Ann Thorac Surg 2002;73:1261-1266
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Effects of in vivo myocardial ischemia and reperfusion on interstitial nitric oxide metabolites
Randy M. Stevens, MDa,
M. Salik Jahania, MDa,
Jennifer E. Stivers, BSa,
Robert M. Mentzer, Jr, MDa,
Robert D. Lasley, PhD*a
a Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky, USA
Accepted for publication December 17, 2001.
* Address reprint requests to Dr Lasley, Department of Surgery, University of Kentucky College of Medicine, MN276, Chandler Medical Center, 800 Rose St, Lexington, KY 40536-0298 USA
e-mail: rlasley{at}pop.uky.edu
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Abstract
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Background. There have been numerous studies examining the role of nitric oxide (NO) in myocardial ischemia-reperfusion injury; however, few studies have included measurements of NO or related reactive nitrogen species. The purpose of this study was to determine the effects of in vivo regional myocardial ischemia on interstitial fluid (ISF) reactive nitrogen species.
Methods. Open chest pigs were submitted to one of three protocols: (1) 15 minutes coronary occlusion and 2 hours reperfusion, (2) 60 minutes coronary occlusion and 2 hours reperfusion, or (3) two-cycle ischemic preconditioning (IPC) followed by prolonged ischemia and 2 hours reperfusion. The stable NO metabolites, nitrite plus nitrate (NOx), in cardiac microdialysis samples were measured by ozone chemiluminescence.
Results. NOx concentration decreased 40% ± 6% (p < 0.05) during brief ischemia but returned to baseline during reperfusion. Dialysate NOx levels decreased further after 60 minutes ischemia (60% ± 3% of baseline, p < 0.01) but reperfusion dialysate NOx concentration increased 34% ± 9% above baseline (p < 0.05). Preconditioning did not increase dialysate NOx but did accelerate the ischemia-induced decrease in NOx levels (p < 0.05). Reperfusion NOx levels in preconditioned pigs were significantly lower than in nonpreconditioned pigs (p < 0.05).
Conclusions. These results suggest that ischemia is associated with decreased ISF NOx concentration. Reperfusion NOx levels are increased after prolonged ischemia, an effect that is significantly blunted by ischemic preconditioning.
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Introduction
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The free radical nitric oxide (NO), produced when arginine is enzymatically oxidized to citrulline by nitric oxide synthase (NOS), exerts numerous effects in mammalian myocardium. The release of low concentrations of NO by constitutive NOS (cNOS) appears to play a role in the regulation of coronary blood flow, inhibition of platelet aggregation, adherence to endothelium, and possibly modulation of myocardial oxygen consumption [1]. Conversely, cytotoxic levels of NO, nitroxyl anion (NO-), peroxynitrite (ONOO-), and other reactive nitrogen species have been postulated to play a role in tissue injury [2]. The effects of NO and related reactive nitrogen species during myocardial ischemia and reperfusion have been the focus of an extensive number of investigations. However, these studies, which have largely relied upon pharmacologic manipulation of the NO pathway, have led to conflicting hypotheses on whether NO exerts beneficial or deleterious effects in ischemic-reperfused myocardium [3–6].
One of the primary limitations of studies on the role of NO in ischemic-reperfused myocardium is the lack of measurements of this short-lived free radical. Although NO and related reactive nitrogen species have been measured during ischemia-reperfusion in other tissues [7, 8], there have been few such measurements in the heart and these have yielded contradictory findings. For example it has been reported that global ischemia in the isolated perfused rat heart is associated with increased NO levels [5]. Conversely interstitial fluid (ISF) NO metabolites decreased during brief, zero flow regional ischemia in the intact dog [9]. The microdialysis technique, which was used in the latter study, has been used by numerous investigators to measure ISF metabolites (adenosine, bradykinin, catecholamines, reactive oxygen species, and lactic acid) during ischemia [10–14]. Despite the simplicity of this technique and its widely accepted use, there has only been the one study [9] in which ISF reactive nitrogen species have been measured using in vivo models of myocardial ischemia and reperfusion. In addition, although there is evidence that NO may play a role in mediating the beneficial effects of acute ischemic preconditioning [15], there have been no reports of ISF reactive nitrogen species measurements in in vivo preconditioned myocardium. Thus, the purpose of this study was to examine the effects of brief and prolonged ischemia and ischemic preconditioning on ISF NOx levels in in vivo porcine myocardium.
