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Ann Thorac Surg 1995;60:852-857
© 1995 The Society of Thoracic Surgeons

III: New Directions in Surgical Myocardial Protection

Reduction in Surgical Ischemic-Reperfusion Injury With Adenosine and Nitric Oxide Therapy

Jakob Vinten-Johansen, PhD, Zhi-Qing Zhao, MD, PhD, Hiroki Sato, MD, PhD

Department of Cardiothoracic Surgery, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina

Abstract

Ischemia and reperfusion impair the inherent capacity of the heart to protect itself from related pathophysiologic events by reducing endogenous oxygen radical scavengers and inhibitors. However, other endogenously produced agents, notably adenosine and nitric oxide, are produced during ischemia, reperfusion, or both. These autacoids have several cardioprotection actions in common, particularly antineutrophil effects and inhibition of endothelial-neutrophil interactions, which are key initial steps in ischemic-reperfusion injury. Studies have shown that nitric oxide exerts cardioprotection primarily during reperfusion. Adenosine, on the other hand, protects the myocardium to some extent during both ischemia and reperfusion, thereby covering both periods during which myocardial injury may be sustained during a cardiac operation. Native adenosine or active analogues, or donors of nitric oxide, may be given before or in conjunction with cardioplegia solutions. However, these endogenous agents can also be pharmacologically recruited to provide a new potent therapeutic approach against surgical ischemic-reperfusion injury. This article reviews the cardioprotective effects of primarily endogenous nitric oxide and adenosine in both nonsurgical and surgical models of ischemia-reperfusion injury. Both adenosine and nitric oxide provide potent cardioprotection in surgical and nonsurgical models of ischemia-reperfusion. An important mechanism in this cardioprotection is attenuation of neutrophil-mediated damage.

Although well-established strategies for protecting the heart from surgically related ischemic and reperfusion injury have evolved over the past decades, older patients presenting with more severe injury as well as very complex surgical cases in all age groups involving prolonged ischemic time require special target- and event-specific therapy to adequately restore contractile function and morphology. In addition, it has become appreciated that ischemia and reperfusion injury strikes more than just myocytes [1--4], and may include reversible and irreversible damage to the coronary vascular endothelium. Indeed, a major event in the initiation of postischemic pathology may be impairment of the autocrine and paracrine function of the vascular endothelium, resulting in unbridled activation and adherence of neutrophils at the blood--vascular endothelial interface [5].

In recent years, several endogenous agents released by endothelial cells as well as myocytes have demonstrated potent cardioprotective properties. Two of these substances, nitric oxide (NO) and adenosine, are synthesized or stored in vascular endothelium and myocytes, and are released into the surrounding vascular and interstitial compartments during the ischemic and perireperfusion periods. Nitric oxide, originally called endothelium-derived relaxing factor [6], is generated not only by vascular endothelium but also by myocytes and macro-phages (inducible NO) during the conversion of L-arginine to citrulline by the highly substrate specific NO synthase (Fig 1Go). This reaction requires oxygen, the absence of which favors the formation of superoxide radicals. Adenosine is formed by the catabolism of the nucleotides adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate, a process that occurs in myocytes and is favored during oxygen deprivation, ie, ischemia or hypoxia. Interestingly, both autacoids share remarkably similar physiologic effects in the myocardium (Table 1Go). Nitric oxide [1, 7] and adenosine [8, 9] are both released basally and are potent vasodilators involved in the homeostatic regulation of coronary blood flow. In addition, both autacoids possess platelet inhibitory actions and potent antineutrophil properties, which include inhibition of neutrophil activities including homotypic aggregation, superoxide generation, and adhesion to the coronary arterial and venous endothelium [1, 10]. Although adenosine cardioprotection is mediated primarily by receptor-mediated processes with some metabolic effects, the protective effects of NO are conferred by non--receptor-mediated mechanisms. Intriguingly, both adenosine [11, 12] and NO [13--15] exert their cardioprotection in ischemia-reperfusion models of irreversible injury (ie, infarction) predominantly during reperfusion, with a lesser degree of protection exerted during ischemia [11, 16]. In models of nonlethal myocyte injury, adenosine at least may inhibit injury during ischemia contributing to contractile dysfunction or metabolic derangements. This observation has important implications for use of both of these therapeutic agents in cardiac surgery, in which injury potentially occurs during both ischemia (preoperative or cardioplegic) and reperfusion. Finally, both endogenous agents have very short half-lives, which favor expression of their actions to localized areas, ie, areas of local tissue inflammation and injury, and for very brief periods of time. Hence, NO and adenosine may be prototypical agents for site-specific (ie, ischemic-reperfused tissue) and event-specific (ie, during ischemia or during reperfusion) therapy.



