© 1998 American Heart Association, Inc.
Original Contributions |
Reduced Nitric Oxide Production and Altered Myocardial Metabolism During the Decompensation of Pacing-Induced Heart Failure in the Conscious Dog
From the Department of Physiology, New York Medical College, Valhalla.
Correspondence to Thomas Hintze, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Thomas_Hintze{at}nymc.edu
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Abstract—The aim of the present study was to determine whether cardiac nitric oxide (NO) production changes during the progression of pacing-induced heart failure and whether this occurs in association with alterations in myocardial metabolism. Dogs (n=8) were instrumented and the heart paced until left ventricular end-diastolic pressure reached 25 mm Hg and clinical signs of severe failure were evident. Every week, hemodynamic measurements were recorded and blood samples were withdrawn from the aorta and the coronary sinus for measurement of NO metabolites, O2 content, free fatty acids (FFAs), and lactate and glucose concentrations. Cardiac production of NO metabolites or consumption of O2 or utilization of substrates was calculated as coronary sinus-arterial difference times coronary flow. In end-stage failure, occurring at 29±1.6 days, left ventricular end-diastolic pressure was 25±1 mm Hg, left ventricular systolic pressure was 92±3 mm Hg, mean arterial pressure was 75±2.5 mm Hg, and dP/dtmax was 1219±73 mm Hg/s (all P<0.05). These changes in hemodynamics were associated with a fall of cardiac NO metabolite production from 0.37±0.16 to -0.28±0.13 nmol/beat (P<0.05). O2 consumption and lactate uptake did not change significantly from control, while FFA uptake decreased from 0.16±0.03 to 0.05±0.01 µEq/beat and glucose uptake increased from -2.3±7.0 to 41±10 µg/beat (P<0.05). The cardiac respiratory quotient also increased significantly by 28%. In 14 normal dogs the same measurements were performed at control and 1 hour after we injected 30 mg/kg of nitro-L-arginine, a competitive inhibitor of NO synthase. O2 consumption increased from 0.05±0.002 mL/beat at control to 0.071±0.003 mL/beat after nitro-L-arginine, while FFA uptake decreased from 0.1±0.01 to 0.06±0.01 µEq/beat, lactate uptake increased from 0.15±0.04 to 0.31±0.03 µmol/beat, glucose uptake increased from 8.2±5.0 to 35.4±9.5 µg/beat, and RQ increased by 23% (all P<0.05). Our results indicate that basal cardiac production of NO falls below normal levels during cardiac decompensation and that there are shifts in substrate utilization. This switch in myocardial substrate utilization also occurs after acute pharmacological blockade of NO production in normal dogs.
Key Words: MVO2 • lactate • free fatty acid • glucose • respiratory quotient
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Introduction |
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One of the proposed mechanisms of cardiac dysfunction in heart failure attributes a major role to an excessive production of nitric oxide (NO) in the heart and, specifically, in myocytes.1 2 Circulating proinflammatory cytokines, found in high concentrations in plasma of patients with heart failure,3 would stimulate the expression of inducible NO synthase (iNOS) with consequent overproduction of NO. NO has, among other functions, negative inotropic effects at high concentrations, as demonstrated in vitro.4 5 6 A similar mechanism of cardiac depression has been recognized previously in septic shock, although the levels of circulating cytokines and NO catabolites in this syndrome are much higher than those found during heart failure.3 7 8 9
However, to date, evidence of an increase in cardiac production of NO, sufficient to cause a negative inotropic action during heart failure, has not been provided. The finding that iNOS is expressed in tissue from failing hearts does not necessarily imply that cardiomyocytes are exposed to toxic concentrations of NO. Indeed, it is the amount of NO and not the enzyme isotype generating it that determines the degree to which cardiac function would be depressed. Numerous studies suggest that NO release is rather low in heart failure. In clinical and animal studies,2 10 pharmacological blockade of NO synthases (NOS) did not alter baseline hemodynamics, indicating that, rather than being characterized by overproduction, systemic NO synthesis could already be minimal. Several investigations, including our own, in patients and in animal models of heart failure report an impairment of endothelial release of NO in large arteries and in coronary microvessels.11 12 13 14 The reduced vascular NO production is likely the result of reduced gene expression of constitutive NOS.15 Under these circumstances, cardiomyocytes, each surrounded by 3 capillaries, would lose, during heart failure, the tonic exposure to NO from the neighboring endothelium, and, despite the expression of iNOS, the overall action of this molecule could be markedly attenuated. In the present study the first aim was to determine whether cardiac NO production changes during development and progression of pacing-induced heart failure. The time course of pacing-induced dilated cardiomyopathy, as produced in our laboratory, is highly reproducible and offers the possibility of an accurate monitoring over time of the changes of hemodynamics and humoral factors leading to heart failure. Since our previous studies suggest that NO may regulate myocardial metabolism,16 to determine the relationship between NO production and changes in cardiac O2 consumption (MVO2) and substrate utilization during the development of cardiac decompensation was the second goal of our study. To establish whether this relationship was determined by a pure association of events or by a cause-effect sequence, cardiac substrate uptake was also measured in a group of normal dogs after competitive inhibition of NO production with the use of nitro-L-arginine (NLA), a specific NOS inhibitor.
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Surgical Procedure and Instrumentation
Male dogs (n=22) weighing 25 to 27 kg were sedated with acepromazine maleate (1 mg/kg IM), anesthetized with sodium pentobarbital (25 mg/kg IV), and ventilated with room air. A thoracotomy was performed in the left fifth intercostal space. Catheters (Tygon) were placed in the descending thoracic aorta and left atrial appendage for pressure measurements. A third catheter was inserted in the coronary sinus (CS) with the tip leading away from the right atrium. During the surgery, a blood sample was taken from the CS catheter and immediately measured on a pH/blood gas analyzer. If the PO2 was >25 mm Hg, the catheter was repositioned and tied into place. A solid-state pressure gauge (P6.5, Konigsberg Instruments, Inc) was inserted in the left ventricle through the apex. A Doppler flow transducer (Parks Electronics) was placed around the left circumflex coronary artery, and a pair of 3-MHz piezoelectric crystals was placed on opposing endocardial surfaces at the base of the left ventricle (LV). A human, screw-type, unipolar myocardial pacing lead was placed on the LV. Wires and catheters were run subcutaneously to the intrascapular region, the chest was closed in layers, and the pneumothorax was reduced. Antibiotics were given after surgery, and the dogs were allowed to fully recover. After 10 days, dogs were trained to lie quietly on the laboratory table. The protocols were approved by the Institutional Animal Care and Use Committee of the New York Medical College and conform to the guiding principles for the care and use of laboratory animals published by the National Institutes of Health.