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Material and methods
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All animals in this study received humane care according to the guidelines set forth in "The Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources (National Institutes of Health publication 86-23, revised 1996). In addition, animals were used in accordance with the guidelines of the University of Kentucky Institutional Animal Care and Use Committee.
Animal preparation
Studies were conducted in domestic farm pigs weighing 16 to 36 kg. Ketamine (20 mg/kg, intramuscular) was used for induction of anesthesia and sodium pentobarbital (15 mg/kg, intravenous) was given after ear vein access was obtained. Additional pentobarbital (1.5 to 2.0 mg/kg, intravenous) was administered every 15 minutes for maintenance of anesthesia. A tracheostomy was performed and ventilation was maintained by using a large animal ventilator (Harvard Apparatus, Holliston, MA). Tidal volume, respiratory rate, and fraction of oxygen inspired air were adjusted to maintain normal arterial blood gas and pH values. Core body temperature was monitored through an esophageal temperature probe and maintained at 38.0 ± 0.5°C with heating pads. Normal saline was administered through a peripheral ear vein or femoral vein at 5 to 7 mL · kg-1 · h-1 after an initial bolus of 15 to 20 mL/kg. A femoral artery catheter was used to monitor arterial blood pressure and heart rate and to obtain blood gas samples.
A segment of left anterior descending (LAD) coronary artery, distal to the origin of the first diagonal branch, was carefully dissected free of surrounding tissue. The area at risk was delineated by a brief (< 20 second) occlusion of the LAD with a vascular occluder. A ligature was placed around the artery to be used for occlusion. A transit time perivascular flow probe (Transonic Systems Inc, Ithaca, NY) was placed distal to the occluder to measure coronary blood flow.
Cardiac microdialysis
Cardiac microdialysis fibers were made as previously described in detail [14]. Briefly, probes were constructed using dialysis fibers (200 µm internal diameter, molecular weight cutoff 5,000) connected on both ends with inert silica tubing (SGE Inc, Austin, TX). The silica tubing and dialysis fiber were glued together with cyanoacrylic glue so that the length of exposed dialysis fiber was 15 mm. The fibers were perfused at 2 µL/min with phosphate buffered saline (PBS), which was freshly prepared before each experiment. Fibers were placed in the midmyocardium of the LAD and left circumflex (LCX) coronary artery perfusion beds. Correct placement of the fiber in the ischemic bed was verified during the brief LAD occlusion; the LCX fiber was placed several centimeters removed from the region at risk. Dialysate samples, collected every 5 minutes, were immediately diluted with 10 µL nitrate-free distilled water, placed on ice, and then stored in a -80°C freezer until samples were analyzed. In vitro recovery experiments (37°C) indicated that 15 mm dialysis fibers, perfused at 2 µL/min, recovered 80% ± 2% (n = 6) of sodium nitrate (10 µmol/L) in PBS.
