© 2000 American Heart Association, Inc.
Review |
Role of Endothelium-Derived Nitric Oxide in the Regulation of Cardiac Oxygen Metabolism
Implications in Health and Disease
From the Department of Physiology (J.-N.T., G.K., T.H.H.), New York Medical College, Valhalla, NY, and Clinique Cardiologique et des Maladies Vasculaires (J.-B.B.), University Hospital of Nantes, France.
Correspondence to Thomas H. Hintze, PhD, New York Medical College, Department of Physiology, Basic Science Building, Valhalla, NY 10595. E-mail thomas_hintze{at}nymc.edu
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Abstract |
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 Top Abstract IntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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Abstract—Endothelium-derived NO is considered to be primarily an important determinant of vascular tone and platelet activity; however, the modulation of myocardial metabolism by NO may be one of its most important roles. This modulation may be critical for the regulation of tissue metabolism. Several physiological processes act in concert to make endothelial NO synthase–derived NO potentially important in the regulation of mitochondrial respiration in cardiac tissue, including (1) the nature of the capillary network in the myocardium, (2) the diffusion distance for NO, (3) the low toxicity of NO at physiological (nanomolar) concentrations, (4) the fact that low PO2 in tissue facilitates the action of NO on cytochrome oxidase, and (5) the formation of oxygen free radicals. A decrease in NO production is involved in the pathophysiological modifications that occur in heart failure and diabetes, disease states associated with altered cardiac metabolism that contributes to the evolution of the disease process. In contrast, several drugs (eg, angiotensin-converting enzyme inhibitors, amlodipine, and statins) can restore or maintain endogenous production of NO by endothelial cells, and this mechanism may explain part of their therapeutic efficiency. Thus, the purpose of this review is to critically evaluate the role of NO in the control of mitochondrial respiration, with special emphasis on its effect on cardiac metabolism.
Key Words: endothelial nitric oxide synthase–derived nitric oxide • endothelium • mitochondria • cardiac oxygen consumption
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Introduction |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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Since the discovery of the endothelial dependence of acetylcholine-induced vasorelaxation in vitro by Furchgott and Zawadzki,1 NO has been identified as the prototypic endothelium-derived relaxing factor. NO is synthesized from the amino acid L-arginine by a family of enzymes, the NO synthases (NOSs). NO synthesized by the endothelium of small vessels is involved in the control of vascular tone and plays an important role in the regulation of blood pressure.2 3 4 5 6 Shear stress acting on the endothelial lining of blood vessels is believed to be the most important physiological stimulus for the release of NO.7 Studies have demonstrated the presence of endothelial NOS (eNOS) enzyme in and the production of NO by all of the vessels of the coronary circulation.8 9 NO has the ability to dilate large vessels10 11 and is likely to have a role in the control of capillary perfusion pressure and filtration (Figure 1
). Metabolism (ie, O2
consumption and substrate utilization) is the main determinant of organ
function and is therefore an important determinant of blood
flow.12 The increase in
blood flow during exercise, to active skeletal muscle and the heart,
increases O2 delivery and at the same time shear
stress, and consequently NO release. However, several studies have
shown that blockade of NO synthesis has little or no effect on changes
in coronary blood flow in conscious dogs during acute
exercise.13 14
Since the discovery of another major role of NO, ie, a direct effect on
the regulation of mitochondrial respiration, an alternative explanation
for this discrepancy has been
provided.15 16 17 18
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The present review will focus on the role of NO in the
regulation of O2 consumption in vivo and in
vitro. The modulation of O2 consumption depends
on the interaction of NO and O2, their
respective diffusion distances, and their common binding site on
cytochrome oxidase
(Figure 2). The physiological and pathophysiological
consequences of this regulation and therapeutic implications will be
discussed.
