Published online before print September 25, 2003, doi: 10.1161/01.RES.0000097762.64561.D2
© 2003 American Heart Association, Inc.
Integrative Physiology |
Cardiac Nerves Affect Myocardial Stunning Through Reactive Oxygen and Nitric Oxide Mechanisms
From the Cardiovascular Research Institute (C.-H.H., S.F.V., A.P.P., G.Y.), Department of Cell Biology and Molecular Medicine, UMDNJ–New Jersey Medical School, Newark, NJ; Department of Surgery (C.-H.H.), National Yang-Ming University School of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Clinical Sciences (R.K.K.), Tufts University School of Veterinary Medicine, North Grafton, Mass.
Correspondence to Raymond K. Kudej, DVM, PhD, FAHA, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Cardiovascular Research Institute, 185 S Orange Ave, MSB-G609, Newark, NJ 07101. E-mail Raymond.Kudej{at}tufts.edu
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Abstract |
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The goal of this study was to investigate the role of cardiac nerves on the response to 90-minute coronary artery stenosis (CAS), which reduced coronary blood flow by 40% for 90 minutes, and subsequent myocardial stunning after reperfusion in chronically instrumented conscious pigs. In pigs with regional cardiac denervation (CD), myocardial stunning was intensified, ie, at 12 hours reperfusion wall thickening (WT) was depressed more, P<0.05, in CD (-46±5%) as compared with intact pigs (-31±3%) and remained depressed in CD at 24 hours reperfusion (-45±6%). Although the TTC technique was negative for infarct, histopathological analysis revealed patchy necrosis present in 11±2% of the area at risk. In intact pigs, WT had essentially recovered at 24 hours without infarct. In CD pigs treated with either an antioxidant, N-2-mercaptopropionyl glycine (MPG, 100 mg/kg per hour) or systemic nitric oxide synthase inhibition using N
-nitro-L-arginine (L-NA, 30 mg/kg for 3 days), recovery of wall thickening was similar to that in pigs with intact nerves and without evidence of infarct. Immunohistochemistry analysis for 3-nitrotyrosine in tissue after CAS and 1 hour reperfusion demonstrated enhanced peroxynitrite-related protein nitration in pigs with regional CD compared with pigs with intact cardiac nerves, and pigs with regional CD and MPG or L-NA. Thus, reperfusion after myocardial ischemia in the setting of CD results in enhanced stunning and development of infarct. The underlying mechanism appears to involve nitric oxide and reactive oxygen species.
Key Words: cardiac denervation • coronary stenosis • myocardial stunning • reactive oxygen species
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Introduction |
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The mechanisms mediating myocardial stunning are radically different in larger mammals, where it involves alteration of calcium1 and reactive oxygen,2 versus rodents, where it involves degradation of troponin I.3,4 These differences might be attributed to species, but it is also important to recognize the fact that most of the rodent work was conducted in isolated hearts, which are also denervated.3–7 Interestingly, the role of nitric oxide (NO) on myocardial stunning is generally beneficial in innervated hearts, but is more controversial in isolated hearts.8 Furthermore, the effects of NO on myocardial function can be mediated by neural mechanisms.9,10 It therefore becomes important to understand the role of cardiac nerves in modulating the response to myocardial ischemia and subsequent stunning after reperfusion.
Accordingly, we examined the effects of coronary artery stenosis (CAS) and reperfusion in intact conscious pigs and pigs with regional cardiac denervation. This model of 90-minute CAS elicits a prolonged period of myocardial stunning after reperfusion and does not result in myocardial necrosis.11,12 Because the pigs with regional denervation demonstrated more intense myocardial stunning and developed patchy subendocardial necrosis, the next goal of this study was to determine the mechanism of the adverse effects observed in the denervated hearts. To determine whether the cardiac nerves influence oxidative stress in this model, we also examined the effects of CAS and reperfusion in denervated pigs treated with an antioxidant and examined tissue from all groups for the accumulation of the reactive oxygen product, 3-nitrotyrosine. Finding enhanced nitrotyrosine in the denervated hearts, we then examined the effects of inhibition of NO synthase on the response to CAS and reperfusion.