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  		Fig 1. . Production of nitric oxide (NO) from the L-arginine (L-Arg)--NO synthase (NOS) pathway in endothelial cells (EC). Receptors on the luminal side of the endothelial cells for acetylcholine (ACh), histamine (Hist), adenine diphosphate (ADP), and serotonin (Ser) participate in physiologic or pharmacologic agonist-stimulated augmentation of NO production by NOS. The calcium ionophore A23187 is used to stimulate NO production independent of receptors on the endothelium. Nitric oxide inhibits (-) neutrophils (PMN) and platelets on the luminal side, and stimulates soluble guanylate cyclase (sGC) to increase cyclic guanosine monophosphate (GMP) to initiate smooth muscle cell (SMC) relaxation in a dose-dependent manner.

 

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  		Table 1. . Physiologic Actions of Adenosine and Nitric Oxide
 
Nitric Oxide Therapy

Impairment of the release or production of NO has been associated with the pathogenesis of numerous disease states [17]. Damage to the coronary vascular endothelium is associated with increased neutrophil activity including adherence, superoxide generation, and release of cytokines and proteases, followed by emigration into the myocardial parenchyma. Further injury to the endothelium and surrounding myocytes ensues subsequent to activation of this cascade. In a recent study by Nakanishi and associates [3], canine hearts were subjected to cardiopulmonary bypass with 45 minutes of normothermic global ischemia with or without blood cardioplegia (1 hour) and reperfusion. The capability of the coronary artery endothelium to produce NO (ie, endothelial function) was assessed by agonist-stimulated relaxation responses to acetylcholine (endothelial-dependent, receptor-dependent stimulator of NO) and acidified NaNO2 (NO donor) in coronary artery rings immersed in organ baths. As shown in Figure 2AGo, the endothelium was slightly damaged after 45 minutes of normothermic ischemia, but sustained significant dysfunction after reperfusion with unmodified blood. One hour of intermittent, hypothermic, hyperkalemic blood cardioplegia given to these normothermic ischemic hearts neither exacerbated nor reversed this modest endothelial dysfunction, despite the additional cardioplegic ``ischemic'' time. However, subsequent reperfusion of these hearts was associated with marked dysfunction. Therefore, the greatest progression of endothelial dysfunction in the surgical setting occurred during reperfusion with or without intervening cardioplegia, although more prolonged periods of normothermic global ischemia (exceeding 45 minutes) may cause progressive endothelial dysfunction in the absence of reperfusion [18]. Injury to the endothelium after reperfusion attenuated the basal as well as the agonist-stimulated generation of NO dramatically. This impairment of a basal, endogenous cardioprotective mechanism may in turn compromise the myocardium's endogenous defense mechanisms against postischemic injury. In support of this notion, pharmacologic inhibition of NO production by blockade of the highly stereospecific NO synthase enzyme with a reversible inhibitory analogue of L-arginine, L-NA, increased infarct size after coronary occlusion-reperfusion [16], suggesting that the withdrawal of endogenous NO counteracted an endogenous anti-infarct process. This effect occurred predominantly during reperfusion [16], because blockade at reperfusion only increased infarct size to the same extent as blockade during both ischemia and reperfusion. Similar results were obtained with the nonmetabolized enantiomer D-arginine, again predominantly at reperfusion [13, 16].



