© 2000 American Heart Association, Inc.
Integrative Physiology |
Myocardial Glucose Uptake Is Regulated by Nitric Oxide via Endothelial Nitric Oxide Synthase in Langendorff Mouse Heart
From Departments of Physiology (H.T., C.I.T., F.A.R., K.E.L., M.O., G.K., T.H.H.) and Pathology (C.J.S.), New York Medical College, Valhalla, NY; Division of Hypertension and Vascular Research (E.G.S.), Henry Ford Hospital, Detroit, Mich.
Correspondence to Thomas H. Hintze, PhD, Professor, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Thomas_Hintze{at}nymc.edu
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Abstract |
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Abstract—Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N
-nitro-L-arginine methyl
ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose
uptake was much greater than in normal mice, whereas myocardial glucose
uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from
normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and
ecNOS (+/+) mice increased significantly in the presence of L-NAME. At
a workload of 800 g · beats/min, L-NAME increased glucose uptake
from 0.1±0.1 to 3±0.4 µg/min · mg in ecNOS (+/-) mice and
from 0.2±0.1 to 2.7±0.7 µg/min · mg in ecNOS (+/+) mice.
Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine
3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or
S-nitroso-N-acetylpenicillamine (SNAP), a
NO donor essentially shut off glucose uptake, and in hearts from ecNOS
(+/-) mice,
1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one
(ODQ), an inhibitor of cGMP, increased the glucose uptake
significantly. These results indicate clearly that cardiac NO
production regulates myocardial glucose uptake via a
cGMP-dependent mechanism and strongly suggest that ecNOS plays a
pivotal role in this regulation. These findings may be important in the
understanding of the pathogenesis of the diseases such as
ischemic heart disease, heart failure, diabetes mellitus,
hypertension, and hypercholesterolemia, in
which NO synthesis is altered and substrate utilization by the
heart changes.
Key Words: cardiac work • mice, knockout • arginine • length-tension
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Since the discovery of nitric oxide (NO), its actions on blood vessels have been extensively studied.1 2 3 In contrast to these vascular effects, the potential role of NO in the control of myocardial metabolism has received little attention. In recent years, several investigators indicated that NO may have an important role in the regulation of cardiac metabolism. Our previous studies have demonstrated that the inhibition of NO synthesis with nitric oxide synthase (NOS) inhibitors nitro-L-arginine (NLA) or methyl ester of NLA (L-NAME) increased tissue oxygen consumption.4 The site of action is most likely cytochrome oxidase,5 6 and a recent elegant study by Clementi et al7 using cultured endothelial cells supports this conclusion. Furthermore, we have recently found that endothelial nitric oxide synthase (ecNOS) plays a pivotal role in the control of myocardial oxygen consumption using transgenic mice lacking ecNOS.8
In addition, inhibitors of NOS protect the heart against ischemic injury and improve the postischemic functional recovery in vitro.7 This protection may be related to stimulation of glucose uptake and glycolysis, resulting in a better maintenance of high-energy phosphates. These data suggest that NO plays an important role in the regulation of myocardial glucose metabolism. Although the use of arginine analogs has indicated a tentative role for NO in the regulation of myocardial glucose metabolism,9 10 and we have tentatively described a role for NO in the control of free fatty acid and glucose uptake in the heart during exercise and heart failure,11 12 questions remain as to which isoform of NOS is involved in this regulation. The aim of the present study was to further define the role of NO in the control of myocardial glucose metabolism using hearts from mice lacking ecNOS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals
Normal mice (C57BL/6J) obtained from the Jackson Laboratory (Bar Harbor, Maine) were used as controls. Heterozygote ecNOS (+/-) mice, originally developed by Shesely et al,13 were interbred to generate ecNOS heterozygotes (+/-), homozygous (-/-), and wild-type (+/+) mice.8 The ecNOS mice were genotyped by Southern blot analysis of DNA from tail snips as described previously (Figure 1
), to discern ecNOS
(+/-), (-/-), and (+/+) mice. All protocols were approved by the
Institutional Animal Care and Use Committee of New York Medical College
and conform to the current National Institutes of Health and American
Physiological Society guidelines for the use and
care of laboratory animals.
