reactivity. These findings suggest that delayed ischemic preconditioning effects evoked by brain ischemia may mediated by iNOS. The present study indicates that patients with coronary atherosclerosis may benefit from treatment with NO-enhancing agents or preconditioning techniques. The organ protection is generated by ischemia rather than by ischemia and reperfusion and may mediated by iNOS.