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  		Fig 2. . (A) Concentration--response curves to incremental concentrations of acetylcholine in coronary arteries from hearts of normal controls ({circ}), normothermic ischemia only ({square}), ischemic-reperfused ({triangleup}; no cardioplegia), ischemic and 1 hour cardioplegic interval without reperfusion ({blacktriangleup}), and ischemic-cardiopleged with blood cardioplegia and reperfused (•). (Cx = circumflex artery; LAD = left anterior descending coronary artery.) (Reprinted with permission from The Society of Thoracic Surgeons [Ann Thorac Surg 1994;58:191--9].) (B) Infarct size as area of necrosis versus area at risk ratio (percent An/Ar) in hearts treated with standard unsupplemented blood cardioplegia (BCP), BCP supplemented with 10 mmol/L L-arginine (L-Arg), and BCP supplemented with 10 mmol/L L-Arg in the presence of the nitric oxide synthase inhibitor L-NA. Bars represent means +/- standard error; circles represent individual data points. (*p < 0.05 versus BcP, L-NA; **p < 0.05 versus BcP, L-ARG.) (Reprinted with permission from Sato H, et al. Supplemental L-arginine during cardioplegic arrest and reperfusion avoids regional ischemic injury. J Thorac Cardiovasc Surg 1995;109.) (C) The benefits of a nitric oxide donor agent (SPM-5185) on global left ventricular performance assessed by the slope of the end-systolic pressure--volume (conductance catheter technique) relationship (Ees) before (Pre) and after (Post) antecedent normothermic arrest followed by blood cardioplegia and reperfusion. (SPM-H = 10 mmol/L of blood cardioplegia; SPM-L = 1 mmol/L of blood cardioplegia; VEH = unsupplemented BCP; *p < 0.05 versus Pre; +p < 0.05 versus Post of VEH group.) (Reprinted with permission from Nakanishi K, Zhao ZQ, Vinten-Johansen J, Hudspeth DA, McGee DS, Hammon JW Jr. Blood cardioplegia enhanced with the nitric oxide donor SPM-5185 counteracts postischemic endothelial and ventricular dysfunction. J Thorac Cardiovasc Surg 1995;109:1146--54.)

 
Two basic approaches may be adopted to overcome this obtunded endogenous NO release: substrate enhancement with L-arginine, the precursor of NO, may augment NO production in a concentration-dependent manner [19], or supplementation with an NO donor agent may increase systemic NO concentrations. Modulation of endogenous NO release has been shown to alter infarct size [13, 16, 20, 21] and contractile dysfunction [13, 14, 22]. L-arginine given only at reperfusion after coronary occlusion reduced infarct size [13, 21]. When used as a supplement to blood cardioplegia, L-arginine significantly improved postischemic contractile function and endothelial function. Furthermore, L-arginine-enhanced blood cardioplegia reduced infarct size in the ``revascularized'' myocardium (Fig 2BGo), possibly by attenuating neutrophil accumulation [13, 23]. However, augmentation of endogenously produced NO by precursors may be limited if the endothelium is damaged before treatment is initiated, resulting in impaired endothelial release of NO and depletion or impaired transport of L-arginine to the intracellular compartment. This limitation to augmenting endogenous NO may be overcome with exogenous NO donor agents. In a recent study, Nakanishi and associates [15] demonstrated that supplementation of blood cardioplegia with the cysteine-containing NO donor agent SPM-5185 significantly improved postischemic contractile performance (Fig 2CGo). In addition, SPM-5185 also reduced endothelial injury and neutrophil accumulation, assessed by myeloperoxidase activity in left ventricular myocardium. Furthermore, there was a tendency for the degree of postischemic endothelial dysfunction to correlate with the degree of postischemic contractile dysfunction.

