© 1999 American Heart Association, Inc.
Rapid Communication |
Endogenous Endothelial Nitric Oxide Synthase–Derived Nitric Oxide Is a Physiological Regulator of Myocardial Oxygen Consumption
From the Departments of Physiology (K.E.L., P.I.M., J.M.T., C.I.T., G.K., M.S.W., T.H.H.) and Pathology (C.J. Smith, C.J. Stackpole), 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, 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—Our objective was to determine the precise role of endothelial nitric oxide synthase (eNOS) as a modulator of cardiac O2 consumption and to further examine the role of nitric oxide (NO) in the control of mitochondrial respiration. Left ventricle O2 consumption in mice with defects in the expression of eNOS [eNOS (-/-)] and inducible NOS [iNOS (-/-)] was measured with a Clark-type O2 electrode. The rate of decreases in O2 concentration was expressed as a percentage of the baseline. Baseline O2 consumption was not significantly different between groups of mice. Bradykinin (10-4 mol/L) induced significant decreases in O2 consumption in tissues taken from iNOS (-/-) (-28±4%), wild-type eNOS (+/+) (-22±4%), and heterozygous eNOS(+/-) (-22±5%) but not homozygous eNOS (-/-) (-3±4%) mice. Responses to bradykinin in iNOS (-/-) and both wild-type and heterozygous eNOS mice were attenuated after NOS blockade with N-nitro-L-arginine methyl ester (L-NAME) (-2±5%, -3±2%, and -6±5%, respectively, P<0.05). In contrast, S-nitroso-N-acetyl-penicillamine (SNAP, 10-4 mol/L), which releases NO spontaneously, induced decreases in myocardial O2 consumption in all groups of mice, and such responses were not affected by L-NAME. In addition, pretreatment with bacterial endotoxin elicited a reduction in basal O2 consumption in tissues taken from normal but not iNOS (-/-)–deficient mice. Our results indicate that the pivotal role of eNOS in the control of myocardial O2 consumption and modulation of mitochondrial respiration by NO may have an important role in pathological conditions such as endotoxemia in which the production of NO is altered.
Key Words: endothelial nitric oxide synthase–derived nitric oxide • cardiac oxygen consumption
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Introduction |
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Evidence for the effect of nitric oxide (NO) on mitochondrial function was reported before the discovery of NO by Granger et al1 in 1980. Their initial observations demonstrated that activated mouse peritoneal macrophages severely inhibited O2 consumption in numerous tumor cell lines obtained from different tissues and animal species in cultures by an unknown mechanism. Evidence now suggests that the macrophage-induced cytotoxic effect on mitochondrial metabolism is NO related.2 3 NO inhibits respiration by nitrosylating the iron-sulfur centers of aconitase, complexes I and II of the electron transport chain, and through a very potent reversible alteration in the activity of cytochrome c oxidase.4 5 6 Recently, we and others have provided direct evidence to suggest that under physiological conditions NO plays a modulatory role on mitochondrial respiration and tissue O2 consumption. For instance, L-arginine analogues, which are nonspecific inhibitors of the 3 isoforms of nitric oxide synthase (NOS),7 increase O2 consumption in whole body,8 heart, skeletal muscle, and kidney both in vivo9 10 11 12 and in vitro.12 13 14 We have interpreted our previous studies to suggest that endothelial nitric oxide synthase (eNOS), the most highly expressed isoform of NOS in vascular tissue under physiological conditions, is responsible for the control of tissue O2 consumption by NO. However, we have yet to determine which isoform of NOS regulates mitochondrial O2 consumption, because almost all cells are capable of expressing all 3 different NOS isoforms. Studies of the effects of bacterial endotoxins have attributed a substantial role for inducible nitric oxide synthase (iNOS) in the development of shock and perhaps other pathological states. To address the role of NO in both physiological and pathophysiological states in the control of mitochondrial respiration, we used tissues from mice deficient in iNOS and eNOS and 3 additional groups, ie, control C57BL/6x129, control outbred wild-type eNOS (+/+), and heterozygous eNOS (+/-) mice to better understand the sources of NO responsible for the control of O2 consumption.