Hemodynamic Recordings
The aortic catheter was attached to a P23ID strain-gauge
transducer for measurement of aortic pressure. LV pressure was measured
with the solid-state pressure gauge. The first derivative of LV
pressure, LV dP/dt, was obtained with the use of an operational
amplifier (National Semiconductor LM 324), and triangular wave signals
with known slope were substituted for the pressure signals to calibrate
the differentiator directly. Cerebral blood flow (CBF) was measured
with a pulsed Doppler flowmeter (model 100, Triton Technology). LV
diameter was measured by connecting the implanted piezoelectric
crystals to a Transit Time ultrasonic dimension gauge, which generates
a voltage linearly proportional to the transit time of ultrasounds
traveling between the 2 crystals (1.55 ·
103 m/s). All signals were recorded on a
14-channel tape recorder (Bell and Howell 3700B) and played back on
an 8-channel direct-writing oscillograph (Gould RS 3800). Mean values
of aortic pressure and coronary flow were obtained by filtering
the respective signals at 2 Hz. Heart rate was measured with a
cardiotachometer (model 9857B, Beckman Instruments) from the LV
pressure pulse interval. For some data analysis, the tape was
played back and the analog signals were stored in computer memory
through an analog-digital interface (National Instruments), at a
sampling rate of 250 Hz.
Calculated Hemodynamic Parameters
LV cardiac work was calculated by integrating the mean
pressure-diameter area over 10 beats. This measure of LV work has been
used previously.17 Late diastolic
coronary resistance was obtained by dividing the late
diastolic aortic pressure by the instantaneous
coronary flow measured at the same time. The triple
product, an index of mechanically related cardiac
MVO2, was calculated as Heart
RatexdP/dtmaxxLV Systolic
Pressure.17
Cardiac NO Metabolites
NO metabolites (NOx) (ie, nitrate, nitrite, and NO)
concentration in millimoles per liter was measured in plasma obtained
from aortic and CS blood samples after centrifugation
at 1000g for 15 minutes. Plasma was stored at -20°C until
the day of analysis. The method for NOx analysis has
been described in detail.18 Briefly, plasma was
incubated with Aspergillus nitrate reductase and then acid
under argon gas, so that NOx were converted to NO. The gaseous NO was
injected into a NO chemiluminescence analyzer (Sievers, Inc).
In the analyzer, NO combines with ozone to produce photons, the
number of which is directly proportional to the amount of NO injected,
that is, to the NOx from the plasma sample. CS-arterial
difference of NOx concentration was multiplied by mean coronary
blood flow (MCBF, assumed as double of mean flow measured in the left
circumflex coronary artery19 ) to obtain
cardiac production per minute of NOx.
Cardiac Metabolites
Blood samples from aorta and CS were collected into plastic
syringes treated with either heparin or EDTA and immediately stored on
ice. Special care was taken to withdraw blood slowly from the CS
catheter to avoid potential contamination of the sample with right
atrial blood. Blood gases were measured in a blood gas analyzer
(model 170, Corning). PO2 was
multiplied by 0.003 and added to O2 content
measured by a hemoglobin analyzer (CO-Oximeter, Instruments
Laboratory) to obtain total oxygen content (vol/vol). Hematocrit levels
were obtained by centrifugation. Lactate was measured
from whole blood with a YSI 1500 sport lactate analyzer (Yellow
Springs Instrument Co). Glucose and free fatty acid (FFA)
concentrations were determined in plasma after
centrifugation of the blood samples at 1000g
for 15 minutes at 0°C. Glucose was measured with a Beckman glucose 2
analyzer (Beckman Instruments). FFA analysis was
performed on plasma from EDTA-treated samples with the use of a
calorimetric assay (NEFA C kit from WAKO Pure Chemical Industries, Ltd)
and a spectrophotometer (Kontron Instruments). The
CS-arterial concentration difference of
O2, lactate, glucose, and FFA contents was
multiplied by MCBF to calculate cardiac consumption. We have described
these methods previously.17
Cardiac Production of CO2 and Respiratory
Quotient
Total cardiac CO2
concentration in arterial and CS blood was calculated
according to well-established methods as described by
Davenport20 :
[CO2]b=[CO2]px(1-Htc)+[CO2]cxHtc+[carbamino-CO2],
where [CO2]b is the CO2
concentration (mmol/L) in whole blood, [CO2]p
is the plasma CO2 concentration,
[CO2]c is the concentration of
CO2 dissolved in red cells,
[carbamino-CO2] is the concentration of
CO2 bound to hemoglobin, and Htc is the
hematocrit expressed in decimals. [CO2], either
in plasma or in red cells, was calculated by adding bicarbonate
concentration to the concentration of physically dissolved
CO2. The latter is given by
axPCO2, where
a is 0.0301 and 0.025 for plasma and red cells,
respectively.20 Bicarbonate concentration,
[HCO3-], was
calculated by the equation of Henderson-Hasselbach:
pH=6.1+log([HCO3-]/aPCO2).
pH of red cell cytoplasm was calculated on the basis of the plasma pH,
according to the relation between the two, mathematically described by
Duhm.21 We calculated
[carbamino-CO2], in millimoles per liter, as
0.00588x[Hb]x(1-RHb)+0.0105x[Hb]xRHb, where [Hb] is the
hemoglobin concentration in grams per liter and RHb is the fraction of
reduced hemoglobin as measured by the hemoglobin analyzer.
Total [CO2] in arterial and CS
blood was converted in volume percent, multiplying the millimoles per
liter by 2.226.20 Consequently, cardiac
production of CO2
(MCO2) was obtained as follows:
(CS-A)[CO2]xMCBF, where CS-A indicates
CS-arterial difference. Finally, the respiratory quotient
(RQ) was given by
MCO2/MVO2, which can be
simplified as follows:
(CS-A)[CO2]/(A-CS)[O2].
Values of RQ range between 0.707, corresponding to oxidation of FFA as
the only substrate, and 1, corresponding to oxidation of carbohydrates
as the only substrate.22
For some comparisons, RQ was also calculated from the percentage of calories derived from carbohydrates (% carb) over the total calories produced by complete oxidation of substrates, according to the linear correlation determined by Zuntz, Schumburg, and Lusk22 and described by the equation RQ=0.002907x(% carb)+0.7048. The caloric equivalent is 2338 cal/mmol for FFA, 326 cal/mmol for lactate, and 686 cal/mmol for glucose.23 For FFA, the caloric equivalent of palmitate was used, since it represents the main fatty acid consumed by the heart. This second method of RQ determination is valid if uptaken substrates are almost completely oxidized, as occurs in normal hearts.
Induction of Heart Failure and Protocol
Heart failure was induced in 8 dogs. On the day of the
experiment, dogs were weighed and placed on the laboratory table.
Hemodynamic measurement and blood samples were taken in
presence of stable heart rate and blood pressure. After this
experimental protocol was performed as control, the heart was paced at
210 bpm for 3 weeks, and then the pacing rate was increased to 240 bpm
until overt heart failure was observed. We used external pacemakers
(model EV4543, Pace Medical), carried by the dog in a vest. The
protocol was repeated each week for the first 3 weeks and every other
day after the third week. All experiments were performed with the pacer
turned off and the heart in spontaneous rhythm. Dogs were killed when
LV end-diastolic pressure (LVEDP) reached 25 mm Hg
and clinical signs of severe decompensation were observed.
