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Ann Thorac Surg 1995;60:847-851
© 1995 The Society of Thoracic Surgeons

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III: New Directions in Surgical Myocardial Protection

Attenuation of Myocardial Ischemia-Reperfusion Injury With Nitric Oxide Replacement Therapy

Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania

Abstract

The coronary vascular endothelium produces nitric oxide (NO) during the conversion of L-arginine to L-citrulline. Although NO is a potent vasodilator, at lower concentrations, it also has antineutrophil actions that reduce the inflammatorylike components of ischemia-reperfusion injury. The endothelium is damaged in the early minutes after reperfusion, ie, before neutrophils accumulate and before myocardial necrosis fully develops, and this suggests that endothelial injury is a springboard event in the postischemic inflammatory cascade. Studies of coronary artery occlusion and reperfusion suggest that early damage to the coronary endothelium impairs NO production, which, in turn, abrogates the endogenous antineutrophil effects of NO. However, this impaired endogenous NO-related cardioprotection can be restored either by providing specifically at the onset of reperfusion the precursor to NO (L-arginine) or by providing agents that donate NO. In studies, L-arginine or NO donors reduce infarct size in models of coronary occlusion and reperfusion. The mechanism or mechanisms of this cardioprotection involve preservation of endothelial function and inhibition of neutrophil accumulation in ischemic-reperfused tissue. The cardioprotective potential of NO offers a new therapeutic approach to the reduction of ischemia-reperfusion injury after coronary artery occlusion.

The vascular endothelium was previously thought to be a relatively inert ``cellophane'' layer over the underlying structures of arteries, veins, and capillaries [1] that participated primarily in homeostasis and transport of ions and organic substances, and as a local area for bioconversion of substances. However, in the past 15 years, the endothelium has been identified as an extremely important secretory organ that is involved in numerous physiologic and biochemical mechanisms, including autoregulatory control of vascular tone, hemostasis, and very recently, cardioprotection [2]. Since the seminal observations of Furchgott and Zawadzki [3] identifying a vasodilator substance requiring the presence of the vascular endothelium and called endothelium-dependent relaxing factor, there has been a virtual explosion of interest and research on the function of the vascular endothelium. Endothelium-dependent relaxing factor was subsequently found to be identical to nitric oxide (NO) [4], which is produced in the vascular endothelium during the conversion of L-arginine to L-citrulline [5–7] by a constitutive enzyme, NO synthase [8].

Nitric oxide has a number of physiologic properties that make it an excellent candidate as a cardioprotective agent. It is a potent vasodilator in ischemic myocardium and may dilate constricted vessels during the delivery of cardioplegic solutions, thereby improving the distribution and total volume of cardioplegic solution delivered. In addition, NO is a potent inhibitor of neutrophil adherence to vascular endothelium. Neutrophil adherence is an important event initiating further leukocyte activation, superoxide radical generation, and release of other cytodestructive agents (eg, elastase), which, in turn, leads to injury to the endothelium and perivascular myocardium. Because these neutrophil-mediated events may occur primarily during reperfusion [9–11], their inhibition by NO therapy might attenuate the degree of ischemia-reperfusion injury.

Cardioprotection From Reperfusion Injury With Nitric Oxide Therapy

The initial experience of my colleagues and myself [12, 13] with the cardioprotective properties of NO was to administer the authentic gas in a well-established model of feline coronary occlusion and reperfusion. The left anterior descending coronary artery of anesthetized cats was occluded for 90 minutes, after which the ligature was released and the myocardium reperfused for 4.5 hours. Thirty minutes into the ischemic period, a solution of authentic NO (bubbled into deoxygenated distilled water or 0.9% NaCl) was infused intravenously at subhypotensive doses, and the infusion was continued throughout the period of reperfusion. This NO solution produced concentration-dependent relaxation of precontracted aortic rings in vitro, confirming the availability of bioactive NO. In animals given NO solution, infarct size estimated by histochemical staining with nitro blue tetrazolium was significantly reduced compared with that in a nontreated group (6% ± 3% versus 25% ± 5% of the area at risk; p < 0.05).