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Materials and Methods |
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Animals Studied
iNOS-deficient mice were bred by pairing homozygous mutant iNOS (-/-) mice originally developed by MacMicking et al.15 C57BL/6x129 mice obtained from the Jackson Laboratories were used as wild-type controls. Heterozygous eNOS (+/-) mice, originally developed by Shesely et al,16 were interbred to generate eNOS wild-type (+/+), heterozygotes (+/-), and homozygous mutant (-/-) mice. The eNOS mice were genotyped by Southern analysis of DNA as described previously,16 with the eNOS wild-type used as littermate controls for the eNOS (+/-) 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.
Preparation of Cardiac Muscle Tissue Slices and Measurement of
Tissue O2 Consumption
Mice were anesthetized with pentobarbital sodium (65
mg/kg IP), and hearts were removed immediately. The atria, right
ventricle together with connective tissues, and fat and large
coronary arteries were discarded. The left ventricle was then
bisected such that each piece of muscle contained the septum, free
wall, and apex. Tissues were then incubated in Krebs bicarbonate
solution containing (mmol/L) NaCl 118, KCl 4.7,
CaCl2 1.5, NaHCO3 25,
KH2PO4 1.2,
MgSO4 1.1, and glucose 5.6 at 37°C, bubbled
with 21% O2/5% CO2/74%
N2 (pH 7.4) to equilibrate for at least 2 hours.
At the end of the incubation period, each piece of tissue was placed in
a stirred bath with 3 mL of air-saturated Krebs bicarbonate solution
containing 10 mmol/L HEPES (pH 7.4). The bath was sealed using a
Clark-type platinum O2 electrode (Yellow Springs
Instruments) that was connected to an O2 monitor
(model YSI 5331); hence, the uptake of O2 by the
tissue was recorded. Increasing concentrations
(10-7 to 10-4 mol/L) of
bradykinin (Sigma) or
S-nitroso-N-acetyl-penicillamine (SNAP, Sigma) on
O2 uptake were studied in the absence or presence
of NOS inhibitors (10-4 mol/L)
N-nitro-L-arginine (NLA) or
N-nitro-L-arginine methyl ester
(L-NAME). Sodium cyanide (10-3 mol/L, Sigma), an
inhibitor of complex IV of the electron transport chain,
was given at the end of each experiment to confirm that changes in
O2 consumption originated from mitochondria.
Pretreatment of Lipopolysaccharide in Normal and iNOS
(-/-) Mice
In the lipopolysaccharide (LPS)-treated mice,
Escherichia coli LPS (serotype 026:B6, Sigma) was
administered at 0.75 mg/kg IP. After 3 to 4 hours, mice were
anesthetized, blood samples were collected by cardiac puncture, and
hearts were removed and prepared as described in the previous
section.
Measurement of Plasma Nitrate/Nitrite
Plasma nitrate/nitrite (NOx) assay was performed using a method
previously described by our laboratory.17 Briefly, after
centrifugation, plasma was incubated in an air-tight
tube containing Aspergillus nitrate reductase to reduce
nitrate to nitrite, then converting nitrite into NO by the addition of
hydrochloric acid. Gaseous NO produced was then injected into a NO
chemiluminescence analyzer (Sievers, Inc). The NO content was
determined by combining with ozone to produce photons that are directly
proportional to the amount of NO injected; hence, the NOx in the plasma
sample.
Calculation of Tissue O2 Consumption and
Statistical Analysis
Tissue respiration was calculated as the rate of decrease
in O2 concentration, assuming an initial
O2 concentration of 224 nmol/mL18
and was expressed as nanomoles of O2 consumed
per minute per gram of tissue. The effect of bradykinin or SNAP on
tissue O2 uptake is expressed as a percentage of
change in baseline O2 consumption. All data in
the Table
, text, and figures are presented as mean±SEM.