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Materials and Methods |
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Animals used in this study were maintained in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, revised 1996).
In Vivo Studies
Forty-two domestic swine (Animal Biotech Industries, Danboro, Pa), weighing 28.9±0.5 kg, were divided into 5 groups. All pigs were anesthetized and instrumented using aseptic technique as described previously.11,13 Group 1 (n=11), regional cardiac denervation; group 2 (n=7), regional cardiac denervation treated with the hydroxyl radical and peroxynitrite scavenger, N-2-mercaptopropionyl glycine (MPG, 100 mg/kg per hour); group 3 (n=8), regional cardiac denervation treated with NO synthase inhibition using N-nitro-L-arginine (L-NA, 30 mg/kg IV) for 3 days; group 4 (n=9), normal cardiac innervation; and group 5 (n=7), normal cardiac innervation treated with MPG. For group 2 and group 5 pigs, intravenous MPG administration was initiated 1 hour before, during, and for the first hour of reperfusion after CAS. For pigs in groups 1 to 3, regional cardiac denervation was accomplished with a combination of surgical and chemical techniques as described previously.14 Briefly, the left anterior descending coronary artery (LAD) and the epicardial surface over the region of myocardium subtended by it were dissected carefully and phenol (88%) was then applied topically. All animals received morphine as a pre- and postoperative analgesic at 0.2 mg/kg IM and fentanyl (75 µg/hr) was then administered transdermally for 3 days.
The experiments were conducted 7 to 10 days after surgery. Valium was administered at 0.5 to 1.0 mg/kg for tranquilization before initiation of the experimental protocol and additionally as required, ie, if the pig became agitated transiently. Hemodynamics were measured and recorded, and radioactive microspheres used to assess tissue blood flow, as described previously.11,12 In all pigs the LAD constriction was created by inflating the occluder to reduce coronary blood flow by 40% for 90 minutes followed by full reperfusion for either 4 days or 1 hour (for nitrotyrosine labeling).11,12 Hemodynamic data were recorded before and during CAS, throughout the first 3 hours and at 12, 24, 48, 72, and 96 hours after reperfusion. At this point, 22 of 27 pigs were anesthetized and the heart excised. In 5 pigs with regional cardiac denervation, 4 of which were pretreated with MPG and 1 with L-NA, full and rapid recovery of function was observed after CAS, in contrast to the remainder of the data collected in pigs with CD. To demonstrate that it was the intervention rather than a difference in the denervation technique, after full recovery from these experiments, a second 90-minute CAS and 4-day reperfusion was examined in the absence of pretreatment, after which the pigs were anesthetized and the heart excised. Methods for defining the area at risk and evaluation of ischemic necrosis were similar to those described previously.11 Briefly, at the end of the experiments, the animals were anesthetized with sodium pentobarbital (50 to 100 mg/kg IV to effect) and heparinized (400 USP U/kg). The ascending aorta was cannulated (distal to the sinus of Valsalva) and perfused retrogradely with Alcian blue dye (0.05% solution). The coronary artery was cannulated at the site of occlusion and perfused with saline. The driving pressure was maintained at approximately 120 to 140 mm Hg for both cannulas. After completion of perfusion, the LV was cut beginning at the apex of the heart into 6 to 7 slices, incubated in 1% triphenyl tetrazolium chloride (TTC) in PBS at 37°C for 10 minutes, and immersion-fixed in 10% phosphate-buffered formalin. The functional area at risk was calculated on the basis of computer tracings (Image-Pro Plus) made from digital photographs of each heart section and the section weight, ie, the fractional percent area at risk for each section was multiplied by that section’s weight and these individual values were summed to give the weight of the functional area at risk for the entire heart. The percent area at risk was calculated as 100xarea at risk/LV+septum weight.