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Role of NO in the Regulation of Oxygen Consumption |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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The discovery by Hibbs and colleagues of the biological synthesis of NO by activated macrophages provided the conceptual underpinnings for the regulation of O2 consumption by NO in the myocardium. While examining mechanisms by which cytotoxin-activated macrophages produce cytostasis during cocultivation with neoplastic cells, Granger et al19 showed that mitochondrial energy metabolism (and DNA synthesis) was severely inhibited in tumor cells. These experiments demonstrated that the inhibition of neoplastic cell growth was associated with a depression in O2 consumption. Granger and Lehninger20 showed that the reduction in respiration in this model was caused by the inhibition of complex I (NADH–ubiquinone oxidoreductase) and complex II (succinate–ubiquinone oxidoreductase) of the mitochondrial electron transport chain. The cytotoxic mechanism was associated with the loss of intracellular iron.21 This would explain the inhibition of these enzymes that require Fe for their catalytic function. In addition, cytotoxin-activated macrophages caused rapid inhibition of mitochondrial aconitase in tumor cells.22 These mechanisms were dependent on extracellular L-arginine, which was converted to L-citrulline during this process,23 and the effects of macrophage-induced toxicity were inhibited by NG-monomethyl-L-arginine.24
Finally in 1989, Hibbs et al25 identified NO as the effector molecule of this cytotoxicity. They showed that NO was synthesized from L-arginine by activated macrophages and that NO gas induced the same pattern of toxicity and inhibition of mitochondrial respiration. NG-monomethyl-L-arginine specifically inhibited this toxicity. As iron-sulfur centers of proteins are sensitive targets for formation of Fe-NO complexes, their results suggested that L-arginine–dependent cytoxocity was related to the interaction of NO with the iron-sulfur center of the enzymes.26 Stuehr and Nathan27 reported similar effects of NO in cytostasis and respiratory inhibition in tumor target cells. Their work clearly demonstrated the synthesis of NO in eukaryotes and the importance of L-arginine metabolism in the regulation of mitochondrial respiration. In the aforementioned studies, the pathway leading to the production of NO was not constitutive; nevertheless, the data clearly defined the mechanism for the physiological regulation of mitochondrial respiration by NO.
Work on the L-arginine dependence of macrophage cytotoxicity for tumor cells was extended to defense against microorganisms and demonstrated the importance of L-arginine as a substrate to inhibit replication (Cryptococcus neoformans). A strong correlation was also shown between macrophage fungistasis and production of nitrite/nitrates. The effect of L-arginine was concentration dependent, and fungistasis was specifically inhibited by NG-monomethyl-L-arginine.28 29 In a model of Leishmania major–infected macrophages, NO appears to produce iron efflux, which could result in inhibition of Fe-dependent enzymes.30 Furthermore, the production of cytokine-induced NO is associated with increase in resistance of cultured murine cells to other pathogens, such as Toxoplasma, Mycobacterium leprae, M. tuberculosis, and Plasmodium.31 32 33 34
Brown and Cooper35 in 1994 demonstrated that nanomolar concentrations of NO, ie, physiological concentrations as would be released by eNOS, directly and rapidly inhibited isolated cytochrome oxidase. The inhibitory concentration of NO for cytochrome oxidase was found between 60 and 270 nmol/L, and the inhibition in competition with O2 was reversible, perhaps as a result of the ability of cytochrome oxidase to metabolize NO. These results suggested that the levels of NO that inhibit the iron-sulfur centers are high in comparison with the levels of NO expected to be present in vivo. Using N-nitrosoglutathione (which decomposes to GSSG and NO with a rate of NO production of 0 to 7.6 nmol/Lxmin-1 for concentrations of GSNO of 0 to 500 µmol/L), Cleeter et al36 demonstrated a reversible inhibition of O2 utilization, consistent with the inhibition of complex IV. This inhibition occurred within 4 minutes after the administration of substrates. In isolated rat heart mitochondria, others showed that at nanomolar concentrations NO reversibly blocked respiration due to the inhibition of cytochrome oxidase.37 38 39 This inhibition of respiration was also found in mitochondria from isolated skeletal muscle, liver, and cultured endothelial cells.40
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Production of NO |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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Using an amperometric NO sensor to examine the release of NO from cultured human umbilical vein endothelial cells, Tsukahara et al41 showed that the basal release of NO by endothelial cells was 104 to 408 nmol/L. In endothelium-denuded rings of rabbit thoracic aorta, 15 nmol/L NO produced relaxation of vascular smooth muscle.42 The concentration of NO detected by the porphyrinic electrode on the membrane of endothelial cells was in the range of 2x10-7 to 2x10-6 mmol/L, a concentration that is 3 to 4 times higher than in cytoplasm.43 Kelm and Schrader44 showed that the threshold concentration of NO that induced coronary vasodilation was 1 nmol/L, and EC50 was 7 nmol/L. eNOS is constitutively expressed in vascular endothelial cells, including capillary endothelium (Figure 3
). In the normal heart, eNOS is the primary NOS
enzyme and is located primarily in the vascular
endothelium.45
Immunohistochemical staining has also shown a significant presence of
brain NOS in the atria46 and
in perivascular nerve fibers in the myocardium of the
ventricle.47
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Immunocytochemical staining studies have shown the
presence of eNOS in the mitochondria isolated from rat
heart.48 This mitochondrial
NOS located in the inner membrane has been shown to be constitutively
expressed and active and may account for NO production to modulate
mitochondrial respiration.49
However, NO released from the vascular endothelium may be the most
important source of NO in the myocardium under physiological conditions
and could easily affect adjacent myocytes
(Figure 3
).