Statistical analysis on baseline O2
consumption was performed using 1-way ANOVA followed by Tukey test for
multiple comparisons, and the changes in O2
consumption caused by bradykinin or SNAP were analyzed using
2-way ANOVA followed by multiple comparison using Student-Newman-Keuls
method.
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Results |
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Baseline Cardiac Tissue O2 Consumption in Normal and Genetically Altered Mice
Baseline tissue O2 consumption was not different in any group in the absence or presence of NOS inhibitors NLA or L-NAME (Table
).
Effects of Cardiac Tissue O2 Consumption in Response to
Bradykinin and SNAP in Normal Mice
Cumulative doses of bradykinin (10-7 to
10-4 mol/L) in tissues from control mice caused
concentration-dependent decreases in O2
consumption (Figure 1A). These responses
were attenuated after blockade of bradykinin B2
receptors with the B2 receptor
antagonist HOE-140 (10-5 mol/L)
(10-5 mol/L, control: -25±4% versus HOE-140:
7±11%, P<0.05, t test, n=5).
Bradykinin-induced reduction in O2 consumption
was attenuated by NLA (10-4 mol/L, control:
-31±4% versus NLA: -12±4%, P<0.05; Figure 1A).
Administration of SNAP (10-4 mol/L) decreased
tissue O2 consumption in control C57BL/6x129 mice
by 29±4%. In contrast to bradykinin, responses to SNAP were not
affected by NLA (data not shown).
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Effects of Cardiac Tissue O2 Consumption in Response to
Bradykinin and SNAP in iNOS (-/-)– and eNOS (-/-)–Deficient
Mice
Bradykinin caused concentration-dependent decreases in
O2 consumption in tissues from iNOS-deficient
mice (10-4 mol/L, iNOS: -28±4%; Figure 1B), and this was reduced in the presence of NLA (Figure 1B). Similarly, administration of bradykinin decreased
O2 consumption in tissues from both wild-type and
heterozygous eNOS mice [10-4 mol/L, eNOS
(+/+):-20±4% versus eNOS (+/-):-22±6%; Figure 2A and 2B] in a concentration-dependent
manner. These responses were significantly attenuated by L-NAME (Figure 2A and 2B). In contrast, bradykinin had no
inhibitory effect on O2 consumption
in tissues obtained from eNOS-deficient mice
[10-4 mol/L, eNOS (-/-):-3±4%; Figure 2C]. However, concentration-dependent decreases in
O2 consumption were observed in response to SNAP
in cardiac tissues from eNOS (-/-)–deficient mice (Figure 2D). In addition, responses to SNAP were not significantly
different between tissues of mice, whether wild-type, heterozygous, or
homozygous, for the disrupted eNOS gene [ie,
10-4 mol/L, eNOS (+/+):-27±10% versus eNOS
(+/-):-30±6% versus eNOS (-/-):-31±6%; P=NS, 1-way
ANOVA].
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Effects of LPS Treatment on Cardiac Tissue O2
Consumption in Normal and iNOS (-/-)–Deficient Mice
Administration of endotoxin significantly lowered resting
myocardial O2 consumption in normal mice (Figure 3A). This effect was accompanied by an
increase in levels of NOx (Figure 3B). In contrast, endotoxin
treatment had no effect on either resting O2
consumption or plasma NOx in iNOS (-/-)–deficient mice (Figure 3A and 3B).
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5 in each group). |
Discussion |
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In the present study, we have demonstrated that the constitutive isoform of eNOS plays a pivotal role in the regulation of myocardial tissue O2 consumption. These findings support our speculation in previous studies that NO released from the vascular endothelium not only controls tissue blood flow but also affects tissue respiration. Our data show that the ability of bradykinin to reduce tissue O2 consumption was abolished in the myocardial tissues taken from the hearts of mice lacking functional eNOS, but such responses were still present in tissues from the hearts of iNOS-deficient mice. Furthermore, induction of NO production by endotoxin significantly reduced basal myocardial tissue O2 consumption from normal but not iNOS (-/-)–deficient mice, indicating that iNOS may be important in the pathogenesis of endotoxemia and sepsis.
