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Am J Physiol Heart Circ Physiol 282: H423-H428, 2002; doi:10.1152/ajpheart.00609.2001
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Vol. 282, Issue 2, H423-H428, February 2002

Enhanced iNOS function in myocytes one day after brief ischemic episode

Song-Jung Kim1, Young-Kwon Kim1, Gen Takagi1, Cheng-Hsiung Huang1, Yong-Jian Geng3, and Stephen F. Vatner1,2

1 Cardiovascular Research Institute and Department of Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark 07103; 2 Hackensack University Medical Center, Hackensack, New Jersey 07601; and 3 Cardiology Division, University Texas-Houston Medical School, Houston, Texas 77030


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

There is increasing evidence that nitric oxide (NO) produced by inducible NO synthase (iNOS) plays a key role in cadioprotection during the "second window of protection" (SWOP). The goals of this study were to determine 1) whether a transient ischemic episode [10-min coronary artery occlusion (CAO), followed by full reperfusion] enhances NOS function in cardiac myocytes, 2) which specific NOS isoform is responsible for the enhanced NOS function in myocytes, and 3) to localize iNOS expression during SWOP. To address these questions, 10 dogs were instrumented to measure aortic and left ventricular pressures and wall thickness. At 1-2 wk after recovery, myocardial ischemia was induced regionally by a 10-min left circumflex CAO. After 24-h reperfusion, cardiac myocytes were isolated from the previously ischemic and nonischemic regions (n = 6). Myocyte contractile function was assessed using a video motion detector at 1 Hz (35 ± 2°C). At baseline, myocyte contractile function (% contraction) was similar in the two regions (ischemic 7.8 ± 0.5% vs. nonischemic 7.8 ± 0.2%). L-Arginine (1 mM) significantly reduced (P < 0.05) myocyte contraction in the ischemic (-34 ± 3%, P < 0.05) but not (-7 ± 4%) nonischemic regions; these responses were abolished by NG-nitro-L-arginine (1 mM), a nonspecific NOS inhibitor, as well as 2-amino-5,6-dihydro-6-methy-4H-1,3,thiazine (1 mM), a specific iNOS inhibitor. Immunohistochemistry also revealed enhanced iNOS expression in the myocardium and in particular the interstitial spaces in the ischemic zone. These results indicate that a brief ischemic episode upregulates iNOS function in myocytes as well as in the interstitial space between blood vessels and myocytes, strategically where it can regulate both vascular and myocyte function during the SWOP.

preconditioning; nitric oxide; contraction; second window of protection


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

ISCHEMIC PRECONDITIONING INVOLVES a brief ischemic episode, which increases the tolerance of the heart to subsequent myocardial ischemia (14, 21, 24). In addition, the late or delayed phase of preconditioning also referred to as the "second window of protection" (SWOP) induces cardioprotection 12-24 h after the initial ischemic stimulus. The protection conferred by the SWOP is sustained longer (3-4 days) than the early phase of preconditioning (2-3 h) in both myocytes and coronary vessels (17, 20, 22, 27, 28) and is modified by several pathways including nitric oxide (NO) (2, 6, 7, 13, 29, 34). However, it remains unclear whether upregulation of NO synthase (NOS) during the SWOP alters myocyte contractile function and which specific isoform is responsible for the enhanced NOS function in cardiac myocytes. In the present study, we induced a brief episode (10 min) of regional myocardial ischemia in the canine model, where the heart is large enough that NO regulation of myocyte contractile function and localization of NOS expression could be compared within the same heart from ischemic and nonischemic regions. Therefore, the first goal of the current study was to determine whether a transient ischemic episode enhances NOS function in cardiac myocytes. The second goal of the study was to determine which specific NOS isoform is responsible for the enhanced NOS function in myocytes and to localize it anatomically using immunohistochemistry.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In Vivo Studies