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Isolated Mouse Heart Preparation
Isolated heart preparation was performed using a method modified
for the mouse heart.14 Mice (either sex) were
anesthetized with sodium pentobarbital (65 mg/kg IP), and
heparin (100 U) was injected intravenously. The thorax was
opened. The heart was quickly excised, placed in ice-cold saline, and
immediately mounted, via the ascending aorta, onto a perfusion
apparatus. The heart was perfused with a nonrecirculating
perfusate at a constant flow (1.6±0.1 mL/min) and pressure of
100 mm Hg (Langendorff preparation). The perfusate was
a modified Krebs-Henseleit solution containing (in mmol/L) NaCl
117, KCl 4.7, MgSO4 1.1,
KH2PO4 1.2, glucose 5.5,
CaCl2 2.5, ascorbate 0.1, and
L-arginine 1.0. The perfusate was equilibrated with
5% CO2/95% O2 at 37°C,
and pH was adjusted with NaHCO3 (20 to 25
mmol/L) to 7.40. The perfusate in the reservoir was
continuously pumped through a 3-µm filter to prevent particulate
matter from entering the coronary circulation.
A metal hook was inserted into the apex of the heart to control and
record tension and heart rate. Tension was measured using a FTO3C
transducer (Grass Instrument Co, Quincy, Mass) and recorded on a
Dynograph recorder R511A (Sensor Medics, Anaheim, Calif). In some
studies, 10-4 mol/L of
N-nitro-L-arginine
methyl ester (L-NAME), 10-4 mol/L of
8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), 50
µmol/L of S-nitroso-N-acetylpenicillamine
(SNAP), or 10-4 mol/L of
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
(ODQ) (Sigma) were added to the perfusate.
Cardiac Glucose Uptake
Hearts were perfused at up to three different workloads to
stimulate glucose utilization (peak-systolic tension from 1 to
9 g). Heart work was estimated as the product of developed
tension (peak-systolic tension-end-diastolic
tension) and heart rate. Perfusate leaving the heart was
collected over 1 minute for the measurement of glucose during steady
state at each level of work. Glucose in perfusate was measured
using Glucose [HK] 10 from Sigma. Glucose uptake was calculated by
the following equation:
[Glucose Uptake](µg/min · mg)={[G]in-[G]out} x[Flow Rate](mL/min)/heart weight (mg)
[G]in: glucose concentration, inflow (µg/mL),
[G]out: glucose concentration, outflow (µg/mL)
Pacing Procedure
In some studies, the hearts were paced at 200 bpm to keep
the heart rates the same. One electrode was attached to the metal hook,
and the other one was inserted into the perfusion apparatus
just above the ascending aorta, and then the heart was stimulated (33
Hz, up to 10 V, 1-ms duration) using a Grass S44 stimulator (Grass
Instrument Co).
Statistical Analysis
Data were calculated as mean±SEM. Linear regression was
performed using least-squares analysis (Microsoft Excel).
Graphs were produced using Microsoft Excel. Statistical
analyses of heart work and myocardial glucose uptake were
performed using unpaired t test, and that of linear
regression lines were performed using ANOVA. P<0.05 was
considered statistically significant.
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Results |
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The age, body weight, and sex of all mice are shown in Table 1
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Isolated Mouse Heart
Initially, each mouse heart was stretched to 1 gram-tension and
allowed to equilibrate. To ensure that each heart responded in a
similar fashion, end-diastolic tension was increased in one
to two additional steps (Figure 2A). To
ensure that hearts from different genotypes responded to
stretch, the relationship between end-diastolic tension and
peak-systolic tension was plotted (Figure 2B). There was
a linear relationship between end-diastolic tension and
peak-systolic tension in all genotypes of mice and in
the presence of L-NAME (Table 2). There
was no significant difference among the groups.
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Role of NO in the Regulation of Myocardial Glucose
Metabolism
The effects of changes in cardiac work versus glucose uptake are
shown in Figure 3A. In the hearts from
normal mice, little glucose uptake was observed at any level of heart
work. However, myocardial glucose uptake of normal mice increased in
the presence of L-NAME (10-4 mol/L), an
inhibitor of NOS. The average changes in heart work and
glucose uptake are shown in Figure 3B. L-NAME markedly increased
glucose uptake in hearts from normal mice.
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Significance of ecNOS in the Regulation of Myocardial Glucose
Metabolism
Myocardial glucose uptake of ecNOS (-/-) mice was much greater
than that of normal mice (Figures 3A
and 3B), whereas myocardial
glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice were not different
from normal mice (Figures 3A and 3B). In addition, myocardial
glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice increased
significantly in the presence of L-NAME (10-4
mol/L) (Figures 3A and 3B).
Role of cGMP in the Regulation of NO-Mediated Myocardial
Glucose Metabolism
8-Br-cGMP (10-4 mol/L), a cGMP analog, or
SNAP (50 µmol/L), a NO donor, essentially shut off glucose
uptake in the hearts from ecNOS (-/-) mice (Figure 4). Furthermore, ODQ
(10-4 mol/L), a selective and potent
inhibitor of cGMP, increased glucose uptake remarkably in
the hearts from ecNOS (+/-) mice (Figure 4). In these
protocols, every heart was paced at 200 bpm throughout the experiment.
