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1 Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut 06030-1110; and 2 Institute of Anatomy and 3 Department of Pharmacology, University of Milan, 20133 Milano, Italy
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Resveratrol, a natural antioxidant and polyphenol found in grapes and wine, has been found to pharmacologically precondition the heart through the upregulation of nitric oxide (NO). To gain further insight of the role of NO in resveratrol preconditioning, mouse hearts devoid of any copies of inhibitory NO synthase (iNOS) (iNOS knockout) and corresponding wild-type hearts were perfused with 10 µM resveratrol for 15 min followed by 25 min of ischemia and 2 h of reperfusion. Control experiments were performed with wild-type and iNOS knockout hearts that were not treated with resveratrol. Resveratrol-treated wild-type mouse hearts displayed significant improvement in postischemic ventricular functional recovery compared with those of nontreated hearts. Both resveratrol-treated and nontreated iNOS knockout mouse hearts resulted in relatively poor recovery in ventricular function compared with wild-type resveratrol-treated hearts. Myocardial infarct size was lower in the resveratrol-treated wild-type mouse hearts compared with other group of hearts. In concert, a number of apoptotic cardiomyocytes was lower in the wild-type mouse hearts treated with resveratrol. Cardioprotective effects of resveratrol was abolished when the wild-type mouse hearts were simultaneously perfused with aminoguanidine, an iNOS inhibitor. Resveratrol induced the expression of iNOS in the wild-type mouse hearts, but not in the iNOS knockout hearts, after only 30 min of reperfusion. Expression of iNOS remained high even after 2 h of reperfusion. Resveratrol-treated wild-type mouse hearts were subjected to a lower amount of oxidative stress as evidenced by reduced amount of malonaldehyde content in these hearts compared with iNOS knockout and untreated hearts. The results of this study demonstrated that resveratrol was unable to precondition iNOS knockout mouse hearts, whereas it could successfully precondition the wild-type mouse hearts, indicating an essential role of iNOS in resveratrol preconditioning of the heart.
nitric oxide; reactive oxygen species; ischemia-reperfusion; heart; apoptosis
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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RESVERATROL (trans-3,5,4'-trihydroxystilbene) is a phenolic phytoalexin present in grape skins and wines, especially red wines (5, 26). It exerts a wide variety of biological effects, including an estrogenic property (14), an antiplatelet activity (2), and anti-inflammatory function (11). Its anti-inflammatory function has been attributed to its ability to inhibit cyclooxygenase. Recently, resveratrol has been found to protect kidney, brain, and heart cells from ischemia-reperfusion injury (14, 17, 29).
The ability of resveratrol to stimulate nitric oxide (NO) production during ischemia-reperfusion is believed to play a crucial role for its ability to protect kidney cells from ischemic reperfusion injury (1, 3). The maintenance of constitutive NO release is a critical factor in the recovery of function after an ischemic injury. Release of constitutive NO is significantly reduced after ischemia-reperfusion (10), and maintenance of NO by any means such as induction of NO production with L-arginine can restore the postischemic myocardial function (21).
A recent study from our laboratory demonstrated the cardioprotective ability of resveratrol (29). Thus resveratrol was able to protect the ischemic reperfused myocardium by improving postischemic ventricular function and by attenuating myocardial infarction due to both necrosis and apoptosis. Although the in vivo antioxidant ability of resveratrol is believed to be at least partially responsible for the cardioprotective properties of resveratrol, the mechanism(s) of action is not completely understood. Since resveratrol was recently found to augment NO production in endothelial cells (19) and the kidney (14), and NO plays a crucial role in resveratrol preconditioning (16), we wanted to confirm if the cardioprotective properties of resveratrol is definitely through NO by using transgenic mouse hearts devoid of any copies of inhibitory NO synthase (iNOS).
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
All animals used in this study received human care in compliance with
the principles of laboratory animal care formulated by the National
Society for Medical Research and Guide for the Care and Use of
Laboratory Animals prepared by the National Academy of Sciences
and published by the National Institutes of Health (Publication No. 96, Revised 1996). Adult male wild-type (+/+) (B6129F1/JAw
J/AW) F2
hybrid mice and iNOS gene knockout (
/) B6,
129P3/J-Nos2tm1Lau hybrid mice were purchased
from the Jackson Laboratory (Bar Harbor, ME). Mice were
randomly assigned to one of four groups: a wild-type control group, a
wild-type transresveratrol, an iNOS knockout control group, and an iNOS
knockout transresveratrol group. Additionally, wild-type mice were
divided into another three groups: group I served as
control, whereas group II was treated with resveratrol only
and group III was treated with resveratrol plus aminoguanine (AG).