Ten mongrel dogs (6 for myocyte contractile studies; 4 for immunohistochemistry studies) of either sex weighing 25-30 kg were sedated with acepromazine (0.3 mg/kg im) and anesthetized with pentobarbital sodium (25 mg/kg iv). With the use of sterile surgical techniques, the heart was chronically instrumented to measure left ventricular (LV) function, coronary blood flow, pressures, and regional wall function as previously described (17). A hydraulic occluder was placed around the left circumflex coronary artery to induce myocardial ischemia. After 10-14 days of postoperative recovery, myocardial ischemia was induced regionally so that myocytes from the previously ischemic and nonischemic regions could be isolated and compared in the same heart. In brief, before a 10-min coronary artery occlusion (CAO), all animals received an injection of morphine sulfate (0.2 mg/kg im) before CAO (17). Hemodynamic variables [aortic pressure, LV pressure, left atrial pressure, the rate of change of LV pressure (dP/dt), LV anterior and posterior wall thickness, heart rate, and lead II electrocardiogram] were monitored continuously throughout the study. After baseline hemodynamic measurements were recorded, a 10-min CAO was accomplished by inflating the hydraulic occluder in a conscious state. Ventricular premature contractions were prevented and treated with bolus left atrial injections of 2% lidocaine. After 10 min of CAO, the coronary artery occluder was released slowly over a period of 30 s and followed by 24-h full reperfusion. Animals used in this study were maintained in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996).

In Vitro Studies

Myocyte preparation. After completion of in vivo experiments, calcium-tolerant myocytes were isolated from the LV 24 h after reperfusion, at which time the effect of the SWOP was most prominent (7, 17). The animals were anesthetized with pentobarbital sodium. The still-beating hearts were then removed and immediately placed in ice-cold physiological saline solution (0.9% NaCl). Cardiac tissues (~15-20 g) incorporating the left circumflex artery (ischemic region) and the left anterior descending artery (previously nonischemic normal region) were isolated. Each coronary artery was cannulated, the distal branch was ligated, and the tissue was then perfused with Krebs-Henseleit solution composed of (in mmol/l) 130 NaCl, 4.8 KCl, 1.2 MgSO4, 12 HEPES, 2.5 NaHCO3, 1.2 NaH2PO4H2O, and 12.5 glucose, containing 75 U/ml each of collagenase 1 and 2 (Worthington) on a perfusion apparatus (19). Perfusion pressure was monitored continuously through an in-line pressure transducer during digestion with an initial perfusion pressure of 15-25 mmHg. All perfusion procedures were performed at 35 ± 2°C and all solutions were continuously bubbled with a gas mixture of 95% O2-5% CO2. The digested tissues from both nonischemic and ischemic area were then cut into small pieces, added to Krebs-Henseleit solution containing 2.5% bovine serum albumin, 0.3 mM CaCl2, and collagenase 2 (100 U/ml), and bubbled with a gas mixture of 95% O2-5% CO2. This second digestion provided better control for preventing myocytes from overdigesting; i.e., after every 20 min, the respective suspension was filtered with a nylon mesh (150 µm diameter) and cells were allowed to settle at room temperature. The first and second batches of myocytes were discarded because of possible overdigestion primarily from the initial digestion by the perfusion system. The third and fourth batch of myocytes, which are the highest quality myocytes, i.e., rod shape with clear z-line and without membrane blebs, were used for myocyte function studies. These myocytes were gradually resuspended in Krebs-Henseleit solution containing 0.6, 1.0, and 1.8 mM CaCl2. Myocytes were stored at room temperature and mechanical studies were completed within 6 h after isolation to minimize deterioration due to prolonged storage of cells.

Myocyte contractile and relaxation function were measured using a video motion edge detector at 1 Hz (35 ± 2°C) (18). Contractile (% contraction), the rate of shortening (-dL/dt) and relaxation [the rate of relengthening (+dL/dt) and the time for 70% relaxation (TR 70%)] properties were calculated from the cell length data. Myocyte contractile and relaxation function from nonischemic and ischemic area were assessed with 1) sodium nitroprusside (SNP; 10 µM) in the presence and absence of methylene blue, a guanylate cyclase inhibitor, to determine the extent to which the NO donor alters myocyte contractile function; 2) L-arginine (10-5-10-3 M), an NO substrate, to determine the extent to which NOS function in myocyte is altered; 3) L-arginine (1 mM) in the presence of NG-nitro-L-arginine (L-NNA) (1 mM), a NOS inhibitor, to determine whether the altered responses were NO dependent; 4) 2-amino-5,6-dihydro-6-methy-4H-1,3,thiazine (AMT, 1 µM), a potent and selective inducible NO synthase (iNOS) inhibitor, to determine whether the altered responses were iNOS dependent. Nakene et al. (25) demonstrated (25) that AMT was a more potent inhibitor of iNOS activity (~1,000 fold) than other widely used NOS inhibitors (e.g., NG-methyl-L-arginine, L-NNA, L-aminoguanidine) and was 10- to 40-fold more selective for iNOS than endothelial NOS (eNOS).