Nox metabolite measurement
In solution, NO readily reacts with O2 to form the very stable anion nitrite (NO2- ) which is further oxidized to nitrate (NO3-) in in vivo systems. NO also reacts with oxyhemoglobin and superoxide anion to form NO3-. The stability of NO2- and NO3- in solution permit their use as reliable markers of NO metabolism. Dialysate NO2- plus NO3- levels (NOx) were measured by ozone chemiluminescence with the Sievers 280 NO analyzer (Sievers Instrumentation, Boulder, CO). Five µL of each dialysate sample was injected into the reaction chamber of the NO analyzer containing a heated (95°C) solution of vanadium chloride and hydrochloric acid, which reduces NO2- and NO3- to authentic NO. Each dialysis sample was analyzed in duplicate or triplicate. With each analysis, distilled water blanks and samples of the PBS used as the dialysis fluid were assayed to check for background NO2- and NO3-. Initial findings indicated that NO2- represented only 6% ± 3% of total NOx levels (n = 3 experiments), thus nitrite was not measured separately in the remainder of the studies. This result is similar to that of Zeballos and associates [4] who noted in dog plasma that total NOx consisted of only 10% NO2-.
Experimental protocols
Three groups of pigs were submitted to regional myocardial ischemia. All animals were equilibrated for 30 minutes after instrumentation and dialysis fiber placement before initiating the experimental protocols, based on initial findings that dialysate NOx values stabilized within 30 minutes. One group of pigs (n = 7) was submitted to 15 minutes of LAD occlusion followed by 2 hours of reperfusion. The second group of animals (n = 8) was submitted to 60 minutes of LAD occlusion and 2 hours of reperfusion. The third group of pigs (n = 5) was preconditioned with two cycles of 5 minutes LAD occlusion and 10 minutes reperfusion before 60 minutes regional ischemia followed by 2 hours of reperfusion. At the conclusion of the experiment the heart was removed for determination of fiber placement. The tract of the microdialysis fiber was carefully examined and dissected within the muscle to verify that the fiber was not exposed on the subendocardial surface.
Statistical analysis
Data are expressed as means ± SE. Although pigs were fasted the night before experimentation to minimize exogenous nitrate from the diet, there was considerable interanimal variability in baseline NOx concentrations. Thus dialysate NOx values during ischemia and reperfusion were expressed as a percent of preischemia values. Within group data were analyzed by repeated measures ANOVA followed by Dunnett’s post hoc test. Significant differences between groups were determined by two-way analysis of variance. A p value less than 0.05 was accepted as an indication of statistical significance.
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Results
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There were no differences in hemodynamic measurements among the three groups (data not shown). Twenty of the 26 pigs that were entered into the study survived the protocols and had correct dialysis fiber placement. Five pigs experienced sustained ventricular fibrillation refractory to direct current defibrillation and were excluded from analysis. One of the pigs in the 60-minute ischemia group was excluded owing to incorrect fiber placement.
Brief ischemia protocol
Baseline dialysate NOx concentration in this group was 15.5 ± 5.8 µmol/L (range 4.7 to 32.2 µmol/L). The effects of brief ischemia and reperfusion on dialysate NOx levels, expressed as percent of basal levels, are illustrated in Figure 1.
Dialysate NOx levels decreased to 78% ± 4% of baseline values in the first 5 minutes of LAD occlusion, and after 15 minutes ischemia dialysate NOx decreased to 60% ± 6% of preischemic values. Upon reperfusion NOx concentration returned to baseline within 10 minutes (99% ± 3%) and remained at this level for the remainder of the experiment (99% ± 6% of baseline values). The LCX fiber did not show significant changes in NOx levels throughout the entire experiment (Fig 1).
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Fig 1. Dialysate nitric oxide (NO) metabolite concentration (NOx) in the left anterior descending (LAD) artery and left circumflex (LCX) coronary artery beds during 15 minutes of LAD occlusion (ISCH) and 2 hours reperfusion. Values are expressed as percent change from preischemic (PreISCH) baseline. *p < 0.05 versus baseline.