Competitive Inhibition of NOS
Hemodynamic measurements and
arterial and CS blood samples were taken from 14 normal
dogs placed on the laboratory table. The heart was paced at 132±1 bpm,
which corresponded to the spontaneous heart rate observed in end-stage
failure. Cardiac pacing was then stopped, and a dose of 30 mg/kg of
NLA, a specific NOS inhibitor, was given to the dogs
intravenously. As previously established, this dose reduces
the vasodilation to acetylcholine by >60% in conscious dogs and
abolished the basal release of NOx by the
heart.17 Hemodynamic changes were
monitored during the following 45 minutes. At this time cardiac pacing
was started again, and blood samples were taken after allowing 15
minutes of stabilization, ie, 1 hour after NLA injection.
Statistical Analysis
Data are presented as mean±SEM. Statistical
analysis was performed with the use of commercially available
software (Sigma Stat 2.0). Changes in hemodynamics and
metabolites over time were tested by one-way ANOVA followed by
Dunnett's test. NO production, MVO2, and
substrate consumption were normalized by heart rate and expressed as
per beat. The normalization was used for a better comparison of data at
different times, since spontaneous heart rate changed during the
evolution of heart failure. Data expressed as per minute, however, are
also provided. Correlations between groups of values were evaluated
calculating the best fit, based on least-squares regression
analysis. The regression lines were then
represented and the determination coefficients
(r2) indicated. For all the statistical
analyses, significance was accepted at P<0.05.
Because one aim of our study was to determine changes in NO and metabolites during cardiac decompensation, we focused some of our data analyses on days 21 through 29. In our previous studies this was determined to be the time of cardiac decompensation, as recognized by the development of conditions such as edema and cachexia.13 15 16 Thus, experiments were performed every 2 to 3 days after day 21. Because there is some heterogeneity between animals in the time to euthanasia (defined as LVEDP of 25 mm Hg, cachexia, and lethargy), the last day in each animal was considered the same. The intervening days were adjusted to group the means. Thus, an error appears in the time points (x axis). In addition, curve fits were conducted over these times with the use of least-squares analysis. When the best fits were found and to predict the order in which metabolism changed, the time to a 30% change in metabolites, NO, oxygen, and RQ was calculated from the equation describing the curves. A 30% change was chosen arbitrarily as a "conservative measure" of the threshold time for changes.
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Pacing-Induced Heart Failure
End-stage heart failure was characterized by a LVEDP of 25±1 mm Hg and by severe clinical signs such as dyspnea, ascites, pale mucosa, and lethargy. The mean time to euthanasia was 29±1.6 days.
Hemodynamics
Changes over time of mean arterial pressure, LV
systolic and diastolic pressure, and
dP/dtmax are shown in Figure 1
. There were significant changes in
hemodynamics after the first week of pacing. For
instance, mean values of dP/dtmax, percent
diameter shortening, and LV work decreased by 36%, 30%, and 51%,
respectively. LVEDP increased exponentially over the entire period of
pacing, with a faster increment after 21 days. After the first week,
mean arterial pressure, LV systolic
pressure, dP/dtmax, and LV work showed a slow
decrease, with a sharp drop after 27±1.4 days. Values of other
hemodynamics are summarized in Table 1. It is important to note that
mean CBF did not change significantly during the progression of heart
failure. Late diastolic coronary resistance fell at
3 weeks and was statistically different from the control after 24±1
days. Changes in the triple product resembled those of
dP/dtmax.
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Cardiac Production of NO
Figure 2 displays the net cardiac
NOx production per beat during the course of heart failure.
Positive at control, NOx production changed significantly after
24±1 days. The production became negative, ie, there was an
apparent uptake of NO metabolites during the late stage of heart
failure. Arterial and CS concentrations of NOx were,
respectively, 3.36±0.8 and 4.87±1.2 µmol/L at control and 4.96±0.8
and 4.43±0.9 µmol/L at 29±1.6 days. At 29±1.6 days, the
CS-arterial difference of NOx concentration was
-0.52±0.22 µmol/L versus 0.78±0.406 µmol/L at control
(P<0.05). Values per minute of NOx production were
34±12 nmol/min at control and –35±14 nmol/min in end-stage failure.
An inverse, linear relationship (coefficient
r2=0.90 and P<0.05) was found
between mean values of NO production and LVEDP after the second
week of pacing (Figure 2B), indicating that the progressive
ventricular dysfunction, indicated by an increase in
end-diastolic pressure up to 25 mm Hg, was associated
with a fall in cardiac NO production.
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Cardiac Metabolism
Arterial PO2 and
concentration of O2, FFA, lactate, and glucose,
at different times, are presented in Table 2. Consumption per beat of
O2, FFA, glucose, and lactate at different times
are shown in Figure 3.
PaO2 and O2
content fell significantly at 29±1.6 days, and consumption per beat of
O2 also tended to decrease, although there was no
statistically significant change. O2 consumption
per minute was 5.46±0.36 mL/min at control and 5.05±0.72 mL/min at
29±1.6 days (P=NS). A significant decrease of FFA uptake
was observed after the third week, while glucose uptake increased
significantly only at 27±1.6 days. FFA and glucose uptake per minute
were, respectively, 12.5±1.5 µEq/min and –0.16±0.6 mg/min at
control and 6.3±0.7 µEq/min and 5.3±1.4 mg/min at 29±1.6 days
(P<0.05). It is important to note that after the first
significant fall at 24±1 days, FFA uptake was stable, while glucose
uptake continued to rise. This is also reflected by the relationships
between mean values of NOx production per beat and mean values
of FFA uptake and glucose uptake after the second week of pacing
(Figure 4). The first relationship is
exponential, with a flat portion in end-stage failure, whereas the
second is linear, indicating that the continuous fall of cardiac NO
production and increase in glucose uptake were correlated.
Although lactate uptake showed a tendency to increase during the
progression of failure, the changes did not reach statistical
significance (Figure 3D).
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CO2 Production and RQ
To determine whether the shift in uptake of cardiac substrates
corresponded to their oxidation, the RQ of the heart, ie,
the ratio CO2
production/MVO2, was calculated at
control and at times after the second week of pacing. In Table 3, CS-arterial difference of
O2 and CO2 are listed
together with the RQ. There was a significant and progressive increase
until end-stage failure, when RQ value was 1, which indicated that the
only oxidized substrates were carbohydrates. Therefore, between day
24±1 and day 29±2, although FFA uptake was almost unchanged, the
oxidation of these substrates was progressively reduced and finally
disappeared.