Immunohistochemistry for iNOS. To localize iNOS expression, cardiac tissues from both previously ischemic and nonischemic regions were embedded in optimum cutting temperature medium and immediately frozen (9). Frozen sections of previously ischemic and nonischemic regions were fixed in cold acetone for 10 min and blocked with 2% fat-free milk in PBS at room temperature for 30 min. After the blocking, the slides were incubated with a polyclonal antibody against iNOS (USB, 1:100) at 4°C overnight, washed in PBS, and then stained with biotinylated horse antibody (Sigma) to rabbit IgG. The immunostain was visualized with the use of an ABC kit (Vector). Control experiments were performed with normal rabbit IgG.

Data Analyses

The data from all cells studied were averaged for each animal and statistics were performed using the average of all cells from one animal as a single data point. These data are expressed as means ± SE. Comparison of the data between previous ischemic and nonischemic region were performed by Student's t-test for grouped comparisons with significant differences taken at P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Systemic Hemodynamics and Regional Myocardial Function

Table 1 includes mean values for systemic hemodynamics (mean aortic pressure, left atrial pressure, LV dP/dtmax, and heart rate) before CAO, during CAO, at 1-h coronary artery reperfusion (CAR), and 1-day CAR. During CAO (at 9-min CAO), mean aortic pressure, left atrial pressure, and heart rate increased significantly, P < 0.05. The posterior wall thickening (ischemic area) demonstrated complete loss of systolic thickening (-99 ± 11% from baseline, P < 0.05) and remained significantly reduced at 1-h CAR, indicating myocardial stunning, but the anterior wall thickening (nonischemic area) remained at pre-CAO levels. At 1 day CAR, all systemic hemodynamic variables and posterior wall thickening were completely recovered (Table 1).

                              
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  		Table 1.   In vivo hemodynamics in response to 10-min coronary artery occlusion and followed by 1-day coronary artery reperfusion

Myocyte Contractile Function in Responses to SNP and L-Arginine

Table 2 summarizes myocyte length and indices of contractile and relaxation function in myocytes obtained from ischemic and nonischemic regions at 1 day CAR. All of the indexes of contractile and relaxation function were similar in myocytes from the previously ischemic and nonischemic areas.

                              
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  		Table 2.   In vitro myocyte contractile and relaxation function during 1-day CAR after 10-min CAO

Figure 1 summarizes contractile function (% contraction) in response to SNP (10 µM) in the presence and absence of methylene blue. Percent contraction in response to SNP was reduced similarly in myocytes from both the previously ischemic (from 8.0 ± 0.4 to 5.4 ± 0.5%) and nonischemic regions (from 8.3 ± 0.4 to 6.1 ± 0.5%). The reduced contractile response was abolished by 1 µM methylene blue. Figure 2 shows representative myocyte contraction recordings at baseline and in response to L-arginine (1 mM). Although baseline contractile function was similar in myocytes from both regions (Table 2), L-arginine caused a significant decrease in contractile function in the myocytes from the previously ischemic region (-34 ± 3%, P < 0.05), whereas L-arginine did not alter myocyte contractile function from the nonischemic region (-7 ± 4%, not significant). D-Arginine did not reduce contractile function in the myocytes from the both regions (data not shown). Figure 3 summarizes the dose response to L-arginine (10-5-10-3 M) for contractile function in myocytes from both regions. L-Arginine caused a significant (P < 0.05) dose-dependent decrease in contractile function in the myocytes from the previously ischemic region, but not from the nonischemic region. The impaired myocyte contractile function at the highest concentration of L-arginine (1 mM) was abolished by L-NNA (1 mM). To determine whether iNOS is responsible for the enhanced NOS function in myocytes from the previously ischemic region, myocyte contractile function was assessed in response to 1 µM AMT, a specific iNOS inhibitor. The impaired contractile function in myocytes from the previously ischemic area in response to L-arginine was also abolished by AMT, indicating that the reduced contractile function in response to L-arginine is iNOS dependent (Fig. 3). However, none of the inhibitors had a significant effect on myocytes from the nonischemic zone, indicating that there were no nonspecific effects complicating the interpretation of the data.