Myeloperoxidase activity, a marker of neutrophil accumulation, was determined in myocardial biopsy specimens taken from nonnecrotic and necrotic myocardium within the ischemic zone. Infusion of NO 20 minutes before reperfusion reduced myeloperoxidase activity in both the nonnecrotic area at risk and the necrotic zone relative to the nontreated vehicle group, a finding suggesting that treatment with NO reduced the degree of neutrophil infiltration in the ischemic-reperfused myocardium. Therefore, NO therapy initiated during the period of occlusion reduced infarct size possibly by inhibiting neutrophil accumulation and neutrophil-mediated pathology. Nitric oxide probably exerted the majority of its cardioprotection during reperfusion, but this was not absolutely clear from the study.

Nitric Oxide Donor Compounds
Data suggest that reperfusion injury in the setting of coronary artery occlusion occurs within the first 30 minutes of reflow [14, 15] and may affect the vascular endothelium as soon as 2.5 minutes after reflow [16]. Therefore, the question arises whether NO exerts cytoprotection during reperfusion specifically. Various NO donor compounds (ie, organic nitrates that readily release NO in solution) have been developed over the years, the prototype of which is nitroglycerin. However, nitroglycerin is a poor donor of NO, as the process not only requires bioconversion by a cysteine-containing enzyme that is partially depleted during ischemia plus reperfusion but also can induce tolerance readily.

The sydnonimine class of compounds releases NO spontaneously and nonenzymatically at physiologic pH, is soluble in aqueous systems, and does not induce tolerance. In a study performed in 1992 [17], the cardioprotective potential of the sydnonimines SIN-1 and C87-3754 was studied in the feline model of ischemia plus reperfusion, already described with the important exception that infusion of the NO donors began just 10 minutes before reperfusion, thereby affecting only the reperfusion period. Both sydnonimines were given by intravenous infusion of subhypotensive doses; 0.1 mg/kg bolus followed by 1 mg • kg^-1 • h^-1 until the end of reperfusion. SIN-1 and C87-3754 both reduced infarct size from 29% ± 3% in a saline vehicle–treated group to 9% ± 2% and 11% ± 5%, respectively (Fig 1). The nonnitrosylated, inactive control compound C88-3934 failed to reduce infarct size (31% ± 3%).

View larger version (42K): [in this window] [in a new window]   Fig 1. . Area at risk as ratio of total left ventricle and area of necrosis relative to area at risk and to total left ventricle. Percentages were derived from tissue masses (grams). (A) Vehicle-treated group (MI + Vehicle) and ischemia plus reperfusion + SIN-1 (MI + SIN-1). (B) Ischemia + C88-3934 (inactive control compound) (MI + C88-3934) or C87-3786 (MI + C87-3786). Numbers in boxes represent the number of experiments. Data are shown as the mean ± the standard error of the mean. (MI = myocardial infarction; NS = not significant.) (Reprinted from [17] by permission of ASPET.)

View larger version (13K): [in this window] [in a new window]   Fig 2. . Analog tracings of isometric tension produced by isolated coronary arteries preconstricted with U46619 (arrow). In cats having a sham operation (Sham MI), the coronary artery relaxed to both acetylcholine (ACh) and NaNO2. In untreated ischemic-reperfused arteries (MI + Vehicle), vasorelaxation responses to ACh were severely depressed, whereas smooth muscle relaxation to NaNO2 was normal. In contrast, nitric oxide donor–treated cats (MI + SIN-1) showed a marked restoration of vasorelaxation to ACh. Dots indicate incremental concentrations of drug (ACh or NaNO2) added to organ bath. (MI = myocardial infarction.) (Reprinted from [17] by permission of ASPET.)

L-Arginine
The 1992 study [17] and subsequent studies have shown that the coronary artery [16, 18–21] and venous [22] vascular endothelium is functionally damaged by ischemia-reperfusion injury. Recently, Ma and colleagues [19] showed that the basal release of NO is also impaired after reperfusion of the ischemic artery. Similar injury is suggested to occur in patients [23].