Evaluation of Ischemic Necrosis
Because the TTC technique did not detect infarct in the experiment in pigs with cardiac denervation, as has recently been demonstrated in another study using a similar model,15 we utilized histopathological techniques to quantitate necrosis. Transmural samples of the ischemic and nonischemic regions, as defined by the dual perfusion, from each slice of each heart were embedded in paraffin, sectioned at 5-µm thickness, and stained with hematoxylin and eosin. The stained sections of the area at risk were observed under a light microscope equipped with a video camera that was connected to a computer workstation. The images from each layer of the heart were recorded, digitized, and printed in color. The areas of normal and patchy necrotic zones within the area at risk were calculated using an overlying grid and point-counting system or computer tracings and percent infarct values were averaged from multiple sections (2 to 3 per heart). In animals that had received two periods of CAS (n=5), lesions that resulted from the second period of CAS (4 days reperfusion) were characterized by early healing necrosis, ie, loss of nuclei and striations and an inflammatory infiltrate of neutrophils, whereas the lesions from the first period of CAS (11 to 14 days reperfusion) were characterized by early replacement fibrosis, ie, well-developed granulation tissue with new collagen deposition and lack of inflammatory infiltrate.
Tissue Norepinephrine Content
To confirm the efficacy of regional cardiac denervation, tissue samples from the anterior and posterior portions of the LV were analyzed from 4 animals after regional cardiac denervation for tissue norepinephrine levels using a radioenzymatic assay.16
Nitrotyrosine Labeling
Animals studied for tissue nitrotyrosine labeling were euthanized after 90-minute CAS and 1-hour reperfusion: group 1 (n=4); group 2 (n=3); group 3 (n=3); group 4 (n=2); and group 5 (n=3). Immunofluorescence staining for nitrotyrosine labeling was performed as previously described.17 Briefly, tissue samples were fixed in 10% neutral formalin, embedded in paraffin, and sectioned at 5-µm intervals. The sections were blocked with 5% goat serum in PBS. Primary antibody, polyclonal antibody against nitrotyrosine (Upstate Biotechnology) was diluted at 5 µg per mL in PBS containing 5% goat serum, and applied on the sections for 1 hour at 37°C. After washing, goat anti-rabbit IgG labeled with FITC (VECTOR) was applied. Sections treated with peroxynitrite were used as positive control. Degraded peroxynitrite (Upstate Biotechnology) was used as a negative control for this reaction. Myocytes were detected by 
-sarcomeric actin (Sigma), anti-mouse IgG were used as secondary antibodies. Nuclear counter-staining was done with propidium iodide. Immunofluorescence staining for nitrotyrosine labeling was quantified by scoring the ischemic and nonischemic regions in each of these pigs from 0 to 4.
Statistical Analysis
All data are expressed as mean±SEM. Hemodynamic data at individual time points during CAS and reperfusion were analyzed using repeated measures ANOVA among the groups with a Student-Newman-Keuls test for post hoc comparison of means. A value of P<0.05 was taken as the level for significance.
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Results |
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Hemodynamic measurements for groups 1 to 5 at baseline, the average measurements during CAS, and at 12 hours and 4 days reperfusion are shown in Table 1. Hemodynamic variables were similar among groups, except that L-NA increased afterload and decreased heart rate (Table l).
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Effects of CAS and Reperfusion on Ischemic Zone Wall Thickening in Pigs With Regional Cardiac Denervation Versus Intact Innervation
Representative LV pressure, LV dP/dt, and wall thickness waveforms from a pig with intact cardiac nerves and regional cardiac denervation at baseline, during coronary stenosis, and at 12 hours and 2 days of reperfusion are shown in online Figure 1 (available in the online data supplement at http://www.circresaha.org). The reduction in coronary blood flow induced by CAS (39±1%) was not different among groups by experimental design (Table 1), and the effects of reperfusion on coronary blood flow were also similar among groups. The flowmeter measurements were confirmed using radioactive microspheres (Table 2). Average ischemic zone wall thickening decreased similarly during CAS in pigs with regional cardiac denervation versus intact innervation (-56±3% versus -54±4%). Therefore, the ischemic insult was similar in these two groups. After 12 hours reperfusion, coronary blood flow had returned to baseline levels in both groups, but ischemic zone wall thickening was depressed significantly more (P<0.05) in pigs with regional cardiac denervation (-46±5%) versus pigs with intact innervation (-31±3%). Further, ischemic zone wall thickening in pigs with regional cardiac denervation remained depressed by 30±3% from baseline after 4 days reperfusion (Figure 1), whereas at 1 day after reperfusion ischemic zone wall thickening had essentially fully recovered to baseline in pigs with intact cardiac innervation (Figure 1). Thus, cardiac denervation did not affect the flow-function relationship during CAS, but intensified myocardial stunning after reperfusion. An additional group of pigs (n=4) with intact innervation were studied with CAS in the presence of MPG. The postischemic recovery in pigs with intact innervation and MPG was similar to pigs with intact cardiac innervation (Figure 1).