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Compared Rates of Change in Cardiac NOx Production, FFA and
Glucose Uptake, and RQ
Since all the significant changes over time in cardiac NOx
production, FFA and glucose uptake, and RQ occurred during
cardiac decompensation, ie, after the third week of pacing, the best
curve fit was calculated for each series of data points, from day 21 to
day 29±1.6 of pacing (Figure 5). A curve
fit was also calculated for MVO2. From the
mathematical function describing these curves, it was possible to
calculate the time corresponding to a fixed change in each
variable. We have arbitrarily chosen a change equal to 30% of the
difference between values at 21 and at 29±1.6 days. The time
corresponding to that variation was defined as
t30 and was used as an index of the threshold for
change in production, consumption, and RQ. The regression lines
are shown in Figure 5. The coefficients for the curve fits and
t30 are listed in Table 4. A 30% change occurred first
for the decrease in FFA uptake at 21.5 days, followed by a
simultaneous decrease in NOx production and
MVO2 at 22.6 days, and, 1 day later, by an almost
simultaneous increase in glucose uptake and RQ.
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Competitive Inhibition of NOS in Normal Animals
Hemodynamics
During cardiac pacing at 132±1 bpm, CBF, mean
arterial pressure, LV systolic pressure, and
dP/dtmax were, respectively, 33±1.5 mL/min,
113±3 mm Hg, 132±3 mm Hg, and 2715±89 mm Hg/s at
control and 41.5±2.9 mL/min, 152±3.5 mm Hg, 169±4 mm Hg,
and 2336±152 mm Hg/s after NLA (all P<0.05 versus
control).
Cardiac Metabolism and RQ
Changes in MVO2 and FFA, glucose, and
lactate uptake at control and 1 hour after NLA are shown in Figure 6. To facilitate a comparison with the
corresponding data in heart failure, values are displayed as per beat.
MVO2 and FFA, lactate, and glucose uptake per
minute were, respectively, 7.0±0.6 mL/min, 13.5±1.1 µEq/min,
16.3±2.7 µmol/min, and 1.1±0.7 mg/min at control and 9.3±0.9
mL/min, 7.5±1.3 µEq/min, 41.4±4.5 µmol/min, and 4.9±1.3
mg/min after NLA. All these changes were statistically significant
(P<0.05). The arterial concentrations of FFA,
lactate, and glucose were, respectively, 0.55±0.06 mEq/L,
1.01±0.09 mmol/L, and 89.6±2 mg/dL at control and 0.28±0.05
(P<0.05), 1.1±0.08 (P=NS), and 83.5±1.4 mg/L
(P=NS) after NLA.
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RQ was 0.754±0.05 at control and 0.93±0.06 after NLA (P<0.05). The RQ calculated by using the theoretical percentage of calories derived from carbohydrate oxidation was 0.76±0.02 at control and 0.84±0.03 after NLA (P<0.05). This result indicated that, if all the substrates were completely oxidized after NLA, 47% of the developed calories would derive from carbohydrates, but, on the basis of the RQ calculated from real CO2 production and MVO2, the effective percentage was 77%.
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Discussion |
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The major findings of the present study are as follows: (1) the onset of cardiac decompensation, during pacing-induced heart failure, occurs only after the third week of pacing (26±1.4 days); (2) the transition to decompensated heart failure is associated with a significant fall of cardiac NO production; (3) there are profound changes in myocardial metabolism at this time; and (4) after acute inhibition of NO production in healthy, conscious dogs there is an alteration in cardiac substrate utilization similar to that in heart failure. To our knowledge, this represents the first study in which the time course for transition to decompensated heart failure has been determined and a marked decrease of total cardiac NO production during the process leading to cardiac decompensation has been demonstrated. Furthermore, this is the first study to indicate that acute inhibition of NOS alters substrate utilization by the heart.
A significant fall in LV dP/dtmax, percent diameter shortening, and work occurred at 1 week of pacing and was not associated with cardiac decompensation. At this time there was no change in blood gases and no change in cardiac NO production, MVO2, or substrate utilization. It was only later, at 22 to 23 days, that dramatic changes in hemodynamics, clinical state, gas exchange, and cardiac metabolism were observed. We defined this time as the onset of cardiac decompensation. Although some clinical studies propose an increased NO production by iNOS in myocardiocytes as a possible maladaptive mechanism and cause of cardiac dysfunction in heart failure,1 2 7 no direct measure of NO release was provided. Very recently, the only clinical study in which cardiac NOx production was measured reported no changes in patients with heart failure versus normal subjects.24 Any possible increase in NO, regardless of the isotype or localization of the enzyme that generates it, must be reflected by augmented NO metabolites in the coronary venous blood, since the primary method for clearing NOx is filtration by the kidney.18 A previous study from our laboratory has demonstrated a direct correlation between arterial NOx and creatinine concentration during pacing-induced heart failure, indicating that the rise in plasma NOx was due to a decreased renal function.25 NO concentration in cardiac tissue must reach very high values to impair cardiomyocyte function.6 26 Such high levels are clearly present, for example, in endotoxemic shock in humans9 and in dogs.27 We did not detect a significant increase in NO metabolites during the progression to cardiac failure. On the contrary, the onset of cardiac decompensation was characterized by the first statistically significant reduction of cardiac NOx production. Previous studies provided strong evidence that changes in NOx production reflect changes in NO synthesis. In particular, we have shown that cardiac NOx production can increase in response to enhanced coronary flow during dynamic exercise and can be abolished by blocking NOS with NLA.17 Moreover, a recent study in which the isotope 18 O was used demonstrated that NOS inhibition by 30 mg/kg of NLA reduces by 91% the formation of NOx in vivo.28 It is possible that the changes in cardiac NOx production observed in the present study were simply due to an altered distribution of coronary flow, with enhanced perfusion of regions producing less NO. This possibility can be ruled out on the basis of a prior study on the distribution of coronary flow in pacing-induced heart failure.29 Those authors used radioactive microspheres and found a homogeneous decrease in LV and right ventricular flow compared with control, with reduced subendocardial flow reserve but unaltered baseline endocardial-epicardial ratio. In the present study cardiac NOx production was positive at control, as previously reported by us17 18 ; however, it became negative during heart failure, resulting in an apparent cardiac uptake of NOx. The uptake was obviously apparent, since the heart is not the organ responsible for NOx clearance. Nitrites and nitrates, end products of NO oxidation, would rapidly accumulate in the cardiac tissues, reaching toxic concentrations. A possible explanation of the apparent uptake is the redistribution of NOx between plasma and erythrocytes. It is known, for example, that NO3- can exchange with Cl- contained in red cells in <10 seconds, even at 0°C.30 Preliminary data from an ongoing study in our laboratory indicate that part of NOx accumulates in red cells and that the intraerythrocyte fraction is proportional to bicarbonate concentration. The latter is inversely proportional to the PO2. Therefore, the percentage of total blood NOx measured in plasma is lower in CS than in arterial blood, so that the absence of cardiac production would necessarily result in an apparent net uptake.