Exclusions. In total, 73 mice were originally entered into the ischemia-reperfusion experiments. Eleven mice were excluded from further data analysis because of cannulation time delay (>3 min) or cannulation failure (aortic tear, left atrium tear, etc.) or due to the occurrence of severe arrhythmia.
Isolated mouse heart preparation and measurement of contractile function. The work-performing heart preparation has been previously described elsewhere (32, 33). Briefly hearts from 12- to 18-wk-old male mice were perfused in a work-performing mode under load conditions at a constant perfusion pressure of 55 mmHg, and a constant preload pressure 15 mmHg by hydrostatic fluid columns, with Krebs-Henseleit bicarbonate buffer [KHB; composed of (in mM) 118 NaCl, 24 NaHCO3, 4.7 KCl, 1.2 KH2PO4, 1.2 MgSO4, 1.7 CaCl2, and 10 glucose] gassed with 95% O2-5% CO2, pH 7.4.
All mice were anesthetized with an intraperitoneal injection of pentobarbital sodium (200 mg/kg) and heparin sodium (500 U/kg) administered at the same time to prevent intravascular coagulation of blood. The heart was excised immediately after thoracotomy and placed in perfusion buffer. The aorta was cannulated, and the heart was perfused by retrograde Langendorff method. A catheter was inserted from the left atrium to the left atrioventricular orifice and passed through the apex of the heart and attached to a pressure transducer. The circuit was switched to the antegrade working mode. After 10-15 min of stabilization, preischemic baseline contractile function was measured. The left ventricular (LV) pressure (LVP), first maximal derivative of LVP (dP/dt), LV end-diastolic pressure (LVEDP), and heart rate (HR) were recorded. Data of myocardial contractile function were recorded and analyzed in real time using the Cordat II data acquisition, analysis, and presentation system (Data Integrated Scientific Systems, Pinckney, MI; Triton Technologies, San Diego, CA) (32, 33). Data of coronary flow (CF) were recorded by timed collection of the coronary effluent dripping from the heart. After measurement of preischemic baseline and collection of coronary effluent samples, the circuit was then switched to the retrograde Langendorff mode, and the hearts were perfused with either KHB (both control groups) or transresveratrol at a concentration of 10 µM (both transresveratrol-treated groups) for 15 min. We choose this concentration because the 10 µM concentration appears to be optimal, because at a lower concentration of 5 µM resveratrol was found to be only partially protective, whereas at higher concentration of 50 µM, resveratrol caused deterioration of cardiac function. All hearts underwent 25 min of ischemia at 37oC by clamping the aortic cannula followed by 120 min of reperfusion. The functional parameters were recorded at 15, 30, 60, 90, and 120 min of reperfusion. The effluent samples were collected at 0, 3, 5, 30, 60, 90, and 120 min of reperfusion for measurement of malonaldehyde (MDA).Measurement of infarct size.
Myocardial infarct size was determined by methods described by Ray et
al. (32, 33) with the following modifications. At the end
of reperfusion, the heart was excised and stored at 70°C. For
infarct size determination, frozen hearts were sliced perpendicularly to the long axis from apex to base in 1.0-mm-thick sections. Sections were stained by a 10% (wt/vol) solution of triphenyltetrazolium in
phosphate buffer (88 mM Na2HPO4, 1.8 mM
NaH2PO4) for 15 min and fixed in 10%
paraformaldehyde. Mouse heart cross sections were then placed between
two microscope slides and digitally imaged using an Apple computer
Power PC 7100/80 and a single-pass, flat-bed full-color scanner
(Hewlett-Packard Scanjet 5p). The cross section was imaged at
the maximum scaling and dot resolution that the scanner would allow.
The digitized image was stored in Adobe TIFF file format by the
software package Adobe Photoshop version 5.0.2 (Adobe systems). For
analysis of infarct areas, some enhancements of the image were
necessary to more clearly visualize the areas of staining. To quantify
the areas of interest in pixels, NIH Image 1.62 (a public domain
software package) was used. The infarct area and the entire area of
risk were quantified. The infarct area was compared with the entire
area of risk. The weight of each slice was then recorded to facilitate
the expression of total and infarct masses of each slice in grams. The
total and infarct masses of each heart were then calculated by adding
up them. Infarct size was taken to be the percentage of infarct mass of
total mass for any one heart.