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Diffusion of NO |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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Taking into account the high diffusibility of NO and the close proximity of endothelial cells to myocytes, NO may have the ability to modulate the metabolic function of cardiac cells. Capillaries have the largest cross-sectional area, 100 times higher than all other vessel types combined.50 Significant production of NO by the coronary circulation has been demonstrated both in vitro44 51 52 and in vivo.15 This release of NO may regulate cardiac metabolism, given that capillary endothelium53 provides an abundant source of NO. The concentration of NO in tissue depends on the rate of NO synthesis; its diffusion inside the tissue; and the degradation of NO by its scavengers, oxygen free radicals and hemoproteins. Moreover, the effects of NO also depend on the prevailing O2 tension.
The neutral charge of NO permits its rapid and wide diffusibility in tissue, without a carrier molecule to affect transport. NO diffuses in all directions from its source with a range of 150 to 300 µm within 4 to 15 seconds.54 The diffusion distance may even reach 600 µm.55 The diffusion constant of NO was calculated as 3.3x10-5 cm2xs-1 in aqueous solution at 37°C,56 which is 1.4 times higher than the diffusion coefficient of O2. Taking into account the lipophilic properties of NO, the sarcolemma does not stand in the way of NO diffusion, and moreover, the cell membrane constitutes a storage reservoir for NO. eNOS is primarily a membrane-bound protein57 located in the membrane subfractions called caveolae58 59 in a catalytically active state, bound to caveolin.60 The presence of NO in the membrane may generate a gradient between the membrane and the aqueous phase on both sides of the membrane and facilitate the diffusion of NO to adjacent cells.43
NO reacts with O2 species, metal ions, thiols, and hemoproteins, ie, hemoglobin and cytochrome c, which are present in the microenvironment of the endothelial cell. These factors could decrease the half-life of NO, its diffusion distance, and consequently its biological activity.61
In rabbit thoracic aortic rings, Malinski et
al56 reported the in situ
measurements of NO release from a single endothelial cell and its
subsequent diffusion to the smooth muscle cells with a sensor placed at
a distance of 100±2 µm from the endothelial layer. Bradykinin (10
nmol) injected in the proximity of the sensor placed on the endothelial
cell membrane produced a measurable amount of NO after 100±25 ms, and
the maximum concentration of NO (1.3±0.05 µmol/L) was recorded after
13.3±0.1 seconds. In the muscle, detection of NO was recorded after
3.0±0.2 ms, and a maximum NO concentration of 0.85 µmol/L was
observed 20.2±0.1 seconds after the injection of bradykinin. Malinski
et al56 also showed that the
concentration of NO was the same on both sides of the cell (luminal and
abluminal sides). They observed a time delay of 1.5 seconds between the
theoretical and experimental concentration of NO at 100 µmol/L from
endothelial cell, indicating that 
37% of NO was consumed. They
emphasized that this consumption of NO in the tissues requires a steep
concentration gradient to keep the NO supply by the diffusion process
effective. After stimulation, they detected a maximum concentration of
NO on the cell surface of 1.02±0.08 µmol/L after 12.4±0.1 seconds
and a concentration of NO in the middle of the endothelial cell that
was lower by 60±25% during the first 500 to 800 ms. Those data are
consistent with the hypothesis that the cell membrane can develop a
relatively high concentration of NO within a short period of time and
participate in the creation of a gradient between the endothelial cell
and the aqueous cytoplasm and extracellular fluid. This gradient
facilitates the diffusion of NO to the muscle cell.
The presence of biological membranes in the cells may, on the other hand, partially limit the activity of NO. Liu et al62 showed that disappearance of NO in aqueous solution was accelerated by the presence of hydrophobic phases, in which 90% of the NO reaction with O2 occurs. Mitochondria may participate in the NO oxidation by this mechanism and may be important sites for the metabolism of NO and the formation of NO-derived reactive species. Recently, Zai et al63 suggested that the entry of NO into the cell from the extracellular medium could be facilitated by a transnitrosation mechanism, catalyzed by the cell-surface protein disulfide isomerase (PDI), a protein that catalyzes thiodisulfide exchange reactions. PDI contributes to 0.025% of the cell-surface thiol population. Reduction of expression of PDI, using antisense, leads to a reduction of the thiol pool on the surface of the cell and to modification in access of extracellular NO to the cytoplasm.