Our findings support the studies demonstrating depressed
production of NO in heart failure.31 32
In particular, defective NO-mediated control of coronary
circulation has been well documented in animal models and in
humans.12 13 NOS blockade did not cause baseline
hemodynamic changes in patients with heart failure and
in dogs with pacing-induced heart failure, indicating that the basal
release of NO was already depressed.2 3 4 5 6 7 8 9 10 In dogs
with pacing-induced heart failure, endothelial NOS gene
expression and synthesis were reduced.15 Cardiac
microvessels (
70 µm in diameter) have the potential to produce
large amounts of NO, as demonstrated in vitro, and the release of NO
from coronary microvessels of failing hearts was also
depressed.14
It is possible that the decreased cardiac NOx production observed in the present study mainly reflects the endothelial dysfunction in microvessels. In a previous study we have hypothesized that NO released by coronary microvessels/capillaries is a paracrine factor that might play an important role in modulating metabolism of the adjacent cardiomyocytes.16 The mean distance between capillary endothelial cells and cardiomyocytes is <8 µm,33 whereas the maximal diffusion distance of NO is 200 to 600 µm.34 Other studies showed that NO can modulate calcium sensitivity of myofilaments, most likely through an increase in cGMP.35 36 In particular, some authors have shown that reduced endogenous NO or augmented exogenous NO do decrease or increase, respectively, LV diastolic compliance in vitro and in vivo.37 38 This phenomenon was independent of end-diastolic volume.
Taken together, all these observations would be complemented by the findings of the present study in explaining at least 2 aspects of the pathophysiology of heart failure: diastolic dysfunction and altered metabolism. Our data would also support the known therapeutic efficacy of organic nitrates and angiotensin-converting enzyme inhibitors in the treatment of this syndrome.39 40 41 The highly significant correlation shown in this study, between progressive rise in LVEDP and decrease in cardiac NOx production, likely reveals the loss of control by NO of ventricular relaxation and venous return. In fact, the therapeutic properties of NO donors in heart failure are primarily based on the reduction of ventricular preload.
The alterations of myocardial metabolism in heart failure
are complex and little understood. Our experiments in vitro have shown
that basal myocardial MVO2 was 54% higher in
failing tissue than in normal tissue.16 In the
present study MVO2 did not change
significantly over time, but in end-stage failure, LV work and triple
product, indexes of cardiac MVO2, were
decreased by 83% and 55% versus control, respectively. Moreover, the
failing heart would consume 
12% more oxygen if it used FFA as the
primary substrate instead of glucose. Studies performed in isolated,
working canine hearts and in human hearts documented an increase of
cardiac MVO2, not related to total mechanical
energy, in failing versus normal hearts at a given level of cardiac
contractility.42 43 Such an
increase was interpreted as an elevated basal metabolism
and/or augmented oxygen cost of contractility of the
failing heart. The first interpretation receives additional support
from our data, since an inhibitory function of NO on
mitochondrial respiration has been documented in
vitro16 44 45 and, indirectly, in
vivo.17 46 A failing heart, with reduced NO
production, would lose this tonic modulation and basal
metabolism would be consequently elevated. No data, on the
other hand, document a possible involvement of NO in the control of
oxygen cost of contractility. This cost is due to
excitation-contraction coupling, ie, to the ATP consumed for
Ca2+ cycling and reuptake by the sarcolemmal
membrane. However, several investigations in vitro demonstrated a
modulatory action of NO, through the second messenger cGMP, on calcium
channels of the sarcoplasmic reticulum.47 48 Its
role and importance are not clear yet, but if NO modulates
intracellular Ca2+ influx in vivo, then a lack of
NO would imply more energy expenditure at each excitation-contraction
cycle, in particular at higher levels of contractility,
when enhanced active calcium reuptake is required. In a previous study
performed in our laboratory,17 blockade of NO
synthesis during exercise caused an increase in myocardial
MVO2 at equal levels of cardiac work.
The present data show a profound change in cardiac substrate utilization during decompensated heart failure. During the fourth week of pacing, we observed a 70% reduction of FFA uptake associated with a steep rise in glucose utilization. The time to a 30% change in substrate uptake (t30), after 21 days of pacing, indicates that the fall in FFA consumption preceded either the decrease in NOx or the increase in glucose consumption. It is important to note, however, that the t30 for FFA uptake is heavily influenced by the type of curve fit (exponential), and thus we cannot exclude that the real 30% decrease, after 3 weeks, occurred at a later time. Glucose was very likely oxidized, as indicated by the increase in respiratory quotient versus control. Moreover, lactate was always taken up rather than produced by the heart, indicating that this model of heart failure is not characterized by anaerobic glycolysis. A healthy heart utilizes mostly FFA and, to a lesser extent, lactate during fasting.49 The RQ values that we found at control, 0.73 to 0.76, indicate in fact that oxidation of FFA generated 80% to 90% of the total energy.22 Previous studies have already shown that during the development of heart failure, cardiac muscle relies on glycolysis as the primary source of energy.50 51 52 The present study provides the first direct evidence of changes in cardiac substrate utilization during pacing-induced heart failure. The shift to glucose by the failing heart is considered a recapitulation of fetal metabolism. It is probably an adaptive although insufficient response. Myocardial glucose oxidation in heart failure might in part compensate for the elevated basal MVO2: ATP yield from carbohydrate oxidation is greater for a given rate of MVO2 because of the higher ATP/O2 ratio compared with that of fatty acid oxidation.49 To obtain the same amount of ATP by oxidizing, for instance, palmitate, one of the most abundant FFA in the blood, a failing heart would consume 12% more oxygen. An increased efficiency, ie, ratio of total mechanical energy to MVO2, has in fact been shown in hearts isolated from dogs with pacing-induced heart failure.42 Another advantage of glucose utilization, as proposed by some authors,53 is that glycolytically derived ATP is preferentially used for Ca2+ reuptake into the sarcoplasmic reticulum, and this is essential for optimal diastolic relaxation. We cannot exclude, however, that the observed switch of energy source also plays a role in the progression of heart failure.
