Original articleThe ubiquitous role of nitric oxide in cardioprotection
Introduction
Since the mid-19th century, scientists and clinicians have attempted to understand the biological effects of organic nitrovasodilators. Brunton [1], one of the fathers of pharmacology, documented the efficacy of such compounds in patients suffering angina pectoris as early as 1867. Although it took more than a century to ascribe the biological activity of such compounds to nitric oxide (NO), we now appreciate the critical function of NO as an endogenous modulator of vascular tone [2], [3], [4], and agents that liberate NO continue to be among the most widely used drugs to combat cardiovascular disease.
For more than 15 years, NO has consumed the collective interest of investigators pursuing effective cardioprotective interventions. Because of apparent controversy, for many years the focus of the debate was not how but whether NO protects the heart during ischemia–reperfusion injury. As discussed previously in [5], examination of the literature reveals that the vast majority of studies concluded that NO exerts beneficial effects on myocardial ischemia–reperfusion injury, whilst an ever-shrinking minority of reports indicated a deleterious role of NO. Without oversimplifying the “NO is bad” studies, lessons from Paracelsus regarding dose may be most germane here: industrial doses of NO donors may lack clinical relevance and indeed, the dose makes the poison. The aggregate of the data published over the past 15 years compellingly demonstrate the protective virtues of NO. Review of such extensive data can be found in the predecessor [5] of this mini-review, which documents the evidence for NO-mediated cardioprotection and contains exhaustive experimental details too numerous to mention here. Thus, whether NO is beneficial or detrimental to the ischemic myocardium is no longer an issue and the basic premise of this mini-review is undemanding: NO protects the heart against ischemia–reperfusion injury. Hopefully our attention can now be redirected to the most relevant areas of NO and ischemic biology: What is the role of NO in various forms of cardioprotection, how can we augment the bioavailability of NO, and by which mechanisms does NO protect the heart during ischemia–reperfusion injury? The purpose of this essay is to address these issues, which represent the major areas of uncertainty regarding the role of NO in myocardial ischemia. Particular emphasis is placed on the interaction of NO with mitochondria, which is rapidly emerging as a key mechanism for the beneficial actions of this gas.
Section snippets
Gain-of-function/loss-of-function studies
Despite a bevy of reports on the ability of NO donors to defend the myocardium against ischemia–reperfusion injury, some maintained that NO damaged the heart. The advent of gene-targeted mice made it possible to directly test such hypotheses. Using endothelial nitric oxide synthase (eNOS) deficient mice generated by Huang et al. [6], we found that infarct size was significantly augmented following ischemia–reperfusion injury [7], supporting the actuality that eNOS-derived NO serves as an
Preconditioning and postconditioning
While it is clear that NO is sufficient to confer cardioprotection, it is becoming increasingly apparent that NO bioavailability is also necessary for several protective interventions. Ischemic preconditioning (IPC) remains a quintessential example of a complex, NO-dependent, cardioprotective process. Because of the numerous reviews published on preconditioning, we will limit the present discussion to the salient findings concerning NO in preconditioning and the emerging phenomenon of
Critical role of NO in the cardioprotection afforded by pleiotropic agents
In addition to pre- and postconditioning, NO plays a pivotal role in the cardioprotection induced by a panoply of pharmacologic agents. For example, several drugs used clinically for the treatment of hypercholesterolemia, hypertension, and even erectile dysfunction may improve NO bioavailability. HMG CoA reductase inhibitors, or statins, are widely known for their ability to markedly reduce serum cholesterol levels and attenuate the severity of coronary disease in patients [21], [22]. Soon
Is it possible to achieve long-term protection with NO?
The evidence supporting NO as a potent inducer of cardioprotection is overwhelming [5]. Regardless of the model system used, investigators have consistently implicated NO as a required, if not sufficient, factor in the cardioprotective actions of various pharmacologic, surgical, and physiologic interventions .[5]. Based upon this extensive literature, it seems logical to posit that chronic augmentation of NO bioavailability should be useful, for it would confer long-term protection against
Nitrite: recycling NO?
An exciting area of NO chemistry and physiology involves nitrite, the previously neglected oxidation product of NO. Lefer's group has recently disputed the long-held notion that nitrite is biologically inert in the cardiovascular system and found a significant role for nitrite in ischemia–reperfusion injury [63]. In their study, mice were injected with sodium nitrite at the end of myocardial ischemia and infarct size was evaluated after 1 day of reperfusion. Nitrite-treated mouse hearts
Interaction of NO with mitochondria
The ability of NO to bind to the heme center of guanylate cyclase and augment cGMP levels to dilate blood vessels is well understood. However, the mechanism whereby NO protects the heart against ischemia–reperfusion injury remains unclear. As detailed previously in [5], NO exerts a number of actions that would be expected to be beneficial during myocardial ischemia–reperfusion, including antagonism of beta-adrenergic stimulation, inhibition of influx through L-type calcium channels, activation
Conclusions
It is now clear, and widely accepted, that NO is a powerful cardioprotectant against ischemia–reperfusion injury. It has also become apparent that a wide spectrum of cardioprotective maneuvers operates in an NO-dependent manner. That is, increased NO availability is a common feature of diverse, apparently unrelated, interventions that limit tissue injury during myocardial ischemia and reperfusion, suggesting that this gas may be a final common pathway of cardioprotection. Research on the role
Acknowledgments
This work is supported in part by an AHA National Center Scientist Development Grant (0535270N) and National Institutes of Health grants HL-55757, HL-68088, HL-70897, and HL-78825.
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