Poderoso et al,39 taking into account the myoglobin concentration and the fact that a significant portion of endothelial NO could be trapped by myoglobin, argued that the steady-state NO concentration in myocytes should be in the range of 0.1 to 0.3 µmol/L. Malinski et al64 measured the local concentration of NO in cerebral tissue during and after transient middle cerebral artery occlusion in the rat. The basal NO concentration was below the detection limit of the sensor (10-8 mol/L), but on initiation of ischemia NO increased to 10-6 mol/L. Thus, at the concentration range of NO observed and expected in vivo, cytochrome oxidase is a likely target for NO regulation of mitochondrial respiration.
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Effects of PO2 |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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Several studies suggest that the effect of NO depends on O2 concentration, respiration state, and availability of substrate. Schweizer and Richter65 showed that, at an O2 tension similar to that found in venous blood (
35 mm Hg), micromolar concentrations of NO induced a rapid and
complete but reversible de-energization of mitochondria.
Takehara et al66 also
demonstrated that in liver mitochondria NO reversibly inhibited
mitochondrial respiration in a dose- and O2
concentration–dependent manner. The inhibition occurred at
physiologically low O2 concentrations. Borutaite
and Brown37 showed that the
sensitivity of respiration to NO (1 µmol/L) depended on the
O2 concentration and also on substrate type and
respiration rate in rat heart mitochondria. The inhibition of
O2 respiration rate was greater at 52 to 65
µmol/L O2 than at 126 to 168 µmol/L
O2. Respiration was more sensitive to NO with
pyruvate than with succinate. The sensitivity of respiration rate to NO
was lower in state 4 than in state 3; this may be due to the
extent of control of the coefficient of cytochrome oxidase over
mitochondrial respiration in state
3.67 Torres et
al68 showed that the onset
of inhibition of cytochrome c
oxidase by NO occurred in <15 seconds. This inhibition occurred in
competition with O2 and was more effective at
low O2 concentrations. Clementi et
al69 studied the rate of
O2 consumption of porcine aortic endothelial
cell suspension with glucose in a gas-tight vessel equipped with
electrodes to detect O2 and NO. Cell respiration
was analyzed with O2 concentrations decreasing
from 100 to 0 µmol/L. These experiments showed that the rate of
O2 consumption varied with its concentration and
suggest that endogenous production of NO plays a role in this mechanism
by lowering the affinity of cytochrome oxidase for
O2. At low levels of NO, the inhibition of
cytochrome oxidase is reversible and competitive with that of
O2, but at high levels and long-term exposure
(24 hours), the inhibition of mitochondrial aconitase and of complexes
I and II appears to be irreversible. Half-maximal inhibition of
respiration occurred at 9.8±1.0 µmol/L O2.
Addition of an eNOS inhibitor or the NO scavenger hemoglobin caused an
increase in O2 consumption. Bradykinin, which
increases the production of NO by endothelial cells, induced a
transient decrease in O2 consumption. The
concentration of NO produced was independent of the
O2 concentration, but the importance of the
inhibition of respiration was dependent on the concentration of
O2 (33.9±2.3% and 58.1±2.7% at 80 and 40
µmol/L O2, respectively). To demonstrate that
the inhibition of respiration was dependent on cytochrome
c oxidase, the same experiments
were conducted with an inhibitor of mitochondrial complex III, whereas
cell respiration was maintained via cytochrome oxidase alone, using an
electron donor and ascorbic acid as a primary reducing agent.