It should be noted that not all studies conclude that the L-arginine--NO pathway acts in beneficial ways. Studies by Matheis and colleagues [24] showed that augmentation of NO by L-arginine increased postischemic injury, whereas Woolfson and co-workers [25] reported that blockade of NO synthase activity with an arginine analogue decreased postischemic injury. The mechanism by which NO expresses deleterious effects is suggested to be extreme vasodilation (ie, endotoxic shock) or formation of peroxynitrite, nitrogen dioxygen, and hydroxyl radicals from NO [24, 26]. However, these observed deleterious effects may be model-dependent for hypoxia-reperfusion, endotoxic shock, and in vitro experimental models. Consistent cardioprotection has been reported for ischemic-reperfusion models. In addition, recent evidence argues strongly against the in vivo conversion of peroxynitrite to hydroxyl radicals by showing that NO is recycled to nitrosothiols or NO itself in plasma environments [27]. Therefore, NO-related therapy may be a useful approach for reducing ischemic-reperfusion injury encountered in cardiac operations.

Adenosine Therapy

Recent studies have shown that adenosine possesses potent cardioprotective effects in surgical models and nonsurgical models of irreversible injury (infarct size). Exogenous adenosine reduces infarct size, postischemic microvascular injury, and time to ischemic contracture [28, 29]. Nonselective blockade of interaction between the endogenously released adenosine and the adenosine A1 and A2 receptors with 8-p-sulfophenyl theophylline (8-SPT) resulted in an increase in infarct size when 8-SPT was given before ischemia; a similar increase in infarct size was observed when 8-SPT was given only at reperfusion [11]. These observations suggest that endogenous adenosine exerts cardioprotection predominantly during reperfusion, although adenosine is released into the myocardial interstitium during ischemia [8]. Interestingly, 8-SPT given 30 minutes after reperfusion (presumably after major reperfusion injury has taken place) had no effect on infarct size relative to the vehicle group. An additional study suggested that principally A2-mediated processes were involved during reperfusion, whereas only a relatively small degree of cardioprotection was exerted during ischemia by A1-mediated processes [12]. Data from Cronstein and associates [30] suggest that adenosine may inhibit neutrophil activities. Indeed, adenosine directly inhibits production of superoxide radicals by neutrophils (endothelium-independent action), as well as neutrophil adherence and subsequent damage to the endothelium [31]. Therefore, cardioprotection by endogenous adenosine related to infarction appears to be largely receptor mediated, exerted principally during reperfusion by A2-mediated processes with some lesser A1-mediated effects exerted during ischemia. These effects may be different than those in models of short-term global or regional ischemia producing contractile dysfunction or metabolic dysfunction. In these models, adenosine may exert significant cardioprotection during ischemia, necessitating a pretreatment administration, and this protection may not involve neutrophil inhibition because neutrophils may not become significantly involved in the pathologic sequences until reperfusion [17].

Our laboratory has performed several studies testing the benefits of adenosine and adenosine-regulating therapy as a cardioprotective approach in cardiac surgery. In hearts made vulnerable to ischemia-reperfusion injury by 30 minutes of antecedent normothermic ischemia, adenosine used as an adjunct to blood cardioplegia at 400 µmol/L, preserved postischemic left ventricular performance assessed by end-systolic pressure--volume relations (Fig 3AGo) [32]. This protective effect was reversed by 8-SPT, demonstrating receptor-mediated processes. Therefore, adenosine had similar cardioprotective effects in the surgical setting as reported for the nonsurgical setting [11, 28]. However, whether adenosine exerted cardioprotection during ischemia in this setting has not yet been determined. Data reported by Lasley and Mentzer [29] clearly show that adenosine reduces injury during ischemia as well, because it decreases the time to onset of ischemic contracture.