Cardiomyocyte apoptosis. Immunohistochemical detection of apoptotic cells was performed using an Apop Tag Plus in situ apoptosis detection kit (Oncor; Gaitherburg, MD) according to the following principles: residues of digoxigenin-labeled dUTP are catalytically incorporated into the DNA by terminal deoxynucleotidyl transferase (TdT-mediated dUTP nick-end labeling, TUNEL), an enzyme that catalyses a template-independent addition of nucleotide triphosphate to the 3'-OH ends of double- or single-stranded DNA. The incorporated nucleotide was stained immunohistochemically with peroxidase-conjugated sheep polyclonal anti-digoxigenin antibodies and diaminobenzidine, as described by the manufacturer. Counterstain was performed with methyl green. Positive control samples were prepared by incubating sections with 10 U/ml DNase I for 20 min at 37°C before treatment with terminal deoxynucleotidyl transferase. Negative control slides were processed in the absence of terminal deoxynucleotidyl transferase. The number of TUNEL-positive cardiomyocytes was counted in 60 random high-power fields on the LV free wall at the mid-LV level from the endocardial to the epicardial portion. The percentage of TUNEL-positive cardiomyocytes was calculated by dividing the number of TUNEL-positive cardiomyocytes by the total number of cardiomyocytes in 60 microscopic fields.
MDA formation. MDA formation is considered a presumptive marker for oxidative stress. MDA was measured as a MDA-2,4-dinitrophenyl hydrazine (DNPH) derivative by high-performance liquid chromatography. MDA was assayed as described previously to monitor the development of oxidative stress (4). In brief, coronary effluents were collected and derivatized with DNPH and extracted with pentane. Aliquots of 25 µl in acetonitrile were injected onto a Beckman Ultrasphere C18 (3 mm) column. The products were eluted isocratically with a mobile phase containing acetonitrile-water-acetic acid (40:60:0.1 vol/vol/vol) and measured at three different wavelengths (307, 325, and 356 nm) by using a Waters M-490 multichannel ultraviolet detector. The peak for MDA was identified by cochromaography with a DNPH derivative of the authentic standard, peak addition, ultraviolet light pattern of absorption at the three wavelengths, and by gas chromatography-mass spectroscopy.
iNOS mRNA by Northern blot analysis.
For RNA extraction, hearts were obtained at baseline, after 15 min of
resveratrol pretreatment, after 30 min of ischemia, and during
reperfusion (at 30, 60, 90, and 120 min). Hearts were excised,
instantly frozen in liquid N2, and stored at 70°C for subsequent RNA preparation. At a later date, total RNA was extracted from the heart by the acid-guanidinium-thiocyanate-phenol-chloroform method as described previously (24). For Northern blot
analysis, total RNA was electrophoresed in 1%
agarose-formaldehyde-formamide gel and transferred to Gene Screen Plus.
After prehybridization, membranes were hybridized with a 1.8-kb
fragment of mouse macrophage iNOS cDNA obtained from Cayman Chemical
(Ann Arbor, MI). Each hybridization was repeated at least three times
with different membranes. After each hybridization, the iNOS cDNA was
removed and rehybridized with GAPDH cDNA probe, the result of which
served as loading controls.
Statistical analysis. The results are expressed as means ± SE. Differences among the groups were analyzed by a two-way analysis of variance (ANOVA) followed by Bonferroni's test by using Stat View 4.5 (Abacus Concepts). Unpaired t-test was also used to compare the difference among all the groups for any given parameter. P < 0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of resveratrol on myocardial performance.
The baseline mean values of HR, LVP, LVEDP,
dP/dtmax, aortic flow, CF, and cardial output
were not significantly different between the groups (see below for
Figs. 2-5, Table 1). Also, there was
no significant difference in the body weights of the mice (not shown).
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Effects of resveratrol on myocardial infarction.
Myocardial infarct size, an index of irreversible myocardial injury,
was 36.5 ± 0.018% of the risk zone in the wild-type control group after 2 h of reperfusion (Fig.
2). Treatment with resveratrol reduced
the infarct size to 31 ± 0.6% (P < 0.05 vs.
wild-type control). The resveratrol did not reduce the infarct size of
the knockout control group (41.4 ± 1.0% vs. 42.0 ± 2.6%,
P > 0.05). There was significant difference between
the wild-type resveratrol-treated group and the iNOS knockout
resveratrol-treated group (P < 0.01).
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Effects of resveratrol on cardiomyocyte apoptosis.