Administration of bradykinin elicited a release of NO that inhibited
mitochondrial respiration in the same way as the inhibition occurring
in cells respiring on glucose. Under the same conditions,
N
-nitro-L-arginine
methyl ester (L-NAME) increased O2
consumption. It is also important to note that the half-life of NO is
increased during the decrease in
PO2.70 |
PO2 in Tissues |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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Taking into account the O2 dependence of mitochondrial respiration, it is important to consider whether O2 and NO concentrations match, to support a potential physiological role for NO in the regulation of mitochondrial respiration. At normal cardiac myocardial oxygen consumption (M
O2),
the mean capillary
PO2
is equal to the coronary venous
PO2
(20 torr). The factors that control O2
availability in cardiomyocytes include the following (1)
O2 delivery from the red cells, (2) the
diffusion distance for O2 (2 µm to reach
the sarcolemma and 13 µm to reach the center of the cell), (3) the
blood flow, (4) the transmural distribution of the blood flow, and (5)
the
PO2
gradient from the blood vessel to the myocyte. From the capillaries to
the cytosol, O2 is transported passively by
diffusion.71 The diffusion
equation for O2 in peripheral tissue is
dependent on the capillary surface area and is inversely related to the
squared distance from the capillaries to the mitochondria. A
unit of capillary lumen surface supplies 3 to 5 units of sarcolemma
area, 50 to 200 units of mitochondrial surface, and up to 600 units of
mitochondrial inner
membrane.72 Moreover, the
functional area of capillaries for O2,
determined by the density of red cells, is
smaller.73 Myoglobin in the myocardium binds O2 reversibly and is responsible for the oxygenation of the cytosol. Myoglobin facilitates O2 diffusion and uniform oxygenation in heart cells and maintains an O2-free environment within the cell. O2 delivery to mitochondria occurs through dissolved O2 and the diffusion flux caused by oxymyoglobin. Heterogeneities of muscle fiber dimensions are of minor importance for muscle O2 supply, as they are compensated by the high myoglobin–facilitated O2 diffusivity inside the muscle cell.74 Myoglobin-dependent O2 uptake is proportional to the fraction of sarcoplasmic myoglobin combined with O2, and myoglobin-mediated O2 delivery to mitochondria may contribute importantly to the ability of the heart to sustain maximum work output.75
Wittenberg and
Wittenberg76 calculated the
sarcoplasmic free O2 concentration to be 3.2
µmol at 37°C, and the ratio of myoglobin-bound
O2 to free O2, 30:1.
Gayeski and Honig77
demonstrated in the subepicardium that
PO2
in equilibrium with myoglobin was remarkably uniform among 5 different
species, 4.3 to 7.0 torr. These values were consistent with the
values obtained by other
techniques.78 Gayeski and
Honig77 demonstrated that
minimum myoglobin saturation was 32% in dogs and myoglobin saturation
and
PO2
in equilibrium with myoglobin appeared remarkably uniform, even though
arterial
PO2
ranged between 83 and 326 torr.
Thus, the myocardium has an extremely low
PO2
under physiological conditions. The main determinant of this low
PO2
in tissue is related to the extracellular and intracellular gradient of
O2. Extracellular gradient is the difference of
PO2
between the surface of the red cell in the capillaries and the
sarcolemma and is considered to be 15 torr for a distance of 2 µm
from the capillary lumen to sarcolemma. This gradient can be explained
by the absence of a carrier in the extracellular space
(peri-erythrocyte plasma, capillary endothelium, and interstitial
space79 ), a non-uniform
unloading of red blood
cells,74 and the discrepancy
between capillary surface area and cardiomyocyte sarcolemma area.
Moreover, the distribution of the mitochondria may not be homogeneous
among cells, and some populations of mitochondria are located in
juxtacapillary areas
(Figure 3). The mitochondrial system could be considered as a
syncytial network, and this network may influence
O2 pathway and may imply less of a role for
myoglobin in intracellular
transport.80
There are still a number of controversies concerning the
intracellular gradient of O2 that may affect
cellular energetics and cellular
function.81 82 83 84 85 86
Demonstrating a low intracellular gradient in isolated cardiac
cells,83 it was found that
the O2 dependence of respiration by mitochondria
isolated from cardiac cells was a function of the energy state and
substrate availability and that the O2
dependence of mitochondrial respiration in situ was dependent on both
cellular metabolic state and on the O2
concentration difference between extracellular media and the
mitochondria. In this model, in cells, the region of
O2 dependence began at 20 µmol/L (=14
torr). They concluded that for actively working cells in situ,
the dominant factors are those that affect the delivery of
O2 to the tissue, ie, blood oxygenation,
coronary flow, and functional capillary surface area. Kreutzer and
Jue84 found that above an
intracellular
PO2
of 4 mm Hg, the myocyte is sufficiently oxygenated and shows neither
physiological nor biochemical signs of hypoxia. This critical level of
PO2
was consistent with other studies showing
PO2
values between 8 and 14
mm Hg.87
Takahashi et al88 hypothesized that the gradient in the center of the cell might account in part for the suppression of mitochondrial respiration caused by insufficient diffusional O2 delivery. They concluded that whereas with nonlimiting O2 supply, mitochondrial O2 consumption is principally set by the energy state, at increased cellular O2 demand the center of the cell is more sensitive to hypoxia because of the limitation of O2 diffusion.