Although these studies demonstrated that exogenously applied NO in the form of authentic NO gas in solution or NO donors could reduce postischemic injury, it was not known whether a greater release of NO could be recruited by the coronary endothelium by supplying the biochemical precursor L-arginine. This endogenous release of NO may have some advantages over exogenous NO administration: (1) the release may be both site specific at the endothelium-plasma interface and event specific during reperfusion; (2) the distribution of endogenous NO is not dependent on having an adequate coronary blood flow; (3) the cardioprotective mechanisms may be activated before exogenous sources of NO can reach the site of injury; and (4) potentially deleterious or complicating side effects of high concentrations of NO are avoided. It is known that L-arginine increases the production of NO, which is not stimulated by the nonmetabolized enantiomer D-arginine [6, 7, 24].

Therefore, my colleagues and I tested the hypothesis that administration of L-arginine during reperfusion protects against postischemic injury [24]. Using the described feline model of left anterior descending coronary artery occlusion and reperfusion, L-arginine or D-arginine was infused intravenously just before the onset of reperfusion as a bolus of 30 mg/kg followed by a continuous infusion of 10 mg • kg^-1 • min^-1 for 1 hour of reperfusion. These doses did not produce hypotension or alter coronary artery blood flow or vascular tone.

Compared with previous untreated groups, L-arginine significantly reduced infarct size, whereas D-arginine did not (Fig 3). This infarct size reduction was accompanied by a reduction in neutrophil accumulation in the necrotic region and in the nonnecrotic area at risk. In addition, L-arginine but not D-arginine preserved postischemic endothelial function as assessed by the agonist-stimulated vasorelaxation bioassay. Moreover, the endothelial dysfunction exhibited in hearts given the vehicle could be overcome by incubating the vessels in L-arginine, a finding suggesting that either depletion of endogenous L-arginine or a decrease in kinetics of the constituent nitric oxide synthase were involved. Therefore, consistent with findings in previous studies, the presence of replacement quantities of endogenous NO, obtained by supplying the precursor L-arginine during reperfusion, protected the heart, with attenuation of neutrophil-mediated damage to the endothelium and myocytes being implicated.

View larger version (31K): [in this window] [in a new window]   Fig 3. . Area at risk versus total left ventricle, necrotic myocardium versus area at risk, and necrotic myocardium versus total left ventricle, each expressed as a percentage of tissue mass of each area. Numbers in boxes represent number of experiments. D-Arginine and L-arginine were given intravenously just before onset of reperfusion. Data are shown as the mean ± the standard error of the mean. (MI = 90 minutes of coronary occlusion; NS = not significant.) (Reprinted from [24] by permission of the American Heart Association.)

These studies showed that NO is cardioprotective in the setting of ischemia plus reperfusion. However, controversy has been raised over the possible deleterious effects of NO. Finkel and colleagues [25] and Brady and associates [26] have shown that NO may produce marked cardiodepressant effects. In addition, Buckberg's group [27] has reported that NO and L-arginine have potential deleterious effects in reoxygenation injury after profound hypoxia, similar to those of shock [25, 26]. These purported deleterious effects may be mediated by NO directly (as it is a radical species) or by a metabolite such as peroxynitrite [28–30].

My co-workers and I [31] tested the hypothesis that NO and NO donors or precursors were cardiodepressant in vivo as well as in vitro. With concentrations of NO ranging from 50 to 1,000 nmol/L (measured by an NO electrode), sufficient to completely relax coronary arteries, there was no cardiodepressant effect on the contraction of isolated feline papillary muscles. Challenge of these papillary muscles with sodium pentobarbital or ethanol produced significant contractile depression. In another report [32], intracoronary infusion of the organic NO donor SPM-5185 at a concentration of 500 µmol/L also did not reduce either segmental shortening or segmental work measured by sonomicrometry in canine hearts. Along the same line, Wink and coauthors [33] have found no deleterious effects of NO or peroxynitrite.

Therefore, the alleged deleterious effects of NO may depend on the pathologic condition. Such effects, however, are not a universal finding. At this point, most of the data support the contention that NO given in physiologic amounts exerts a marked and highly significant cardioprotective effect. This has also been confirmed in dogs [34–37].

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 Lefer, Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.

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