The blockade of endogenous NO production using NOS inhibitors NLA or L-NAME had no effect on baseline tissue O2 consumption in normal or genetically altered mice. This observation is consistent with our previous reports of isolated tissue O2 consumption,12 13 14 suggesting that in the absence of shear stress or a chemical stimulus, the influence of basal release of NO on tissue O2 consumption is minimal. When baseline myocardial O2 consumption was analyzed across the different strains of mice, we found that baseline O2 consumption in tissue from the iNOS (-/-) mice is significantly lower compared with O2 consumption in tissue taken from the wild-type eNOS (+/+) mice. This difference could not be explained by the possible upregulation of eNOS/neuronal nitric oxide synthase (nNOS) after iNOS gene deletion, as reported by Meng et al19 in pial arterioles. This should have resulted in enhanced NO production and lowered baseline O2 consumption; however, NOS inhibition with NLA in our study had no effect on baseline O2 consumption. The difference may be due to a different number of mitochondria per cell, a genetically determined value. In the murine model, we demonstrate that endogenous NO released through a B2 kinin receptor–mediated mechanism or exogenous NO inhibits myocardial O2 consumption. The B2 kinin receptor–mediated mechanism is supported by our more recent data showing that the inhibitory effect of bradykinin on O2 consumption was abolished in hearts from mice lacking bradykinin B2 receptors.20
When the involvement of specific NOS isoforms in the regulation of myocardial O2 consumption was examined, similar concentrations of bradykinin were tested in tissues from iNOS- and eNOS-deficient mice. The loss of bradykinin but not SNAP responses on tissue O2 consumption in eNOS (-/-) mice suggests that the bradykinin-induced response requires the expression of eNOS to produce NO to regulate mitochondrial respiration. Although there is evidence suggesting that iNOS may be expressed in tissues or cells under normal conditions (ie, in the absence of bacterial endotoxins or inflammatory cytokine activation) in the kidney21 and even in the heart,22 iNOS is not likely to be the mediator of cardiac tissue respiration, because bradykinin suppressed O2 consumption in tissues lacking iNOS. Furthermore, bradykinin B2 receptor activation leads to the elevation of [Ca2+]i, to stimulate NO synthesis and release in neurons expressing the NOS enzyme. However, if nNOS were responsible for the modulation of mitochondrial respiration, bradykinin administration would have decreased O2 consumption in eNOS (-/-)–deficient mice. These findings strongly suggest that eNOS plays a major role in the physiological regulation of mitochondrial respiration, and the contribution of iNOS and/or nNOS toward myocardial tissue respiration is probably negligible under physiological conditions.
iNOS is well documented in the pathogenesis of sepsis and endotoxemia, conditions of elevated NO levels that contribute to LPS-induced hypotension and mortality. To test the possibility that large amounts of NO produced by iNOS regulate tissue O2 consumption and perhaps play an important pathological role, endotoxin was administered to C57BL/6x129 mice and to iNOS (-/-) mice, and cardiac tissue O2 consumption was measured. Endotoxin treatment significantly reduced basal myocardial tissue O2 consumption from normal but not iNOS (-/-)–deficient mice, suggesting that enhanced NO formation by iNOS suppresses tissue O2 consumption. Thus, iNOS may be only partly responsible for the sepsis-induced hypotension or myocardial dysfunction through the alteration in tissue respiration, because it has recently been demonstrated that mice deficient in the iNOS enzyme are still susceptible to LPS-induced mortality.23
We noted that the inhibition of myocardial respiration was preserved after deletion of a single copy of the eNOS gene. Our findings are congruent with those of Shesely et al16 who showed that heterozygous eNOS (+/-) mice have blood pressures similar to wild-type eNOS (+/+) mice; both groups are in contrast to eNOS (-/-)–deficient mice that develop significantly higher blood pressures, although there is evidence for "gene dosing."24
Several lines of evidence support the findings in the present study: (1) the presence of a remarkably dense capillary network (more than a 100-fold greater than that of conduit vessels), (2) a short diffusion distance between capillaries and adjacent myocytes25 26 (<8 µm in human heart and a NO diffusion distance of 200 to 600 µm under physiological conditions,27 (3) immunohistochemical evidence of eNOS in capillaries,28 and (4) the ability of capillary endothelium to make NO.29 All these studies indicate that NO may readily diffuse from microvessels and affect mitochondrial function in surrounding myocytes.
