Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research

Over the past decade, an enormous number of studies (> 100) have focused on the role of nitric oxide (NO) in myocardial ischemia. It is important to d istinguish the function of NO in unstressed (nonpreconditioned) myocardium from its function in preconditioned myocardium (i.e. myocardium that has sh ifted to a defensive phenotype in response to stress). Of the 92 studies th at have examined the role of NO in modulating the severity of ischemia/repe rfusion injury in non-preconditioned myocardium, the vast majority [67 (73% )] have concluded that NO (either endogenous or exogenous) has a protective effect and only 11 (12%) found a detrimental effect, The proportion of stu dies supporting a cytoprotective role of NO is similar in vivo [35 (71%) ou t of 49] and in vitro [32 (74%) out of 43]. With regard to the delayed acqu isition of tolerance to ischemia [late preconditioning (PQ], overwhelming e vidence indicates a critical role of NO in this phenomenon. Specifically, e nhanced biosynthesis of NO by eNOS is essential to trigger the late phase o f ischemia-induced and exercise-induced PC, and enhanced NO production by i NOS is obligatorily required to mediate the anti-stunning and anti-infarct actions of late PC elicited by five different stimuli (ischemia, adenosine A, agonists, opioid delta (1) agonist's, endotoxin derivatives and exercise ). Thus, NO plays a dual role in the pathophysiology of the late phase of P C. acting initially as the trigger and subsequently as the mediator of this adaptive response ("NO hypothesis of late PC"). The diversity of the PC st imuli that converge on iNOS implies that the upregulation of this enzyme is a central mechanism whereby the myocardium protects itself from ischemia. The NO hypothesis of late PC has thus revealed a cytoprotective function of iNOS in the heart, a novel paradigm which has recently been extended to ot her tissues, including kidney and intestine. Other corollaries of this hypo thesis are that the heart responds to stress in a biphasic manner, utilizin g eNOS as an immediate but short-term response and iNOS as a delayed but lo ng-term defense, and that the fundamental difference between non-preconditi oned and late preconditioned myocardium is the tissue level of iNOS-derived NO, which is tonically higher in the latter compared with the former. Henc e, late PC can be viewed as a state of enhanced NO synthesis. The NO hypothesis of late PC has important therapeutic implications. In exp erimental animals, administration of NO donors in lieu of ischemia can fait hfully reproduce the molecular and functional aspects of ischemia-induced l ate PC, indicating that NO is not only necessary but also sufficient to ind uce late PC. The recent demonstration that nitroglycerin also induces late PC in patients provides proof-of-principle for the concept that nitrates co uld be used as a PC-mimetic therapy for the prophylaxis of ischemic injury in the clinical arena. This novel application of nitrates could be as impor tant as, or perhaps even more important than, their current use as antiangi nal and preload-reducing agents, In addition, gene transfer of either eNOS or iNOS has been shown to replicate the infarct-sparing actions of ischemic PC, suggesting that NOS gene therapy could be an effective strategy for al leviating ischemia/reperfusion injury. Ten years of research have demonstra ted that NO plays a fundamental biological role in protecting the heart aga inst ischemia/reperfusion injury The time has come to translate this enormo us body of experimental evidence into clinically useful therapies by harnes sing the cytoprotective properties of NO. (C) 2001 Academic Press.