We performed double antibody staining using antibody in Apop Tag kit
and the monoclonal antibody recognizing cardiac myosin heavy chain to
specifically identify cardiomyocyte apoptosis. A significant
number of apoptotic myocytes were visible in all hearts except for
resveratrol-treated wild-type hearts subjected to 30 min of
ischemia and 2 h of reperfusion (Fig.
3). The number of apoptotic cells
expressed as a percentage of the total cardiomyocyte population was
significantly lower in the wild-type hearts that were pretreated with
resveratrol compared with all other hearts. Only a few apoptotic
cardiomyocytes were visible in the resveratrol-treated wild-type
hearts.
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MDA formation.
The production of MDA is an indicator for lipid peroxidation and
development of oxidative stress. As shown in Fig.
4, after 3 min of reperfusion, MDA levels
in all hearts were increased significantly compared with the baseline
values. These values remained higher during early reperfusion
and then came down to near-baseline levels. The MDA formation in the
resveratrol-treated wild-type hearts (18.5 ± 0.85 pmol/ml) was
markedly lower compared with the hearts not treated with resveratrol
(39.8 ± 0.92 pmol/ml). This trend was also evident after 5 min
into reperfusion when the control wild-type hearts still exhibited a
significantly higher level of MDA production (41.7 ± 0.67 pmol/ml) than hearts treated with resveratrol (6.2 ± 0.34 pmol/ml). Resveratrol had no effects on the amount of MDA formation in
the iNOS knockout mouse hearts.
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Effects of AG on resveratrol preconditioning.
Because resveratrol exhibited cardioprotective effects only in the
wild-type hearts and not in the iNOS knockout hearts, we performed a
separate set of experiments where we examined the effects of the iNOS
inhibitor AG on resveratrol-mediated cardioprotection in the wild-type
mouse hearts. As shown in Table 2, AG
completely abolished the cardioprotective effects of resveratrol
preconditioning as evidenced by the inability of resveratrol to improve
postischemic ventricular function, myocardial infarct size, and
cardiomyocyte apoptosis. These results further document a
crucial role of iNOS in the resveratrol preconditioning of the heart.
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Effects of AG on resveratrol-mediated iNOS mRNA expression.
To further demonstrate the role of iNOS in resveratrol preconditioning,
we examined the effects of AG on iNOS expression in the hearts. In
resveratrol-pretreated wild-type hearts, induction of the expression of
iNOS mRNA was detected in the hearts reperfused for 30 min after 30 min
of ischemia (Fig. 5). iNOS mRNA
was not detected in the hearts at baseline and after 15 min of
perfusion with resveratrol. The amount of iNOS expression increased
steadily up to 60 min of reperfusion and remained unaltered up to 120 min of reperfusion. Preperfusion of the hearts with AG almost
completely abolished the induction of the expression of iNOS in the
resveratrol-treated wild-type hearts. iNOS knockout mouse hearts did
not exhibit iNOS mRNA expression as expected (data not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Salient findings. In this study we provide further evidence that NO plays a crucial role in the cardioprotective properties of resveratrol. The inability of resveratrol to attenuate myocardial ishemic reperfusion injury in the iNOS knockout mouse strongly supports the notion that resveratrol-mediated cardioprotection is mediated through NO. Postischemic ventricular function was improved in the resveratrol-treated wild-type mouse hearts, but not in the hearts of the iNOS knockout mice. Myocardial infarct size and cardiomyocyte apoptosis was significantly attenuated in the resveratrol-treated wild-type hearts, but not in those of iNOS knockout hearts. Furthermore, AG, an iNOS inhibitor, abrogated the cardioprotective effects of resveratrol preconditioning in wild-type mouse hearts, further confirming a crucial role of iNOS in resveratrol preconditioning of the heart.
Cardioprotective ability of resveratrol has recently been found by several laboratories including our own (7-8, 29). The ability of resveratrol to protect the ischemic heart has been attributed to in vivo antioxidant properties of resveratrol. Recently, Giovannini et al. (14) and Naderali et al. (25) demonstrated that upregulation of NO is a princple factor for the antiischemic function of resveratrol. The recent study by Das and colleagues (33) clearly demonstrated that resveratrol preconditions the rat hearts against lethal ischemic reperfusion injury. The antiischemic effects of resveratrol was blocked by NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, indicating that NO is the mediator of resveratrol preconditioning of the heart. Although resveratrol can scavenge peroxyl radicals in vitro, it is generally known as a poor antioxidant (29). However, in vivo, resveratrol functions as an antioxidant and lowers the amount of oxidative stress developed in the ischemic reperfused myocardium (16, 29). This seemingly different behavior of resveratrol can be explained if indeed this compound functions through the augmentation of NO. Numerous reports exist in the literature demonstrating massive production of reactive oxygen species in the ischemic reperfused myocardium. NO can readily react with the superoxide anion to form the highly reactive peroxynitrite radical ONOO, which in turn should preferentially react
with the thiols and ascorbate, which are also present in the heart. In
this regard, NO can function as an in vivo antioxidant; hence,
resveratrol through NO can also function as a potent in vivo
antioxidant. In fact, like resveratrol, NO also possesses a peroxyl
radical scavenging ability because it was found to inhibit
oxoferryl-myoglobin radical-catalyzed oxidation of cis-parinaric acid
(22).