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Prolonged ischemia protocol
Initial dialysate NOx levels in this protocol ranged from 1.1 to 27.0 µmol/L (9.8 ± 3.0 µmol/L). As shown in Figure 2,
dialysate NOx concentration declined to 54% ± 4% of baseline after 30 minutes LAD occlusion and to 40% ± 3% by 60 minutes ischemia. Reperfusion resulted in a gradual increase in dialysate NOx levels, such that after 15 minutes, NOx concentration increased to 112% ± 5%. After 30 minutes reperfusion LAD [NOx] was 134% ± 9% of preischemic levels (p < 0.05 versus baseline; Fig 2). Dialysate NOx concentrations remained elevated for the remainder of the reperfusion period (130% ± 10% after 2 hours reperfusion). The NOx levels in the nonischemic LCX bed remained relatively stable throughout the protocol although they tended to increase during the LAD occlusion (Fig 2) to 117% ± 7% of baseline. After 2 hours LAD reperfusion LCX NOx values were 99% ± 6% of baseline.
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Fig 2. Dialysate nitric oxide (NO) metabolite concentrations (NOx) in the midmyocardium during 60 minutes of ischemia and 2 hours reperfusion. Values are expressed as percent change from baseline (time 0). Dialysate left circumflex (LCX) coronary artery values during left anterior descending (LAD) artery occlusion were not significantly different from baseline. *p < 0.05 versus baseline. (PreISCH = preischemic.)
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Ischemic preconditioning protocol
Baseline NOx concentration before the first brief occlusion was 5.7 ± 1.6 µmol/L (2.1 to 13.1 µmol/L). The effects of the two-cycle ischemic preconditioning protocol on dialysate NOx concentrations are illustrated in Figure 3.
Dialysate NOx concentration decreased during the first preconditioning occlusion to 76% ± 2% of baseline values and after 10 minutes reperfusion levels returned to baseline (105% ± 3%). Similar effects were seen during the second preconditioning cycle. The effects of ischemic preconditioning on dialysate NOx during prolonged ischemia and reperfusion are shown in Figure 4. Preconditioning was associated with a more rapid decrease in NOx levels during prolonged ischemia (Fig 4A). After 10 minutes ischemia dialysate NOx concentration in the preconditioned group was 47% ± 6% of baseline compared with 66% ± 5% of baseline in the 60-minute ischemia alone group (p < 0.05). A similar pattern was observed at 20 minutes ischemia but after this time point there were no differences in NOx levels between the groups. During reperfusion (Fig 4B) dialysate NOx levels in preconditioned animals returned to values not statistically different (97% ± 7% after 60 minutes) from preischemic values, whereas NOx concentration in the 60 minutes ischemia alone animals was significantly higher (134% ± 3% at 60 minutes reperfusion). As in the other protocols, dialysate NOx level in the LCX perfused bed was stable throughout the experiment.
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Fig 3. The effects of ischemic preconditioning on dialysate (NOx). Preconditioning was induced by two cycles of 5 minutes of ischemia ([ISCH] gray bars) and 10 minutes of reperfusion ([RP] black bars). Values are expressed as percent change from preischemic (PreISCH) baseline. *p < 0.05 versus baseline.
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Fig 4. Dialysate (NOx) during (A) prolonged ischemia and (B) ischemia and reperfusion in 60-minute ischemia alone (60' Isch alone) and ischemic preconditioned (IPC) pigs. All ischemic NOx values (A) were significantly different from respective preischemic (PreISCH) baseline values (p < 0.05) but symbols were not shown for clarity. *p < 0.05 versus control group value; #p < 0.05 versus respective PreISCH value. (LAD = left anterior descending artery.)
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Comment
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We used the microdialysis technique to measure the levels of the stable end products of NO metabolism, NO2- and NO3-, in ISF during in vivo regional ischemia and reperfusion. Dialysate NOx levels decreased immediately upon the onset of ischemia while NOx concentration in the nonischemic bed remained unaltered. Reperfusion after brief (15 minutes) ischemia was associated with rapid recovery of preischemic NOx levels; however, after prolonged ischemia NOx levels increased more than 30% above preischemic values and remained elevated throughout reperfusion. Two-cycle ischemic preconditioning, which itself had minimal effects on ISF NOx, significantly reduced NOx concentration during the first 20 minutes of prolonged ischemia and throughout reperfusion compared with 60 minutes ischemia alone animals.