Thus, the level of PO2 in the myocyte is assumed to be very low, and the gradient between HbO2 in red cells and the sarcolemma may be most important. The levels of PO2 in cardiac cells and near the mitochondria and the concentration of NO in tissue and its diffusion are consistent with a role of NO in the regulation of mitochondrial respiration. Furthermore, molecular O2 has itself a direct regulatory effect on cytochrome c oxidase, ie, a reversible inhibition of cellular respiration in the presence of low PO2, which could allow cells to adapt their respiratory rate to the ambient PO2 in tissue.89
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Toxicity of NO Depends on O2 Concentration |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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The toxicity of NO is mainly determined by its interaction with O2- and should increase with increased PO2 in tissue. Ioannidis et al90 studied the cytotoxic effects of NO on cultured endothelial cells at different O2 concentrations. They used spermineNONOate, an NO donor that, in contrast to SNAP or nitroprusside, decomposes independently of the presence of O2. The toxicity of spermineNONOate was highly dependent on O2 concentration. At 0% and 5% O2 (5% O2
35
mm Hg), toxicity of NO released from 2 mmol/L spermineNONOate
(20 µmol/L of NO) led to <20% cell death after 4 hours of
incubation. At 10% and 21% O2 concentration,
the same concentration of spermineNONOate induced 46% and 73% cell
death, respectively, and reached 95% at 95%
O2. The authors attributed these effects mainly
to the oxidation of NO yielding NO2. The
participation of the interaction of NO with
O2- and/or
H2O2 was discussed, but
the low levels of production of
H2O2 during these
experiments and its rapid degradation by catalase and glutathione
peroxidase seemed to have no additive effect on toxicity. Under these
conditions, the production of
O2- and
ONOO- was unlikely to reach toxic levels.
These results are of great importance because under physiological
concentrations of O2, NO can exert its
regulatory function without cytotoxicity. In these experiments, the
amount of NO produced reaches micromolar concentrations, yet the
physiological level of NO concentration in tissue ranges from 100 to
500 nmol/L at baseline. Even micromolar concentrations of NO do not
seem to have cytotoxic effects as described by Ioannidis et
al.90 |
Role of NO Species in the Control of Oxygen Consumption |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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NO binds to cytochrome c oxidase, and this is a main mechanism for inhibition of mitochondrial respiration. But the effects on mitochondrial respiration could also be related in part to the production of superoxide (O2-) and other NO species, such as peroxynitrite (ONOO-).91 Reaction of NO with O2- produces ONOO-, which reacts with all major classes of molecules and can cause toxicity independent of NO or O2-.92 Activated macrophages produce a significant amount of ONOO-, and ONOO- has been shown to inhibit cellular respiration.93 94 95 The inhibition of mitochondrial respiration therefore could be due to either NO or ONOO-. In the heart, in vitro, Xie et al96 demonstrated that NO, produced by a NO donor (SNAP) or through endogenous NO release (bradykinin or carbachol), suppressed mitochondrial respiration, and endogenous ONOO- formation was not necessary. Tiron, an intracellular scavenger of O2-, or uric acid, a scavenger of ONOO-, did not modify the effects of SNAP. The effect of NO on respiration was completely reversible. O2- released by administration of pyrogallol induced an inhibition of O2 consumption that was partially reversible. Formation of ONOO- from the interaction of NO with O2- (through the simultaneous presence of SNAP and pyrogallol) promoted enhanced suppression of respiration, with a greater suppression of O2 consumption than seen with generation of NO or O2- alone. Xie et al96 concluded that in intact cardiac muscle NO itself has a completely reversible inhibitory effect on respiration, whereas the formation of ONOO- from its interaction with O2- promotes enhanced suppression of respiration that is no longer rapidly reversed. Using a theoretical mathematical model, Kelm and Schrader51 showed that ONOO- is not formed in significant amounts until >90% of oxyhemoglobin is consumed. These data suggest that, in the presence of oxyhemoglobin maintaining a low level of NO, there is very little ONOO- formation in the presence of micromolar amounts of both proteins.61
ONOO- has little or no effect on cytochrome c oxidase but inhibits mitochondrial respiration at complexes I to III and II to III93 and is probably the original mechanism resulting in macrophage toxicity, given that macrophages make both NO and O2-.36 Lizasoain et al97 showed that the direct effect of NO was on complex IV with an IC50 of 2 µmol/L. They showed that ONOO- persistently inhibited respiration at complexes I to III and II to III without affecting complex IV. They also suggested that ONOO-, through its interaction with glucose or reduced glutathione, could also generate NO donors and thus had indirect effects on mitochondrial respiration.
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Regulation of O2 Consumption In Vivo |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
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NO produced by the capillary endothelium can diffuse to the underlying myocytes to regulate O2 consumption by mitochondria98 by altering the affinity of O2 for cytochrome c. Photomicrographs supporting the spatial relationships needed to support this hypothesis are shown in Figures 3B
and 3C.