The significant and linear correlation between fall in cardiac NOx production and increase in glucose uptake represents an important new finding. It raises the question of whether such correlation is a pure association of events or if there is any cause-effect relationship. The preference for glucose, in our group of dogs, might be in part explained by the simultaneous reduction of the competitive FFA uptake, a reduction that could be related to the significant fall in arterial plasma FFA levels. In humans, for instance, cardiac FFA utilization diminishes when the concentration of these substrates in arterial plasma falls below the threshold of 0.3 mmol/L, which really corresponds to 0.3 mEq/L.49 54 In our study, the minimum level reached during cardiac decompensation was not <0.3 mEq/L, yet the threshold in dogs has not been established. Moreover, a low plasma level of FFA can explain the reduction in uptake but not the RQ value of 1 that was found in end-stage failure. This RQ indicated that the residual uptake of FFA did not correspond to their oxidation, since the heart oxidized only carbohydrates. In fact, another cause of reduction in FFA oxidation, in a rat model of heart failure, has been recently attributed to the downregulation of mitochondrial fatty acid ß-oxidation enzymes,55 and an accumulation of long-chain acylcarnitine in tissue from failing heart has been documented.56
To directly address whether changes in NO production can result in switch of substrate utilization by the heart, NLA was administered to normal, conscious dogs. There was an acute and dramatic change in cardiac substrate utilization similar to that observed during cardiac decompensation. These results strongly suggest that the correlation between changes in cardiac NOx release and metabolism, during pacing-induced heart failure, is due to a cause-effect relationship. The switch in substrate utilization 1 hour after NLA administration resembles very closely that observed during decompensated failure. NLA caused a fall of FFA concentration in plasma that could explain the decrease in FFA uptake. However, the increase in RQ was higher than it would have been if substrates were completely oxidized. NOS blockade caused an inhibition of FFA oxidation. We cannot exclude that the fall in plasma concentration of FFA, occurring either in end-stage failure and after NOS inhibition, is also related to decreased production of NO. To date, no mechanisms have been described that could explain the role of NO in FFA uptake and oxidation. On the other hand, it has been demonstrated in vitro that NO can stimulate ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase,57 the enzyme responsible for the first oxidation-reduction reaction of glycolysis. NO-related ADP-ribosylation likely inhibits enzymatic activity, although its role in vivo has not been defined. In heart failure or after NOS blockade, the lack of NO would remove such inhibition to the glycolytic pathway. These observations are curious since several investigations demonstrated that NO potentiates insulin-mediated uptake of glucose in skeletal muscle58 and, indeed, patients with heart failure present moderate insulin resistance.59
In conclusion, we have shown that the onset of cardiac decompensation in pacing-induced heart failure is associated with a dramatic fall in cardiac NO production. This fall is also accompanied by a switch in myocardial substrate utilization. A quantitatively similar shift in substrate utilization occurs acutely after inhibition of NO production with the use of NLA in normal dogs. These findings suggest that one of the pathophysiological mechanisms involved in cardiac decompensation might be the lack of NO, an important modulator of cardiac function, coronary vascular function, and myocardial metabolism.
|
Acknowledgments |
|---|
This study was supported by grants PO-1HL 43023, RO-1HL 50142, and HL 53053 from the National Heart, Lung, and Blood Institute. Patrick I. McConnell was a Sarnoff Foundation Fellow, 1996–1997.
|
Footnotes |
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This manuscript was sent to François M. Abboud, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received October 28, 1997; accepted June 30, 1998.
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References |
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V. Lionetti, A. Linke, M. P. Chandler, M. E. Young, M. S. Penn, S. Gupte, C. d'Agostino, T. H. Hintze, W. C. Stanley, and F. A. Recchia Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure Cardiovasc Res, June 1, 2005; 66(3): 454 - 461. [Abstract] [Full Text] [PDF]
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P. H. McNulty, N. King, S. Scott, G. Hartman, J. McCann, M. Kozak, C. E. Chambers, L. M. Demers, and L. I. Sinoway Effects of supplemental oxygen administration on coronary blood flow in patients undergoing cardiac catheterization Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1057 - H1062. [Abstract] [Full Text] [PDF]
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Y. Chen, M. Hou, Y. Li, J. H. Traverse, P. Zhang, D. Salvemini, T. Fukai, and R. J. Bache Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H133 - H141. [Abstract] [Full Text] [PDF]
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M. P. Chandler, J. Kerner, H. Huang, E. Vazquez, A. Reszko, W. Z. Martini, C. L. Hoppel, M. Imai, S. Rastogi, H. N. Sabbah, et al. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1538 - H1543. [Abstract] [Full Text] [PDF]
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W. J. Paulus and J. G. F. Bronzwaer Nitric oxide's role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H8 - H13. [Abstract] [Full Text] [PDF]
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L. A. Nikolaidis, D. Trumble, T. Hentosz, A. Doverspike, R. Huerbin, M. A. Mathier, Y.-T. Shen, and R. P. Shannon Catecholamines restore myocardial contractility in dilated cardiomyopathy at the expense of increased coronary blood flow and myocardial oxygen consumption (MvO2 cost of catecholamines in heart failure) Eur J Heart Fail, June 1, 2004; 6(4): 409 - 419. [Abstract] [Full Text] [PDF]
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S. D. Prabhu Nitric Oxide Protects Against Pathological Ventricular Remodeling: Reconsideration of the Role of NO in the Failing Heart Circ. Res., May 14, 2004; 94(9): 1155 - 1157. [Full Text] [PDF]
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M. van Bilsen, P. J.H Smeets, A. J Gilde, and G. J van der Vusse Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res, February 1, 2004; 61(2): 218 - 226. [Abstract] [Full Text] [PDF]
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D. A. Wink, K. M. Miranda, T. Katori, D. Mancardi, D. D. Thomas, L. Ridnour, M. G. Espey, M. Feelisch, C. A. Colton, J. M. Fukuto, et al. Orthogonal properties of the redox siblings nitroxyl and nitric oxide in the cardiovascular system: a novel redox paradigm Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2264 - H2276. [Abstract] [Full Text] [PDF]
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J.-N. Trochu, S. Mital, X.-p. Zhang, X. Xu, M. Ochoa, J. K Liao, F. A Recchia, and T. H Hintze Preservation of NO production by statins in the treatment of heart failure Cardiovasc Res, November 1, 2003; 60(2): 250 - 258. [Abstract] [Full Text] [PDF]