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  		Fig. 1.   Myocyte contractile function (%contraction) in response to 10 µM sodium nitroprusside (SNP). A: myocyte contraction in response to SNP was reduced similarly in myocytes from both the previously ischemic and nonischemic regions. B: reduced contractile response was abolished by 1 µM methylene blue (MB). *P < 0.05 vs. respective baseline. Values are means ± SE.



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  		Fig. 2.   Superimposed representative myocyte contraction recordings from the nonischemic (left) and the previously ischemic zone (right) at baseline and response to 1 mM L-arginine. Baseline contractile function was not altered in myocytes from the nonischemic and the previously ischemic zones. However, L-arginine caused a significant decrease in contractile function in the myocyte from the previously ischemic zone but not in the myocyte from the nonischemic zone.



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  		Fig. 3.   A: dose-dependent decrease in myocyte contraction in response to L-arginine (Arg) (from 10-5 to 10-3 M) from the previously ischemic zone but not from the nonischemic zone. B: impaired myocyte contraction at 1 mM L-arginine in myocytes from the previously ischemic area was abolished by 1 mM NG-nitro-L-arginine (L-NNA) as well as 1 mM 2-amino-5,6-dihydro-6-methy-4H-1,3,thiazine (AMT). *P < 0.05 vs. baseline.

Localization of iNOS Expression

Figure 4a shows that tissues from the ischemic region stained positively with iNOS antibody. Perivascular cells, i.e., macrophages and fibroblasts, were prominently stained. Some myocytes also showed positive stains for iNOS. In contrast, little iNOS stain was found in the nonischemic region (Fig. 4b). Control staining with normal IgG revealed very low levels of background signals (Fig. 4c), indicating the specificity of anti-iNOS staining.


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  		Fig. 4.   Immunohistochemistry for inducible nitric oxide synthase (iNOS) in myocardial tissues from previously ischemic area (a), nonischemic area (b), and nonspecific IgG immunostaining (c), showing enhanced iNOS expression selectively in the interstitial spaces in tissue from the previously ischemic area.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The major findings of the current study are that 1) a brief ischemic episode (preconditioning stimulus) induces delayed, enhanced iNOS function in myocytes and 2) the upregulated iNOS was also localized in the interstitial spaces of the perivascular region, where it could strategically regulate both vascular and myocyte function during the SWOP. Most prior studies on SWOP used multiple ischemic preconditioning stimuli. In the current study, only one 10-min period of ischemia was used. Nonetheless, 24 h later there was an upregulation of NO function and a second 10-min period of ischemia resulted in attenuated myocardial stunning (unpublished data).

Since Murry et al. (24) first discovered that the heart naturally adapts itself to become resistant to ischemic injury following preconditioning, studies (14, 21) have demonstrated that preconditioning limits infarct size in various species, including humans, and also found that the protective benefits rapidly disappear within an hour. Later studies (2, 15, 17, 22, 27, 28) observed a gradual reappearance of protection within 24 h after the initial ischemic stimulus and with a longer duration of effect (3-4 days), which has been termed SWOP or the delayed phase of preconditioning. Several proteins have been identified as possible mediators of SWOP, including NOS, cyclooxygenase-2, ATP-sensitive K+ channels, antioxidant enzymes, and heat stress proteins (2, 4, 12, 13, 30). Considerable evidence (2, 4, 13, 15, 17, 27, 28, 31) supports the concept that NO is a mediator of the SWOP in both coronary vessels and myocytes. The cardioprotective effects of NO during the SWOP was confirmed by 1) treatment with a nonselective NOS inhibitor, which abolished the cardioprotective effects (5, 7, 13, 27, 31), 2) administration of exogenous NO donors, which mimicked the late protective effects against both stunning and infarction in conscious rabbits (28), and 3) transgenic iNOS and eNOS knockout mice, which showed no cardioprotection (10, 16, 32). Results have been controversial regarding which NOS is upregulated during the SWOP, e.g., studies (29) have reported that iNOS and neuronal NOS expression were enhanced but not eNOS, whereas Baker et al. (2) demonstrated that both iNOS and eNOS expression were increased in repetitive stunning in pigs. In our previous studies and this study (2, 4, 13, 15, 17, 27, 28, 31), myocardial ischemia was induced regionally so that NOS expression in the ischemic and nonischemic region could be compared in the same heart. In the prior studies, the appearance of NO metabolites in the coronary sinus was enhanced, as were coronary vascular responses to NO (2, 4, 13, 15, 17, 27, 28, 31). The present study extended these findings by utilizing isolated myocyte preparations, which could eliminate the effects of NO originating from the coronary vessels.