In vivo, Shen et
al17 showed that inhibition
of NO synthesis increased total-body O2
consumption and increased body temperature. This was due, in large
part, to an increase in O2 extraction because
cardiac output fell. Furthermore, the increase in
O2 extraction was not due to the
vasoconstriction, because infusion of another vasoconstrictor did not
increase O2 consumption to a similar degree.
King et al16 showed that NOS
inhibition significantly elevated skeletal muscle
O2 uptake. Bernstein et
al15 showed that
O2 consumption in the heart was increased at any
level of cardiac work after inhibition of NOS. This was due again to a
change in myocardial O2 extraction, given that
there was a downward shift in the
MO2–coronary
sinus
PO2
relationship. In the skeletal muscle circulation of the conscious dog
at rest and during exercise, inhibition of NO synthesis also increased
O2 consumption at all levels of external
work,18 independent of the
change in skeletal muscle blood
flow.99 Loke et
al100 observed that bovine
polymerized hemoglobin–based O2 carrying
solution doubled O2 consumption by the heart in
conscious dogs as a result of increased extraction. Angiotensin II
administration induced a similar effect on vascular resistance, but the
increase in
O2
was smaller (31%±12 versus 78%±17%). These results are consistent
with the scavenging properties of hemoglobin-based
O2 carrying on
NO.101 Recchia et
al102 reported that an
acute inhibition of NO synthesis using
N-nitro-L-arginine
increased O2 consumption in normal conscious
dogs. This was associated with an acute change in cardiac substrate
utilization similar to that observed during cardiac decompensation. The
MO2
changes and substrate utilization could be rapidly reversed after
administration of a NO donor. These findings were confirmed in another
study, in which the increase of
MO2
with blockade of NO synthesis could be underestimated by the change in
substrate utilization, the reduction of myocardial free fatty acid
utilization and the increase in carbohydrate (lactate and glucose)
utilization. Switching from free fatty acid to lactate can result in a
reduction of O2 consumption, because lactate is
a more efficient fuel and may account for a 10% reduction of
MO2.103 104
In conscious dogs, the stimulation of free fatty acid uptake by lipid
infusion caused an exaggerated increase in cardiac
O2 consumption in combination with
nitro-L-arginine
administration.105 In
conscious dogs, NO can also play a major role in maintaining a balance
between O2 consumption and sodium reabsorption,
the major ATP-consuming process in kidney, and NO can inhibit
mitochondrial O2 consumption in canine renal
slices as
well.106
|
Regulation of O2 Consumption In Vitro |
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TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
|---|
In isolated rat heart perfused with solutions of increasing concentrations of NO, Poderoso et al39 showed a dose-dependent decrease in myocardial O2 uptake. The decrease in myocardial O2 uptake was related mostly to the inhibition of cytochrome oxidase. Half-inhibition of heart mitochondrial state 3 respiration was achieved at
0.4 µmol/L NO.
These results were consistent with previous studies from the same group
that showed a half-maximal inhibition of cytochrome oxidase at 0.1
µmol/L NO in rat heart
mitochondria.107
In in vitro experiments, Shen et
al108 showed that the
release of NO from skeletal muscle by bradykinin or acetylcholine, or
due to the chemical release of NO by SNAP, led to a reduction in
skeletal muscle O2 consumption. In addition, the
mechanism of action of NO in those studies appears to be through a
cGMP-independent, direct action of NO on mitochondrial metabolism. In
normal myocardial muscle isolated from the left ventricular free wall
of dogs, Xie et al98 showed
that endogenous, endothelium-derived NO can attenuate mitochondrial
respiration of adjacent myocytes. The inhibitory effects of bradykinin
and carbachol, but not of SNAP, were prevented by
N-nitro-L-arginine.
Loke et al109
demonstrated that bradykinin loses its ability to reduce
O2 consumption in myocardial tissues taken from
eNOS-deficient mice
(Figure 4), but the response was still present in hearts of
iNOS–deficient mice. Moreover, Pittis et
al110 showed
(Figure 4) that the coincubation of normal coronary
microvessels with cardiac tissue isolated from mice lacking eNOS or
stimulation of coronary microvascular eNOS by bradykinin produce enough
NO to regulate
MO2.