Although our present findings on the effects of brief ischemia and reperfusion on ISF reactive nitrogen species have been previously reported by Mori and colleagues [12], this is the first report of the effects of prolonged ischemia and acute ischemic preconditioning on ISF NO metabolites in in vivo myocardium. Previous measurements of NO during prolonged myocardial ischemia and reperfusion have been primarily limited to studies in isolated perfused rat hearts using electron spin resonance [5, 16]. This technique does provide measurements of NO in whole tissue and coronary effluent but it does not permit the measurement of ISF NO and is not yet feasible for use in in vivo large animal preparations. Although ozone chemiluminescence does not detect authentic NO, the strong reducing conditions we used for analysis likely reduces all reactive nitrogen species such as peroxynitrite, nitroxyl anion, dinitrogen trioxide, as well as NO2- and NO3- to authentic NO. Given the extremely rapid half-life of NO in in vivo preparations (substantially less than that in hemoglobin-free buffers [1]), measurements of total reactive nitrogen species during ischemia-reperfusion may be more important than NO alone.
The results of our study indicated that NO metabolites decreased during ischemia, in direct contrast to the reports of increased NO measured during global ischemia in isolated perfused rat hearts [5, 6, 16]. In addition to the differences in measurement techniques described above two other explanations for these differences could be differences in NO metabolism in in vitro and in vivo preparations and species differences. Nitrite, the primary NO metabolite in hemoglobin-free solutions, can be readily reduced to NO under acidotic conditions such as those incurred during ischemia [6]. Consistent with the report that NO2- comprises 
10% of plasma reactive nitrogen species [4], we observed very little NO2- in our dialysate samples and no increase during ischemia. A second explanation for our differences with those observed in the rat heart may be the presence of xanthine oxidase. It has been reported that during in vitro hypoxia xanthine oxidase can convert nitrate and nitrite to NO [17], and rat heart in contrast to porcine myocardium exhibits high xanthine oxidase activity [18]. This factor may also explain why NO concentration has been reported to increase during ischemia in the isolated rat heart, despite the observation that NOS activity has been shown to decrease during ischemia in the same preparation [19].
The results of the present study suggest that the ISF reactive nitrogen species levels during reperfusion depend on the duration of ischemia and possibly the magnitude of ischemia-reperfusion injury. After 15 minutes of ischemia ISF NOx levels normalized during early reperfusion, a finding similar to that in canine myocardium [9]. However, reperfusion after 60 minutes ischemia alone was associated with a persistent 30% elevation in ISF NOx levels compared with preischemic levels. Although we did not measure infarct size in the present study, we have previously reported that this same brief ischemia-reperfusion protocol is associated with no necrosis whereas 60 minutes regional ischemia is associated with an infarct size of 60% of the region at risk [20]. The contribution of neutrophils to reperfusion injury in stunned and infarcted myocardium may provide an explanation for the different profiles of ISF NOx after brief and prolonged ischemia. It is generally accepted that neutrophil infiltration and adherence do not play a significant role in myocardial stunning [21]. In contrast there is substantial evidence that neutrophils contribute to irreversible injury [22, 23] and the production of reactive oxygen species after prolonged ischemia [24]. Peroxynitrite, formed when NO reacts with excess superoxide, is formed primarily during reperfusion [25] and peroxynitrite release is elevated during reperfusion in isolated rat heart preparations [25]. Finally, nitric oxide synthase in the absence of normal levels of arginine and the cofactor tetrahydrobiopterin can generate superoxide anion [26, 27]. As the ozone chemiluminescence technique likely detected the majority of the reaction products of NO, including peroxynitrite and nitroxyl anion, that crossed the dialysis fiber, the rebound increase in NOx concentration that we observed during reperfusion is consistent with increased production of both reactive nitrogen and oxygen species.