It has been demonstrated (3, 8, 11, 33) that NO has a negative inotropic effect in isolated myocytes and in the heart. In the current study, a NO substrate, NO donor, NOS inhibitor, and guanylate cyclase inhibitor were utilized to determine the functional role of NOS and its distal pathway in isolated cardiac myocytes during the SWOP. Contractile function in myocytes from the previously ischemic area was similar to that in myocytes from the nonischemic area, which was consistent with the in vivo data assessed by regional wall thickness (17). The response to the NO donor SNP reduced contractile function similarly in myocytes from both areas. Surprisingly, contractile function in response to the NO substrate L-arginine was significantly reduced in myocytes only from the previously ischemic area, and the responses were abolished by L-NNA, a nonspecific NOS inhibitor. These results indicated that the site of upregulation is at the NOS level rather than distal to NOS in the NO pathway. In addition, a specific iNOS inhibitor (AMT) abolished the decreased contractile function induced by L-argnine in myocytes from the previously ischemic area, indicating that iNOS was responsible for the enhanced NOS function in myocytes. These results support previous findings that iNOS is responsible for the cardioprotection during the SWOP, i.e., the treatment of similar selective iNOS inhibitors with aminoguanidine and S-methylisothiourea sulfate abolished the cardioprotective effects against stunning and infarction in prior studies (7, 13, 27, 31). Furthermore, using transgenic mice, Guo et al. (10) found that the cardioprotective effect of the delayed preconditioning is abrogated in the iNOS knockout mouse model.

The signaling pathways for the cardioprotection role of NOS have been studied previously. Recent studies (7, 13, 27, 31) proposed that enhanced iNOS expression is one of the possible signaling mechanisms underlying late preconditioning. The initial sublethal ischemia triggers the SWOP by activating various kinases, e.g., protein kinase C-epsilon , tyrosine kinases, and mitogen-activated protein kinase, which activate transcription factors and then leads to gene transcription including iNOS, cyclooxygenase-2, and manganese superoxide dismutase (7, 13, 27, 31). Although the exact mechanisms are unknown, the cardioprotective mechanisms of the enhanced NO production from eNOS, as well as iNOS, include the following: 1) enhanced coronary perfusion (7, 13, 27, 31), 2) reduced myocardial oxygen consumption (26), 3) enhanced ATP-sensitive K+ channel activity (23), and 4) inhibition of platelet adhesion to endothelial cells (1). Additional evidence for enhanced eNOS function after ischemia-reperfusion include enhanced NO regulation of the coronary vasculature during the SWOP (18) and a study by Baker et al. (2) demonstrating enhanced eNOS expression within endothelial cells 6 h after repetitive stunning in pigs.

In the current study, immuonhistochemistry revealed that the iNOS expression was enhanced in the interstitial spaces of the perivascular region as well as myocytes in the previously ischemic region. The location of the upregulated iNOS, i.e., in the interstitial space between blood vessels and myocytes, places it where it could potentially regulate both vascular and myocyte function during the SWOP.


    ACKNOWLEDGEMENTS

This study was supported in part by National Heart, Lung, and Blood Institute Grants HL-59139, HL-33107, HL-33065, HL-69020, HL-62442, HL-65182, and HL-65183, National Institute on Aging Grant AG-14121, and American Heart Association Grant 0030125N.


    FOOTNOTES

Address for reprint requests and other correspondence: S.-J. Kim, Cardiovascular Research Institute, Univ. of Medicine and Dentistry of New Jersey, MSB C638, 185 S. Orange Ave., Newark, NJ 07103 (E-mail: kimso{at}umdnj.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10.1152/ajpheart.00609.2001

Received 12 July 2001; accepted in final form 11 October 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 282(2):H423-H428
0363-6135/02 $5.00 Copyright © 2002 the American Physiological Society


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