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Effects of CAS and Reperfusion on Ischemic Zone Wall Thickening in Pigs With Regional Cardiac Denervation and MPG Versus Pigs With Regional Cardiac Denervation
Average ischemic zone wall thickening decreased similarly during CAS in pigs with regional cardiac denervation and MPG compared with pigs with regional cardiac denervation (-53±2 versus -56±3%; NS). At 12 hours reperfusion, pigs with regional cardiac denervation and MPG had significantly improved recovery of wall thickening (P<0.05), ie, ischemic zone wall thickening was reduced only by 23±6% and was essentially fully recovered at 48 hours, as compared with pigs with denervation in the absence of MPG (Figure 2).
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Effects of CAS and Reperfusion on Ischemic Zone Wall Thickening in Pigs With Regional Cardiac Denervation and NO Synthase Inhibition Versus Pigs With Regional Cardiac Denervation
Average ischemic zone wall thickening decreased similarly during CAS in pigs with regional cardiac denervation and NO synthase inhibition compared with pigs with regional cardiac denervation (-52±2% versus -56±3%; NS). At 12 hours reperfusion, pigs with regional cardiac denervation and NO synthase inhibition had significantly improved recovery of wall thickening (P<0.05), ie, ischemic zone wall thickening was reduced only by 8±5% and was essentially fully recovered at 24 hours, as compared with pigs with denervation in the absence of NO synthase inhibition (Figure 2).
Dual Experiments in Pigs With Regional CD and Pretreatment With MPG or L-NA
As noted above, the 5 pigs with regional CD pretreatment with either MGP or L-NA behaved similarly to innervated pigs, ie, they exhibited normal recovery of regional function and trivial myocardial necrosis. One explanation for these differences is that pretreatment with MGP or L-NA prevented the adverse effects observed with CAS and reperfusion in pigs with regional cardiac denervation. Another explanation could be that the denervation was incomplete. To test this latter possibility, we monitored these 5 pigs with regional cardiac denervation after CAS with MPG (n=4) or L-NA (n=1) until full recovery and then repeated the CAS and reperfusion protocol in these pigs, but in this case, in the absence of pretreatment with MPG or L-NA. Under these conditions, the responses were almost identical to those in the other group of denervated pigs that did not receive pretreatment (Figure 3), ie, recovery was impaired and subendocardial necrosis was observed. Hemodynamic measurements and regional myocardial function at baseline, during coronary stenosis, and during reperfusion for dual experiments in denervated pigs treated with MPG are shown in online Table 1 (available in the online data supplement at http://www. circresaha.org). In order to determine that the necrosis evolved from the second rather then the first experiment, we utilized the well-recognized evolution of the histopathological development of infarct development, ie, if the infarct emanated from the first experiment, it would be characterized by early replacement fibrosis, whereas if it evolved from the second experiment, it would demonstrate early healing necrosis. Indeed, histopathology failed to reveal infarct, which could have been attributed to the 1st episode (0.6±0.2% of the area at risk), but did demonstrate developing infarct from the second episode of CAS and reperfusion (9.4±1.6% of the area at risk), consistent with the amount of necrosis found in the group of pigs with CD that underwent CAS and reperfusion without pretreatment (11.1±2.3%).
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Tissue Norepinephrine Content
To determine the efficacy of regional cardiac denervation, tissue norepinephrine levels were measured in 4 animals. Tissue norepinephrine was depleted in the denervated anterior wall (6.6±0.9 pg/mg tissue), but not in the posterior wall of the LV (599±158 pg/mg tissue).