The results of our third series of experiments indicated that although acute ischemic preconditioning was not associated with increased ISF NOx production, preconditioning did reduce NOx levels during prolonged ischemia and reperfusion. In our two-cycle preconditioning protocol ISF NOx concentration decreased during ischemia and reperfusion values were not significantly different from baseline. This finding suggests that an increase in NO does not mediate acute ischemic preconditioning in the open chest pig, a conclusion that is supported by the report that the NOS inhibitor L-nitro-arginine did not block ischemic preconditioning in porcine myocardium [28]. Xuan and coworkers [15] reported that acute and delayed ischemic preconditioning in the conscious rabbit was associated with increased myocardial NOS activity and tissue NOx levels. However, these authors used a six-cycle preconditioning protocol whereas we used only two cycles of ischemia. Species differences may also account for these dissimilarities.
Although the focus on NO in mediating acute and delayed preconditioning has been on NOS activity during the preconditioning protocol [15], this is the first report examining ISF NO metabolites during prolonged in vivo ischemia and reperfusion in preconditioned myocardium. Ischemic preconditioning modified the responses to both prolonged ischemia and reperfusion. During the first 20 minutes of prolonged ischemia ISF NO metabolites in preconditioned pigs were lower than NOx values in 60 minutes of ischemia alone animals. This finding is identical to the effects of ischemic preconditioning on ISF adenosine and lactate levels [10, 13]. During reperfusion, ISF NOx levels were significantly reduced at all time points compared with 60 minutes of ischemia alone pigs, a finding similar to the effects of ischemic preconditioning on reperfusion perfusate NO levels in the isolated working rat heart [16]. The attenuated levels of reperfusion NOx in the preconditioned animals are consistent with the infarct size reducing effect of ischemic preconditioning [29, 30] and with both decreased neutrophil accumulation [3] and ROS formation [31]. The similarity in the reperfusion NOx levels in the preconditioning and brief ischemia protocols, both interventions which are typically associated with much less injury than with prolonged, 60 minute coronary occlusion, suggests that elevated ISF NOx levels during reperfusion are associated with more severe ischemia-reperfusion injury. Although these differences could have been due merely to the location of the dialysis fibers in viable versus infarcted tissue, it has been reported that acute myocardial infarction in humans is associated with elevated circulating levels of reactive nitrogen species [32]. As we did not measure infarct size in the present study, we cannot preclude this possibility.
It must be pointed out that microdialysis measurements provide only estimates of ISF metabolite concentrations and changes in these metabolites under different conditions. Dialysate metabolite concentrations are influenced by changes in blood flow [33] and hence washout of the interstitial space. Thus the increased NOx we observed after prolonged ischemia may underestimate the true increase in reactive nitrogen species, just as the lack of a significant increase in ISF [NOx] during ischemic preconditioning may be masked by the reactive hyperemia. Similarly, the decrease in ISF [NOx] during ischemia may underestimate the true decrease because it is known that the cardiac extracellular fluid space decreases during ischemia [34].
Despite these limitations the results of this study indicate that the ISF concentration of NO metabolites decreases during in vivo regional myocardial ischemia. The profile of reactive nitrogen species during reperfusion appears to be dependent on the duration of ischemia and possibly the severity of ischemia-reperfusion injury. Given our present findings and reports that plasma NOx levels are elevated after myocardial infarction [32] and cardiac surgery [35], the release of reactive nitrogen species may be a reliable marker to assess in vivo myocardial ischemia-reperfusion injury.
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Acknowledgments
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This work was supported by funding from an AHA grant (995151OV) to Dr Lasley. Dr Stevens is the recipient of a National Research Service Award (HL67553).
The authors would like to thank Ruth Oremus, Earl Paxton, and Jeff Yates for their technical assistance in this study.
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Abstract
Introduction