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J.-P. Tessier, B. Thurner, E. Jungling, A. Luckhoff, and Y. Fischer Impairment of glucose metabolism in hearts from rats treated with endotoxin Cardiovasc Res, October 15, 2003; 60(1): 119 - 130. [Abstract] [Full Text] [PDF]
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H. Post, C. d'Agostino, V. Lionetti, M. Castellari, E. Y Kang, M. Altarejos, X. Xu, T. H Hintze, and F. A Recchia Reduced Left Ventricular Compliance and Mechanical Efficiency after Prolonged Inhibition of NO Synthesis in Conscious Dogs J. Physiol., October 1, 2003; 552(1): 233 - 239. [Abstract] [Full Text] [PDF]
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A. Linke, G. Zhao, F. A. Recchia, J. Williams, X. Xu, and T. H. Hintze Shift in metabolic substrate uptake by the heart during development of alloxan-induced diabetes Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1007 - H1014. [Abstract] [Full Text] [PDF]
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A. Adler, E. Messina, B. Sherman, Z. Wang, H. Huang, A. Linke, and T. H. Hintze NAD(P)H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1015 - H1022. [Abstract] [Full Text] [PDF]
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S. A. Khan, M. W. Skaf, R. W. Harrison, K. Lee, K. M. Minhas, A. Kumar, M. Fradley, A. A. Shoukas, D. E. Berkowitz, and J. M. Hare Nitric Oxide Regulation of Myocardial Contractility and Calcium Cycling: Independent Impact of Neuronal and Endothelial Nitric Oxide Synthases Circ. Res., June 27, 2003; 92(12): 1322 - 1329. [Abstract] [Full Text] [PDF]
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S. P. Jones, J. J. M. Greer, R. van Haperen, D. J. Duncker, R. de Crom, and D. J. Lefer Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice PNAS, April 15, 2003; 100(8): 4891 - 4896. [Abstract] [Full Text] [PDF]
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M. P. Czubryt, J. McAnally, G. I. Fishman, and E. N. Olson Regulation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha ) and mitochondrial function by MEF2 and HDAC5 PNAS, February 18, 2003; 100(4): 1711 - 1716. [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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R. J. Scheubel, M. Tostlebe, A. Simm, S. Rohrbach, R. Prondzinsky, F. N. Gellerich, R.-E. Silber, and J. Holtz Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2174 - 2181. [Abstract] [Full Text] [PDF]
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D. M. Kaye, M. M. Parnell, and B. A. Ahlers Reduced Myocardial and Systemic L-Arginine Uptake in Heart Failure Circ. Res., December 13, 2002; 91(12): 1198 - 1203. [Abstract] [Full Text] [PDF]
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J. C. Osorio, W. C. Stanley, A. Linke, M. Castellari, Q. N. Diep, A. R. Panchal, T. H. Hintze, G. D. Lopaschuk, and F. A. Recchia Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-{alpha} in Pacing-Induced Heart Failure Circulation, July 30, 2002; 106(5): 606 - 612. [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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J. H. Traverse, Y. Chen, M. Hou, and R. J. Bache Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2278 - H2283. [Abstract] [Full Text] [PDF]
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D. B. Haitsma, D. Merkus, J. Vermeulen, P. D. Verdouw, and D. J. Duncker Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2198 - H2209. [Abstract] [Full Text] [PDF]
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D. B. Sawyer and J. Loscalzo Myocardial Hibernation: Restorative or Preterminal Sleep? Circulation, April 2, 2002; 105(13): 1517 - 1519. [Full Text] [PDF]
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W. F. Saavedra, N. Paolocci, M. E. St. John, M. W. Skaf, G. C. Stewart, J.-S. Xie, R. W. Harrison, J. Zeichner, D. Mudrick, E. Marban, et al. Imbalance Between Xanthine Oxidase and Nitric Oxide Synthase Signaling Pathways Underlies Mechanoenergetic Uncoupling in the Failing Heart Circ. Res., February 22, 2002; 90(3): 297 - 304. [Abstract] [Full Text] [PDF]
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L. A Nikolaidis, T. Hentosz, A. Doverspike, R. Huerbin, C. Stolarski, Y.-T. Shen, and R. P Shannon Catecholamine stimulation is associated with impaired myocardial O2 utilization in heart failure Cardiovasc Res, February 1, 2002; 53(2): 392 - 404. [Abstract] [Full Text] [PDF]
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E. D. Lewandowski, R. K. Kudej, L. T. White, J. M. O'Donnell, and S. F. Vatner Mitochondrial Preference for Short Chain Fatty Acid Oxidation During Coronary Artery Constriction Circulation, January 22, 2002; 105(3): 367 - 372. [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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L. Dai, P. S. Brookes, V. M. Darley-Usmar, and P. G. Anderson Bioenergetics in cardiac hypertrophy: mitochondrial respiration as a pathological target of NO{middle dot} Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2261 - H2269. [Abstract] [Full Text] [PDF]
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L. A. Nikolaidis, T. Hentosz, A. Doverspike, R. Huerbin, C. Stolarski, Y.-T. Shen, and R. P. Shannon Mechanisms whereby rapid RV pacing causes LV dysfunction: perfusion-contraction matching and NO Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2270 - H2281. [Abstract] [Full Text] [PDF]
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T. Ishibashi, K. Kubota, M. Himeno, T. Matsubara, T. Hori, K. Ozaki, M. Yamozoe, Y. Aizawa, J. Yoshida, and M. Nishio Respiratory alkalosis does not alter NOx concentrations in human plasma and erythrocytes Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2757 - H2761. [Abstract] [Full Text] [PDF]
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G. Wiemer, G. Itter, T. Malinski, and W. Linz Decreased Nitric Oxide Availability in Normotensive and Hypertensive Rats With Failing Hearts After Myocardial Infarction Hypertension, December 1, 2001; 38(6): 1367 - 1371. [Abstract] [Full Text] [PDF]
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J. H Traverse, Y. Chen, M. Crampton, S. Voss, and R. J Bache Increased extravascular forces limit endothelium-dependent and -independent coronary vasodilation in congestive heart failure Cardiovasc Res, December 1, 2001; 52(3): 454 - 461. [Abstract] [Full Text] [PDF]
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W. J. Paulus, S. Frantz, and R. A. Kelly Nitric Oxide and Cardiac Contractility in Human Heart Failure: Time for Reappraisal Circulation, November 6, 2001; 104(19): 2260 - 2262. [Full Text] [PDF]
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J. M. Cotton, M. T. Kearney, P. A. MacCarthy, R. M. Grocott-Mason, D. R. McClean, C. Heymes, P. J. Richardson, and A. M. Shah Effects of Nitric Oxide Synthase Inhibition on Basal Function and the Force-Frequency Relationship in the Normal and Failing Human Heart In Vivo Circulation, November 6, 2001; 104(19): 2318 - 2323. [Abstract] [Full Text] [PDF]
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D. J. Grieve, P. A. MacCarthy, N. P. Gall, A. C. Cave, and A. M. Shah Divergent Biological Actions of Coronary Endothelial Nitric Oxide During Progression of Cardiac Hypertrophy Hypertension, August 1, 2001; 38(2): 267 - 273. [Abstract] [Full Text] [PDF]
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Y. Kakinuma, T. Miyauchi, K. Yuki, N. Murakoshi, K. Goto, and I. Yamaguchi Novel Molecular Mechanism of Increased Myocardial Endothelin-1 Expression in the Failing Heart Involving the Transcriptional Factor Hypoxia-Inducible Factor-1{{alpha}} Induced for Impaired Myocardial Energy Metabolism Circulation, May 15, 2001; 103(19): 2387 - 2394. [Abstract] [Full Text] [PDF]