There are several limitations in the present study. First, although
our study provides strong evidence to support the role of capillary
endothelium-derived NO in the modulation of
mitochondrial respiration, we have yet to determine the cellular source
of NO. We cannot rule out the possibility that eNOS from other cell
types regulates mitochondrial respiration, given that agents well-known
to activate the release of endothelium-derived
NO such as bradykinin and carbachol also have direct
physiological and metabolic actions on
cardiac myocytes.30 31 32 33 More recently, the requirement of
eNOS and caveolin interactions increasing cGMP level in the modulation
of cholinergic control of cardiac function in myocytes has been
demonstrated using transgenic mice lacking eNOS.34 35 36 In
contrast to those findings, our previous data10 13 14
suggest that the effect of NO on mitochondria is cGMP independent.
Furthermore, Kanai et al37 have reported in rat cardiac
myocytes that NO is not released by bradykinin at a concentration of
10-5 mol/L (a concentration of bradykinin that
inhibits O2 consumption in the present
study), carbachol, or shear stress. Apart from cardiac myocytes, the
presence of eNOS has also been demonstrated in mitochondrial
preparations from heart, skeletal muscle, kidney, and, more recently,
from the liver.38 39 40 41 In addition, eNOS has even been
suggested to play a role in O2 consumption within
mitochondria.39 Whether all of these sites are
physiologically important sources of NO to
control mitochondrial function requires further investigation. Second,
the use of a Clark-type O2 electrode to measure
O2 consumption in an isolated nonbeating
myocardium and in the absence of blood and bloodborne
products, may not truly reflect the magnitude of the effect of NO
on myocardial O2 consumption under in vivo
conditions. Nevertheless, in vitro examination of tissue
O2 consumption eliminates neurohormonal and
mechanical factors that may influence cardiac O2
consumption to clearly demonstrate the direct effect of NO on
mitochondrial respiration. The current findings are supported by our
previous in vivo studies reporting that whole-body
O2 consumption or O2
consumption across the skeletal muscle, heart, or kidney was elevated
after the inhibition of NO synthesis. In addition, NO has a role in the
regulation of cardiac O2 consumption at
increasing cardiac work loads due to exercise.11 Third,
the use of normal C57BL6x129 mice instead of the age-matched wild-type
iNOS (+/+) mice as controls could have influenced the results in the
LPS study. However, the comparison of the effect of LPS on baseline
O2 consumption was made within the same strain.
More importantly, the effect of bradykinin-induced reduction in
O2 consumption was similar in magnitude in the
C57BL6x129 and iNOS (-/-) mouse hearts (eg, bradykinin decreased
O2 consumption by 
30% in both strains at
10-4 mol/L; Figure 1). This suggests that
the tissue responsiveness to NO agonist in the modulation of
O2 consumption is not different between the 2
strains.
Despite these limitations, our study is the first to provide direct evidence that eNOS serves as an important source of NO to regulate parenchymal cell O2 consumption through the activation of bradykinin receptors, which are found primarily on endothelial cells, in the heart and in other tissues as well. The control of O2 consumption by NO may be altered therapeutically using NO donors,42 angiotensin-converting enzyme inhibitors,43 and possibly modified hemoglobin.44 In pathophysiological states such as endotoxemia and heart failure,14 in which NO production by the vasculature is altered, these alterations may contribute to the disease process.
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Acknowledgments |
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This work was supported by PO-1 HL 43023 and HL 50142 from the National Heart, Lung, and Blood Institute. K.E.L. is the recipient of an American Heart Association postdoctoral fellowship (9820046T). P.I.M. was supported by a fellowship from the Sarnoff Foundation.
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Footnotes |
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This manuscript was sent to Eugene Braunwald, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received December 3, 1998; accepted February 5, 1999.
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