Evaluation of Tissue Necrosis
TTC staining was normal after CAS and reperfusion in all groups of animals, but was inconsistent with microscopic findings. Therefore, histology was used to assess tissue necrosis in the area at risk after 90 minutes CAS and 4 days reperfusion. The percent area at risk of the LV and percent necrosis of the area at risk for each group of pigs are given in Table 3. The area at risk averaged 39.1±1.1% of the LV. The cardiac denervated animals demonstrated 11.1±2.3% necrosis of the area at risk with the majority of the necrosis located in the subendocardium (Figure 4). There was only trivial necrosis in animals with cardiac denervation and MPG (0.6±0.2%, n=4) and animals with cardiac denervation and NO synthase inhibition (0.7±0.2%, n=5), ie, similar to results in pigs with intact cardiac nerves (1.6±0.7%) and pigs with intact cardiac nerves and MPG (1.8±1.3%). The histological findings from the 5 pigs with regional cardiac denervation (4 pretreated with MPG and 1 pretreated with L-NA), which underwent two episodes of 90 minutes CAS 7 to 10 days apart, ie, in the presence and absence of pretreatment, confirmed that the denervation technique did not influence the response to intervention.
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Evaluation of Tissue Nitrotyrosine
Immunofluorescence staining for nitrotyrosine labeling in myocytes is demonstrated in Figure 5. CAS and 1 hour reperfusion in pigs with regional cardiac denervation resulted in enhanced nitrotyrosine labeling compared with denervated pigs with MPG or L-NA infusion, pigs with intact cardiac nerves, and pigs with intact cardiac nerves with MPG. Semiquantitative analysis of the nonischemic zone demonstrated nitrotyrosine staining levels of 0.5±0.3, 0.3±0.4, 0±0, 0±0, and 0±0 for groups 1 to 5, respectively. Semiquantitative analysis of the ischemic zone demonstrated nitrotyrosine staining levels of 2.8±0.7, 0.3±0.4, 0.7±0.4, 0±0, and 0±0 for groups 1 to 5, respectively. Nitrotyrosine staining of the nonischemic zones were similar to that in the ischemic zones for all groups except for group 1.
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Discussion |
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The present study demonstrated a critical role for cardiac nerves, reactive oxygen species, and NO in determining the response to transient sublethal ischemia and the recovery of stunned myocardium in the conscious pig. This conclusion is based on the findings that in conscious pigs with regional cardiac denervation, both the severity and duration of stunning were enhanced following reperfusion after a 90-minute period of CAS. The failure to observe full recovery of regional function may be explained by the development of patchy subendocardial necrosis. Thus, the same ischemic stimulus did not affect the response to CAS but intensified stunning, and tipped the balance between stunning and necrosis in animals without cardiac nerves.
There has been considerable interest in the role of adrenergic control in general and sympathetic nerves in altering response to myocardial ischemia and reperfusion. The studies by Schulz et al18 clearly demonstrated a deleterious effect of inotropic stimulation in the setting of myocardial ischemia. Other studies confirmed that sympathetic stimulation, by increasing oxygen consumption, in the presence of limited coronary reserve, tips the balance between oxygen supply and demand and results in intensification of ischemia. For these reasons, studies finding that cardiac denervation provides benefit to the ischemic heart were particularly appealing.19–23 Unfortunately, carefully controlled studies using conscious animals without the coronary arterial catheters found essentially no benefit of cardiac denervation.16 When a model of total cardiac denervation was used, the effects of total coronary occlusion were exacerbated.24 The adverse effects observed in the latter model were likely due to the rise in LV end-diastolic pressure, which impeded collateral blood flow in dogs, effects that were not observed in pigs with regional myocardial denervation and partial coronary constriction. In the present model, LV end-diastolic pressure did not rise as much as in the prior canine study,24 and importantly, collateral blood flow is not a feature of the porcine coronary circulation.
It is for the same reasons enumerated above that the current results are novel. Specifically, it would be predicted that denervation would be potentially beneficial, but the opposite was actually revealed. Moreover, these differences were not trivial; not only was stunning intensified and prolonged in the denervated heart, but significant subendocardial necrosis developed.