These studies emphasize the pivotal role of eNOS as a source of NO to
regulate parenchymal cell O2 consumption. This
regulatory effect of NO through bradykinin, ramiprilat, amlodipine or
derived from exogenous sources (SNAP) also occurred in the nonhuman
primate heart. Coronary microvessels isolated from the left ventricle
of the primate heart released nitrite in response to the same drugs,
supporting the importance of the coronary microvasculature as a
potential source of
NO.111
|
, n=7).
This effect was significantly attenuated by L-NAME (
, n=6).
Bradykinin had no inhibitory effect on O2
consumption in tissues from
eNOS-/-
mice (
, n=10). *P<0.05 vs
respective eNOS+/+ or
eNOS+/+ in the presence of
L-NAME.Other studies, conducted in the in situ heart of anesthetized open-chest dogs112 or pigs113 or in the sedated canine114 have produced conflicting results. This discrepancy could perhaps be explained by the presence of anesthetic drugs, some of which interfere with cellular respiration at the same site as NO.115 Moreover, the switch in substrate utilization related to NO synthesis blockade, as mentioned above (ie, more efficient fuel), could minimize the increase of O2 consumption, and this may be another explanation for the differences in the studies of the regulation of myocardial O2 consumption by NO in whole animals.
|
Changes in the Modulation of Oxygen Consumption by NO in Heart Failure or Diabetes |
|---|
|
TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
|---|
In heart failure and diabetes, NO production by blood vessels is reduced or abolished.116 117 118 119 120 NO-dependent coronary vasodilation is impaired in conscious dogs after the development of pacing-induced heart failure or alloxan-induced diabetes.5 121 Recchia et al101 showed that the transition to decompensated heart failure is associated with a fall of cardiac NO production and a shift in cardiac substrate utilization. After the development of severe dilated cardiomyopathy and heart failure, the NO-dependent component of both shear stress and agonist-induced arteriolar dilation was also reduced or abolished.122 In tissues from dogs after heart failure98 123 and diabetes,124 the inhibitory effect of endogenous NO on the consumption of O2 is attenuated. The depressed modulation of O2 consumption in tissue was not related to mitochondrial dysfunction or structural changes in mitochondria, because a NO donor still exerts an inhibitory effect on O2 consumption after pacing-induced heart failure or diabetes. The decreased release of NO from the vascular endothelium contributes to the depressed modulation of O2 consumption by endogenous NO after heart failure and diabetes. However, in the failing human heart, the modulation of O2 consumption by both endogenous NO, using agents that stimulate endogenous NO release, and exogenous NO, through NO-releasing compounds, was partially preserved.125
|
Conclusion |
|---|
|
TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
|---|
Because the content of O2 in the early atmosphere was low and the NO concentration higher than today, NO was probably a substrate for early prokaryote life forms.126 127 As suggested by Castresana and Saraste,128 the cytochrome oxidase of the earliest universal ancestor might have metabolized NO rather than O2. NO reductase, the primary enzyme implicated in denitrification, ie, an anaerobic respiratory process that reduces nitrate to dinitrogen (N2) via nitrite, NO, and nitrous oxide,129 has strong homology to cytochrome oxidase. The phylogeny of subunit I of cytochrome oxidase and the first unit of NO reductase suggests that the first oxidase may have evolved from NO reductase and that denitrification preceded aerobic respiration.
The increasing concentration of O2 in the earth’s atmosphere caused by oxygenic photosynthesis of cyanobacteria probably led to the substitution of iron for copper in the ancestral oxidase to reduce O2 more efficiently.130 131 This occurred in combination with changes in the protein environment around the catalytic site and the evolution of proton channels. Several characteristics suggest that mitochondria descend from prokaryotes, ie, size, the presence of circular DNA, and independent enzymatic complexes (ribosomes) that are of the bacterial type. Hence, early eukaryotes probably acquired aerobic respiration when the atmospheric levels of O2 increased, by a symbiotic process between bacteria and eukaryotes some 1.5 billion years ago. NO regulation of mitochondrial function and its physiological role in mammals may be related to this evolutionary process.
|
Acknowledgments |
|---|
This work was supported by NIH Grants HL 50142, HL 61290, and PO-1 HL 43023. J.-N.T. is a recipient of a grant from the French Federation of Cardiology. We thank Anne-Yvonne De Lajartre, MD, for providing Figure 1
. Received October 3, 2000; revision received October 19, 2000; accepted October 19, 2000.
|
References |
|---|
|
TopAbstractIntroductionRole of NO in...Production of NODiffusion of NOEffects of
Po2Po2
in TissuesToxicity of NO Depends...Role of NO Species...Regulation of O2
Consumption...Regulation of O2
Consumption...Changes in the Modulation...ConclusionReferences |
|---|
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