The role of NO is further supported from the observation that
resveratrol possesses vasorelaxing and antiplatelet properties (2, 18), which are also shared by NO. Indeed, NO can cause relaxation to vascular endothelium and inhibit platelet and neutrophil aggregation (27). Furthermore, both resveratrol
(34) and NO (9) possesses anti-inflammatory properties.
The present study was performed with iNOS knockout mouse hearts, which
avoid problems related to the specificity of NO inhibitors. Whereas
resveratrol could successfully precondition wild-type mouse hearts, it
was unable to precondition iNOS gene knockout mouse hearts. There are
three forms of NOS: neuronal NOS or NOS1, endothelial NOS or eNOS, and
iNOS, an inducible form of NOS. All of these isoforms are abundant in
mammalian hearts. A wealth of information is available in the
literature showing the cardioprotective effects of constitutive
expression of NO (9, 20), and our recent study clearly
demonstrates that the cardioprotective property of resveratrol is
linked with its ability to upregulate constitutive NO
(14). The present study further demonstrated that
resveratrol-mediated iNOS induction also plays a crucial role in
cardioprotection. This result is inconsistent with the previous
findings that showed iNOS expression plays a role in ischemic
preconditioning (16).
Ischemic preconditioning mediated by cyclic episodes of
brief periods of ischemia and reperfusion is considered to be
the state-of-the-art technique for myocardial preservation (12, 30). Unlike pharmacological therapeutic interventions,
preconditioning protects the heart by upregulating its endogenous
defense mechanisms (23). Unfortunately, ischemic
preconditioning-mediated cardioprotection has limited lives: classical
or early preconditioning, lasting for several hours, and delayed
preconditioning lasting for several days (6). There is a
definite need to identify a pharmacological preconditioning agent to
render the preconditioning stimulus everlasting. Recently, we and
others (31, 35) found that monophosphoryl lipid A (MLA)
induces a dose-dependent cardioprotection against myocardial
infarction. Such cardioprotection was achieved through the ability of
MLA to upregulate endogenous NO formation (31). Recently,
NO has been found to play an essential role as mediator of
ischemic preconditioning (15). Similar to this,
resveratrol was also found to protect the ischemic myocardium
through NO, because inhibition of NO with L-NAME abolished
the cardioprotective effects of resveratrol (16). The
present findings confirms these results because iNOS knockout mouse
could not be preconditioned with resveratrol further indicating that
this polyphenol provides cardioprotection through NO, and specifically
through, the induction of iNOS. Additionally, the ability of
resveratrol to precondition the heart was abrogated with AG, an iNOS
inhibitor. This also suggests that posttranslational modification of
iNOS is required to synthesize NO, because in another related study,
L-NAME blocked resveratrol-meadiated cardioprotection
(16).
In summary, resveratrol appears to function as a pharmacological
preconditioning agent. Preperfusion with resveratrol could precondition
the wild-type mouse hearts as evidenced by the reduction of myocardial
infarct size, cardiomyocyte apoptosis, and improvement in
postischemic ventricular function. iNOS gene knockout mouse could not be preconditioned with resveratrol, and resveratrol preconditioning in the wild-type mouse hearts was blocked with AG,
indicating an essential role of iNOS in resveratrol preconditioning.
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ACKNOWLEDGEMENTS |
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This study was supported in part by National Heart, Lung, and Blood Institute Grants HL-22559, HL-33889, HL-56803, and HL-56322.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. K. Das, Cardiovascular Research Center, Univ. of Connecticut School of Medicine, Farmington, CT 06030-1110 (E-mail: DDAS{at}NEURON.UCHC.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.01013.2001
Received 21 November 2001; accepted in final form 27 December 2001.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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P < 0.01 vs.
wild-type control or resveratrol-treated iNOS knockout hearts.