It could be argued that the denervated heart requires less myocardial blood flow.25 However, the determinants of myocardial blood flow, ie, heart rate, left ventricular pressure, and dP/dt, were the same, as was wall thickening, in the anterior and posterior regions of the heart. Indeed, myocardial blood flow was normal with cardiac denervation, ie, there were no differences in flow, either at baseline, during CAS, or during reperfusion. Therefore, we have to assume there is another role of the cardiac nerves that make their presence beneficial during CAS and reperfusion. Furthermore, the presence or absence of cardiac nerves did not affect the flow-function relationship during the period of ischemia. Therefore, the adverse effects after reperfusion could not be attributed to more intense ischemia or more severely depressed function during the period of CAS.
In further support of our hypothesis, reviewing the literature reveals very few studies finding deleterious effects of NO during ischemia and reperfusion in animal models with intact innervation.8 In contrast, as reviewed by Bolli,8 approximately 75% of the in vitro studies reported a deleterious effect of endogenous NO during ischemia and reperfusion. In a previous study from our laboratory, inhibition of NO synthase exacerbated the stunning in response to CAS and reperfusion,11 which is apparently contradictory with the current results in the denervated heart, where L-NA improved the stunning in response to CAS and reperfusion. Therefore, it is likely that cardiac nerves play a major role in mediating these effects, which may be related to peroxynitrite and free radical generation.
Enhanced generation of reactive oxygen species has been associated with numerous cardiac insults, eg, myocardial ischemia-reperfusion, ischemic preconditioning, and apoptosis and heart failure.2,26 During oxidative stress, peroxynitrite, a potentially deleterious metabolite that reacts with biological proteins and interferes with enzyme or cellular function, is formed by the rapid reaction between superoxide anion, a potentially deleterious reactive oxygen species, and NO, a reactive oxygen species produced primarily by the vascular endothelium. By impeding the reaction between nitric oxide and superoxide, NO synthase inhibition may also reduce formation of peroxynitrite,27 which may contribute to myocardial stunning.28,29 The results of the present study indicate that NO metabolites appear to exert a greater negative effect on regional function during reperfusion in the absence of cardiac nerves. Inhibition of NO synthase also increased cardiac afterload. It is unlikely that this action of L-NA can explain our results, because we observed amelioration of the response to ischemia in the denervated heart in the presence of L-NA.
In summary, the present study demonstrated a profound protective action on the recovery of stunned myocardium mediated by cardiac nerves. In the absence of cardiac nerves, the impaired recovery of stunned myocardium appears to be due to a mechanism involving NO and reactive oxygen species. Either the nerves play a role in attenuating the generation of reactive oxygen or facilitate some other mediator that acts as a scavenger or prevents the conversion of NO to peroxynitrite. It is also conceivable that neurotransmitters emanating from cardiac nerves stimulate NO release from endothelium, or prevent peroxynitrite formation by averting superoxide formation, resulting from eNOS upregulation. It also needs to be mentioned that nNOS could be involved, because there is recent evidence that nNOS can modulate cardiac function.30
The results of the present investigation have implications for understanding further prior controversial topics, eg, the beneficial or deleterious role of endogenous NO in ischemia and reperfusion, and discrepancies in results with free-radical scavenger therapy, topics which can be affected significantly by the presence of intact cardiac nerves. Furthermore, heart failure is characterized by functional cardiac denervation, and transplantation involves surgical cardiac denervation. It is therefore possible to consider that these same mechanisms may contribute to the responses to myocardial ischemia in these settings. Finally, in view of the major role of NO in mediating ischemic preconditioning, the mechanisms elucidated in the present study may also be involved in the pathogenesis of preconditioning.
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Acknowledgments |
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This work was supported in part by National Heart, Lung, and Blood Institute Grants HL69020, HL33065, HL59139, HL33107, HL37404, HL62442, AG14121, AHA 0030125N, and NIH RR16592.
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Footnotes |
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Original received July 31, 2002; resubmission received May 16, 2003; revised resubmission received September 15, 2003; accepted September 16, 2003.
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References |
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