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S. Adler, H. Huang, K. E. Loke, X. Xu, H. Tada, A. Laumas, and T. H. Hintze Endothelial nitric oxide synthase plays an essential role in regulation of renal oxygen consumption by NO Am J Physiol Renal Physiol, May 1, 2001; 280(5): F838 - F843. [Abstract] [Full Text] [PDF]
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K. E Loke, E. J Messina, E. G Shesely, G. Kaley, and T. H Hintze Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine Cardiovasc Res, January 1, 2001; 49(1): 86 - 93. [Abstract] [Full Text] [PDF]
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G. S. Nelson, R. D. Berger, B. J. Fetics, M. Talbot, J. C. Spinelli, J. M. Hare, and D. A. Kass Left Ventricular or Biventricular Pacing Improves Cardiac Function at Diminished Energy Cost in Patients With Dilated Cardiomyopathy and Left Bundle-Branch Block Circulation, December 19, 2000; 102(25): 3053 - 3059. [Abstract] [Full Text] [PDF]
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J.-N. Trochu, J.-B. Bouhour, G. Kaley, and T. H. Hintze Role of Endothelium-Derived Nitric Oxide in the Regulation of Cardiac Oxygen Metabolism : Implications in Health and Disease Circ. Res., December 8, 2000; 87(12): 1108 - 1117. [Abstract] [Full Text] [PDF]
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S. Mital, X. Zhang, G. Zhao, R. D. Bernstein, C. J. Smith, D. L. Fulton, W. C. Sessa, J. K. Liao, and T. H. Hintze Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2649 - H2657. [Abstract] [Full Text] [PDF]
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S. Mital, K. E. Loke, L. J. Addonizio, M. C. Oz, and T. H. Hintze Left ventricular assist device implantation augments nitric oxide dependent control of mitochondrial respiration in failing human hearts J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1897 - 1902. [Abstract] [Full Text] [PDF]
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Y.-T. Shen, P. S Buie, J. J Lynch, S. M Krause, and X.-L. Ma Chronic therapy with an ETA/B receptor antagonist in conscious dogs during progression of congestive heart failure: Intracellular Ca2+ regulation and nitric oxide mediated coronary relaxation Cardiovasc Res, November 1, 2000; 48(2): 332 - 345. [Abstract] [Full Text] [PDF]
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F. A. Recchia, T. R. Vogel, and T. H. Hintze NO metabolites accumulate in erythrocytes in proportion to carbon dioxide and bicarbonate concentration Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H852 - H856. [Abstract] [Full Text] [PDF]
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J. M. Canty Jr. Nitric Oxide and Short-Term Hibernation : Friend or Foe? Circ. Res., July 21, 2000; 87(2): 85 - 87. [Full Text] [PDF]
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S. Kanno, P. C. Lee, Y. Zhang, C. Ho, B. P. Griffith, L. L. Shears II, and T. R. Billiar Attenuation of Myocardial Ischemia/Reperfusion Injury by Superinduction of Inducible Nitric Oxide Synthase Circulation, June 13, 2000; 101(23): 2742 - 2748. [Abstract] [Full Text] [PDF]
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J. M. Hare, R. A. Lofthouse, G. J. Juang, L. Colman, K. M. Ricker, B. Kim, H. Senzaki, S. Cao, R. S. Tunin, and D. A. Kass Contribution of Caveolin Protein Abundance to Augmented Nitric Oxide Signaling in Conscious Dogs With Pacing-Induced Heart Failure Circ. Res., May 26, 2000; 86(10): 1085 - 1092. [Abstract] [Full Text] [PDF]
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S. D. Prabhu, B. Chandrasekar, D. R. Murray, and G. L. Freeman {beta}-Adrenergic Blockade in Developing Heart Failure : Effects on Myocardial Inflammatory Cytokines, Nitric Oxide, and Remodeling Circulation, May 2, 2000; 101(17): 2103 - 2109. [Abstract] [Full Text] [PDF]
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H. Tada, C. I. Thompson, F. A. Recchia, K. E. Loke, M. Ochoa, C. J. Smith, E. G. Shesely, G. Kaley, and T. H. Hintze Myocardial Glucose Uptake Is Regulated by Nitric Oxide via Endothelial Nitric Oxide Synthase in Langendorff Mouse Heart Circ. Res., February 18, 2000; 86(3): 270 - 274. [Abstract] [Full Text] [PDF]
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D. Sun, A. Huang, G. Zhao, R. Bernstein, P. Forfia, X. Xu, A. Koller, G. Kaley, and T. H. Hintze Reduced NO-dependent arteriolar dilation during the development of cardiomyopathy Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H461 - H468. [Abstract] [Full Text] [PDF]
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C. Depre and H. Taegtmeyer Metabolic aspects of programmed cell survival and cell death in the heart Cardiovasc Res, February 1, 2000; 45(3): 538 - 548. [Abstract] [Full Text] [PDF]
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P. A. MacCarthy, R. Grocott-Mason, B. D. Prendergast, and A. M. Shah Contrasting Inotropic Effects of Endogenous Endothelin in the Normal and Failing Human Heart : Studies With an Intracoronary ETA Receptor Antagonist Circulation, January 18, 2000; 101(2): 142 - 147. [Abstract] [Full Text] [PDF]
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F. A. Recchia, P. I. McConnell, K. E. Loke, X. Xu, M. Ochoa, and T. H. Hintze Nitric oxide controls cardiac substrate utilization in the conscious dog Cardiovasc Res, November 1, 1999; 44(2): 325 - 332. [Abstract] [Full Text] [PDF]
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K. E. Loke, S. K. Laycock, S. Mital, M. S. Wolin, R. Bernstein, M. Oz, L. Addonizio, G. Kaley, and T. H. Hintze Nitric Oxide Modulates Mitochondrial Respiration in Failing Human Heart Circulation, September 21, 1999; 100(12): 1291 - 1297. [Abstract] [Full Text] [PDF]
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W. J Paulus and A. M Shah NO and cardiac diastolic function Cardiovasc Res, August 15, 1999; 43(3): 595 - 606. [Full Text] [PDF]
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H. Drexler Nitric Oxide Synthases in the Failing Human Heart : A Doubled-Edged Sword? Circulation, June 15, 1999; 99(23): 2972 - 2975. [Full Text] [PDF]
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C. Heymes, M. Vanderheyden, J. G. F. Bronzwaer, A. M. Shah, and W. J. Paulus Endomyocardial Nitric Oxide Synthase and Left Ventricular Preload Reserve in Dilated Cardiomyopathy Circulation, June 15, 1999; 99(23): 3009 - 3016. [Abstract] [Full Text] [PDF]
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J. S. Ingwall and R. A. Kelly Nitric Oxide, Myocardial Oxygen Consumption, and ATP Synthesis Circ. Res., November 16, 1998; 83(10): 1067 - 1068. [Full Text] [PDF]
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D. B. Haitsma, D. Merkus, J. Vermeulen, P. D. Verdouw, and D. J. Duncker Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2198 - H2209. [Abstract] [Full Text] [PDF]
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W. F. Saavedra, N. Paolocci, M. E. St. John, M. W. Skaf, G. C. Stewart, J.-S. Xie, R. W. Harrison, J. Zeichner, D. Mudrick, E. Marban, et al. Imbalance Between Xanthine Oxidase and Nitric Oxide Synthase Signaling Pathways Underlies Mechanoenergetic Uncoupling in the Failing Heart Circ. Res., February 22, 2002; 90(3): 297 - 304. [Abstract] [Full Text] [PDF]
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