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  		Fig 3. . (A) Slope of the end-systolic pressure-volume (conductance catheter) relationship (ESPVR) in hearts treated with standard blood cardioplegia (BCP), BCP with 400 µmol/L adenosine (ADO), and hearts treated with 400 µmol/L adenosine in the presence of the adenosine receptor inhibitor 8-p-sulfophenyl theophylline (ADO+SPT). Open bars = before ischemia, dark bars = after reperfusion. (*p < 0.05 versus Pre.) (Data are taken from reference [32].) (B and C) Pressure--volume (conductance catheter) loops of representative hearts treated with BCP and BCP supplemented with the adenosine deaminase inhibitor pentostatin. (LV = left ventricular; Post = after cardioplegia reperfusion; Pre = normal control before ischemia. (Reprinted with permission from The Society of Thoracic Surgeons [Ann Thorac Surg 1994;58:719--27].)

 
Potential side effects of high doses of adenosine, and the attractive benefit of a site- and event-specific action of adenosine, prompted us to examine whether endogenous adenosine could be recruited to protect the heart during surgically relevant ischemia-reperfusion. Augmentation of endogenous adenosine during cardioplegic arrest with 2-deoxycoformycin (pentostatin) provided nearly complete preservation of postischemic left ventricular systolic performance when given as a pretreatment (before aortic cross-clamping) (Fig 3B, 3CGoGo); this protection was associated with dramatic increases in interstitial fluid adenosine concentrations measured by intravital microdialysis (Fig 4Go). However, pentostatin failed to protect the heart when given solely as an adjunct in blood cardioplegia, most likely because adenosine levels were not augmented in a hypothermic environment [33]. The adenosine-mediated protection may have involved inhibition of neutrophil accumulation because myeloperoxidase activity specific for neutrophils was significantly reduced in the pentostatin-pretreated group. Similarly, the adenosine regulating agent acadesine, used as adjunct to blood cardioplegia, avoided severe postischemic contractile dysfunction [34]. A recent study in a nonsurgical model of ischemia-reperfusion confirmed that acadesine does exert cardioprotection by adenosine-related mechanisms exerted primarily during reperfusion, but without increasing interstitial adenosine concentrations [9]. It is postulated that acadesine could increase intravascular adenosine concentrations, raising the possibility of different effects of adenosine in the vascular and interstitial compartments. Our studies agree with others in demonstrating cardioprotection with adenosine and adenosine-regulating agents in the setting of cardiac operations [35, 36]. However, this is not a universal observation for the adenosine regulating agents [37].



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  		Fig 4. . Interstitial adenosine concentrations obtained by intravital microdialysis during the course of ischemia, cardioplegic arrest with intermittent hypothermic blood cardioplegia, and reperfusion in unsupplmented blood cardioplegia group ({blacksquare}), pentostatin-pretreated group (•), and pentostatin--blood cardioplegia group ({blacktriangleup}). (BCP [number] = infusion of blood cardioplegia every 20 minutes during 1 hour arrest; CBE = control beating empty; CBW = control beating working; ISCH = normothermic global ischemia; PBE = after cardioplegia beating empty; PBW = after cardioplegia beating working; *p < 0.05 versus other two groups.) (Reprinted with permission from The Society of Thoracic Surgeons [Ann Thorac Surg 1994;58:719--27].)

 
Conclusion

Further studies are required to understand the roles of adenosine and NO in protecting the myocardium during arrest and reperfusion. Site-specific and event-specific regulating agents may be a new and effective way of capitalizing on the beneficial mechanisms of these autacoids, as well as others, while reducing untoward side effects. In addition, possible differences in the mechanisms of cardioprotection involved in reducing ischemic injury as opposed to reperfusion injury in models of both reversible (contractile dysfunction) and irreversible (infarction) need to be clarified.

Acknowledgments

We thank Ms Sharon Ireland for preparation of the manuscript, and David G. L. Van Wylen, PhD, and Robert D. Lasley, PhD, for their review and comments on the manuscript.

This work was supported in part by a grant from the National Heart, Lung and Blood Institute to Dr Vinten-Johansen and a grant-in-aid from the American Heart Association, North Carolina Affiliate, to Dr Zhao.

Footnotes

Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sep 25--28, 1994.

Address reprint requests to Dr Vinten-Johansen, Department of Cardiothoracic Surgery, Bowman Gray School of Medicine, Winston-Salem, NC 27157-1096.

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