To ensure that these drugs had no effects on cardiac function, the
relationships between end-diastolic tension and
peak-systolic tension were plotted again. There was no
significant difference among the groups (data not shown).
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Discussion |
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Although the effects of NO on blood vessels are well known,1 2 3 the potential role of NO in the control of myocardial metabolism has only recently been appreciated. In the present study, we have demonstrated clearly that NO regulates myocardial glucose metabolism via cGMP in the mouse heart and for the first time that ecNOS is a key enzyme in this regulation. Our studies have clearly shown that removal of NO production using a NOS inhibitor or gene deletion in ecNOS (-/-) mice or inhibition of cGMP in heterozygote mice markedly increases glucose uptake. This is independent of changes in cardiac work, given that the large glucose uptake after L-NAME or in ecNOS (-/-) mice occurred at low cardiac work, ie, the double product, in our studies.
There are some differences in heart work among groups in our study due to the variation of heart rate. However, we can exclude the contribution of heart rate to our results, because all hearts were paced at the same heart rate in studies of the role of cGMP. In addition, even in other protocols, the highest glucose uptake occurred at the lowest workloads. Furthermore, myocardial glucose uptake was much greater in ecNOS (-/-) mice and normal, ecNOS (+/-), ecNOS (+/+) mice with L-NAME than in normal ecNOS (+/-), or ecNOS (+/+) mice. To be certain that a gross difference in cardiac function in mouse hearts of different genotypes was not responsible for the altered glucose uptake, we constructed a length-tension relationship. There was no difference in the relationship between passive and active tension across groups. Therefore, the altered glucose uptake cannot be explained by altered function. Furthermore, although heart rate was low in the ecNOS (-/-) heart and normal heart after L-NAME, this cannot account for the difference in glucose uptake, because high glucose uptake occurred at low workloads. Finally, there was no significant difference in the increase in heart work in ecNOS (+/+) and ecNOS (+/-) mice before and after L-NAME, and yet a significant increase in myocardial glucose uptake occurred after inhibition of NOS.
There were also some differences in age and sex among groups. The ages of ecNOS (-/-) mice were higher than those of normal mice, but the ages of ecNOS (+/-) or (+/+) mice were also higher than those of normal mice. However, glucose uptake of these ecNOS (+/-) or (+/+) mice was not different from normal mice. There were no males in the normal or the normal with L-NAME group. However, myocardial glucose uptake of normal with L-NAME was much higher than those of normal mice. Therefore, we can conclude that age or sex had no effect on these results.
An inhibitory action of NO on glycolysis was first demonstrated in a model of chronic liver inflammation.15 Other investigators have suggested a stimulatory role for NO in the control of glucose metabolism.16 17 Recently, Depre et al18 reported that inhibitors of NOS protect the heart against ischemic injury and improve the postischemic recovery of cardiac function. This protection was related to stimulation of glucose uptake and glycolysis after NOS inhibition. Depre et al proposed that the stimulation of glycolysis after NOS inhibition was mediated by increased glucose transport, because the flux through phosphofructo-1-kinase was smaller than through the transporter, and hence hexose-6-phosphates accumulated. Depre et al19 in another study also demonstrated that cGMP might be involved in this mechanism because 8-Br-cGMP and a NO donor inhibited glucose uptake in Langendorff rat heart. These studies are confirmed by our results and extended further given that ODQ markedly increased glucose uptake in the hearts from ecNOS (+/-) mice.
Recently, we have reported a significant increase in myocardial glucose uptake and decrease in free fatty acid (FFA) uptake associated with significant decrease in cardiac NO production in conscious dogs with pacing-induced heart failure.11 This switch in myocardial substrate utilization also occurred after acute pharmacological blockade of NO production with NLA in normal conscious dogs. In addition, this NLA-induced switch in myocardial substrate utilization from FFA to glucose was rapidly reversed by a NO donor,10 suggesting that cardiac NO production acutely regulates substrate utilization of the myocardium. Furthermore, bovine polymerized hemoglobin-based oxygen-carrying (HBOC) solution increased myocardial glucose and lactate consumption with a significant decrease in FFA consumption in conscious normal dogs,20 again suggesting that HBOCs may improve metabolic efficiency of the heart by shifting metabolism from FFA to glucose and lactate as a result of its ability to scavenge NO. The effects of NLA or HBOCs were not due to altered afterload because infusion of angiotensin II to cause similar hemodynamic actions did not alter FFA or glucose uptake by the heart in the same conscious dogs. Taken together, the present study in mice and our previous studies in chronically instrumented conscious dogs indicate that cardiac NO production may regulate myocardial glucose, lactate, and FFA metabolism.
