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 distinguish the function of NO in unstressed (non-preconditioned) myocardium from its function in preconditioned myocardium (i.e. myocardium that has shifted to a defensive phenotype in response to stress). Of the 92 studies that have examined the role of NO in modulating the severity of ischemia/reperfusion 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 studies supporting a cytoprotective role of NO is similar in vivo[35 (71%) out of 49] and in vitro[32 (74%) out of 43]. With regard to the delayed acquisition of tolerance to ischemia [late preconditioning (PC)], overwhelming evidence indicates a critical role of NO in this phenomenon. Specifically, enhanced biosynthesis of NO by eNOS is essential to trigger the late phase of ischemia-induced and exercise-induced PC, and enhanced NO production by iNOS is obligatorily required to mediate the anti-stunning and anti-infarct actions of late PC elicited by five different stimuli (ischemia, adenosine A1agonists, opioidδ1 agonists, endotoxin derivatives and exercise). Thus, NO plays a dual role in the pathophysiology of the late phase of PC, acting initially as the trigger and subsequently as the mediator of this adaptive response (“NO hypothesis of late PC”). The diversity of the PC stimuli 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 other tissues, including kidney and intestine. Other corollaries of this hypothesis are that the heart responds to stress in a biphasic manner, utilizing eNOS as an immediate but short-term response and iNOS as a delayed but long-term defense, and that the fundamental difference between non-preconditioned and late preconditioned myocardium is the tissue level of iNOS-derived NO, which is tonically higher in the latter compared with the former. Hence, late PC can be viewed as a state of enhanced NO synthesis. The NO hypothesis of late PC has important therapeutic implications. In experimental animals, administration of NO donors in lieu of ischemia can faithfully reproduce the molecular and functional aspects of ischemia-induced late PC, indicating that NO is not only necessary but also sufficient to induce late PC. The recent demonstration that nitroglycerin also induces late PC in patients provides proof-of-principle for the concept that nitrates could 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 important as, or perhaps even more important than, their current use as antianginal 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 alleviating ischemia/reperfusion injury. Ten years of research have demonstrated that NO plays a fundamental biological role in protecting the heart against ischemia/reperfusion injury. The time has come to translate this enormous body of experimental evidence into clinically useful therapies by harnessing the cytoprotective properties of NO.