There are some other and more subtle implications of our study. First, as in our study, most in vitro preparations use only glucose as a substrate because it is difficult to use FFAs. If NO is present, then glucose uptake will be limited and may be reflected in the stability of the preparation. In tissue culture, particularly in isolated cells, where only myocytes are present and NO production is low, the cardiac myocytes will take up glucose. This in no way reflects the normal physiological state during which cardiac cells take up FFAs to the virtual exclusion of glucose.11 12 In in vivo studies, there is no significant glucose uptake in normal hearts when NO is present, and therefore the regulation of myocyte metabolism in vitro may not represent myocyte function in vivo.
Using arginine analogs or HBOCs in previous studies, we were unable to determine which isoform of NOS is involved in the control of substrate uptake by the heart. In the present study, we have provided direct evidence that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism, and that the constitutive isoform of ecNOS plays a pivotal role in this regulation. Our study was not able to determine a role for cardiac myocyte ecNOS, although neuronal NOS seems to be unimportant. The knowledge generated from the present study may contribute to a better understanding of the normal physiological control of cardiac substrate utilization and the pathogenesis of diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is attenuated and cardiac substrate or oxygen consumption is altered.
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Acknowledgments |
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This study was supported by grants from the National Heart, Lung and Blood Institute: HL 50142 and PO-1 43023 (to T.H.H.) and R-29 54081 (to C.J.S.). H.T. was supported by a fellowship from the Biopure Co and K.E.L. by fellowship 9820046T from the American Heart Association NY State Affiliate.
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Footnotes |
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This manuscript was sent to Richard A. Walsh, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received October 28, 1999; accepted November 10, 1999.
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References |
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C.-H. Wang, N. Leung, N. Lapointe, L. Szeto, K. D. Uffelman, A. Giacca, J. L. Rouleau, and G. F. Lewis Vasopeptidase Inhibitor Omapatrilat Induces Profound Insulin Sensitization and Increases Myocardial Glucose Uptake in Zucker Fatty Rats: Studies Comparing a Vasopeptidase Inhibitor, Angiotensin-Converting Enzyme Inhibitor, and Angiotensin II Type I Receptor Blocker Circulation, April 15, 2003; 107(14): 1923 - 1929. [Abstract] [Full Text] [PDF]
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D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]
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G. E. Mann, D. L. Yudilevich, and L. Sobrevia Regulation of Amino Acid and Glucose Transporters in Endothelial and Smooth Muscle Cells Physiol Rev, January 1, 2003; 83(1): 183 - 252. [Abstract] [Full Text] [PDF]
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 P B Massion and J-L Balligand Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice J. Physiol., January 1, 2003; 546(1): 63 - 75. [Abstract] [Full Text] [PDF]
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F. Brunner, R. Maier, P. Andrew, G. Wolkart, R. Zechner, and B. Mayer Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase Cardiovasc Res, January 1, 2003; 57(1): 55 - 62. [Abstract] [Full Text] [PDF]
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 J. N. Rottman, D. Bracy, C. Malabanan, Z. Yue, J. Clanton, and D. H. Wasserman Contrasting effects of exercise and NOS inhibition on tissue-specific fatty acid and glucose uptake in mice Am J Physiol Endocrinol Metab, July 1, 2002; 283(1): E116 - E123. [Abstract] [Full Text] [PDF]
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F. A. Recchia, J. C. Osorio, M. P. Chandler, X. Xu, A. R. Panchal, G. D. Lopaschuk, T. H. Hintze, and W. C. Stanley Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs Am J Physiol Endocrinol Metab, January 1, 2002; 282(1): E197 - E206. [Abstract] [Full Text] [PDF]
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U. K.M. Decking, J. P. Williams, R. Dahmann, T. Stumpe, M. Kelm, and J. Schrader The nitric oxide-induced reduction in cardiac energy supply is not due to inhibition of creatine kinase Cardiovasc Res, August 1, 2001; 51(2): 313 - 321. [Abstract] [Full Text] [PDF]
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N. Paolocci, U. E. G. Ekelund, T. Isoda, M. Ozaki, K. Vandegaer, D. Georgakopoulos, R. W. Harrison, D. A. Kass, and J. M. Hare cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1982 - H1988. [Abstract] [Full Text] [PDF]
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 X.-P. Yang, Y.-H. Liu, D. Mehta, M. A. Cavasin, E. Shesely, J. Xu, F. Liu, and O. A. Carretero Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B2 Kinin Receptor Gene Knockout Mice Circ. Res., May 25, 2001; 88(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
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F. Brunner, P. Andrew, G. Wolkart, R. Zechner, and B. Mayer Myocardial Contractile Function and Heart Rate in Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase Circulation, December 18, 2001; 104(25): 3097 - 3102. [Abstract] [Full Text] [PDF]
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