(Circulation. 1995;92:3505-3512.)
© 1995 American Heart Association, Inc.
Articles |
Nitric Oxide
An Important Signaling Mechanism Between Vascular Endothelium and Parenchymal Cells in the Regulation of Oxygen Consumption
From the Department of Physiology, New York Medical College, Valhalla, NY.
Correspondence to Michael S. Wolin, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Nitric oxide (NO) is known to be an inhibitor of mitochondrial function. However, the physiological significance of endothelium-derived NO in the control of tissue respiration is not established.
Methods and Results Tissue O2 consumption by skeletal muscle slices of the triceps brachii of normal dogs was measured with a Clark-type O2 electrode/tissue bath system at 37°C. S-Nitroso-N-acetylpenicillamine (SNAP), carbachol (CCh), or bradykinin (BK) decreased tissue O2 consumption by 12±3% to 55±8%, 15±6% to 36±11%, or 21±5% to 42±4% at doses of 10-7 to 10-4 mol/L, respectively. The effects of both CCh and BK but not SNAP were eliminated by nitro-L-arginine (NLA, 10-4 mol/L), consistent with SNAP decomposing to release NO and both CCh and BK stimulating endogenous NO production from L-arginine. Oxygen consumption was also decreased by 8-bromo-cGMP. The mitochondrial uncoupler dinitrophenol blocked the effects of 8-bromo-cGMP but only slightly altered those of SNAP, indicating that the major site of action of NO is the mitochondria. In normal, chronically instrumented, resting conscious dogs, blockade of NO synthase by NLA increased mean arterial pressure by 28±2.5 mm Hg and hind limb vascular resistance by 114±12% and decreased blood flow by 39±3%. Most important, NLA also increased O2 uptake by 55±9% in hind limb skeletal muscle (P<.05), associated with decreases in PO2 and O2 saturation and an increase in reduced hemoglobin in hind limb venous blood.
Conclusions Our results indicate that NO release from vascular endothelial cells appears to play an important physiological role in the regulation of tissue mitochondrial respiration in skeletal muscle and perhaps other organ systems.
Key Words: endothelium-derived factors • oxygen • metabolism • muscle, skeletal
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Our recent data1 and studies by others2 have suggested that the production of NO in vivo not only results in vasodilation but also may regulate tissue oxygen consumption. The original data by Furchgott and Zawadzki3 and many subsequent reports reviewed by Ignarro et al,4 Moncada,5 Vane et al,6 and Vanhoutte7 have suggested that the production of NO in muscular blood vessels resulted in a cGMP-dependent relaxation in vitro or vasodilation in vivo. Palmer et al8 suggested that NO is tonically produced in vivo, as the administration of inhibitors of NOS resulted in a prompt and dramatic increase in blood pressure and vascular resistance. We observed similar effects in conscious dogs.9
Before the discovery of NO production by endothelium, there was evidence, primarily from Granger and Lehninger10 and from Drapier and Hibbs11 that activated macrophages produced an undefined substance that suppressed oxygen consumption in bacteria and in many different types of mammalian cells in culture. More recent data suggest that this macrophage-related substance is NO.12 13 NO can reduce the activity of a number of enzymes in the mitochondrial electron transport chain by forming a nitrosyl complex with the iron-sulfur centers of aconitase and complexes I and II of the electron transport chain14 and via an interaction with a heme associated with the oxygen-binding site of cytochrome oxidase.15 16 17 18 Thus, it is now thought that the levels of NO produced in inflammatory situations result in the inhibition of tissue mitochondrial respiration. However, a role for endothelium-derived NO in the control of tissue respiration in vivo remains to be established.
Our recent studies have shown that inhibition of NO formation in vivo using NLA results in both vasoconstriction and an increase in oxygen consumption.1 The vasoconstriction was not responsible for the increase in oxygen consumption because when methoxamine was administered to cause a similar increase in vascular resistance, it did so without increasing oxygen consumption. An alteration in neural outflow was not responsible either, because the increase in oxygen consumption still occurred after blockade of all autonomic outflow. We have tentatively determined that a potential site for this action of NO is the mitochondrion because administration of a barbiturate, known to block complex I of the electron transport chain,19 had no effect on the vasoconstriction caused by NLA but entirely abolished the increase in oxygen consumption. The current investigation was carried out to determine whether endothelium-derived NO controls tissue respiration in isolated skeletal muscle, to identify mechanisms potentially involved in this process, and to examine whether NO-mediated control of oxygen consumption across the hind limb skeletal muscle circulation in conscious dogs is a process of potential physiological relevance.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Materials
Atropine methyl bromide, BK, 8-bromo-cGMP, CCh, DNP, and tetrodotoxin were obtained from Sigma Chem Co. PGI2 (Cayman Chem Co Inc) was dissolved in Trizma base solution (100 mmol/L) at a concentration of 10-1 mol/L, kept on ice, and diluted immediately before use. Materials were obtained from the following sources: NLA (Aldrich Chem Co), HOE 140 (Hoechst-Roussel), sodium cyanide (JT Baker Chem Co), and SNAP (synthesized as described in Reference 4). DNP was dissolved in DMSO. All other materials were dissolved in water, and all of the vehicles were tested and found to have no effect at the final concentrations used. For studies in awake dogs, NLA was dissolved in normal saline at a concentration of 6 mg/mL and administered at a dose of 30 mg/kg.
Animal and Surgical Methods
All of the experiments in dogs
were approved by the IACUC of New
York Medical College and conform to the "Guiding Principles for the
Use and Care of Laboratory Animals" of the American
Physiological Society and the National Institutes
of Health. Each dog was sedated with acepromazine (0.3 mg/kg IM,
Fermenta Animal Health Co) and anesthetized with pentobarbital
sodium (25 mg/kg IV, Anpro Pharmaceutical Co). An endotracheal tube was
inserted into the trachea, and the dog was artificially ventilated with
a respirator (Harvard Apparatus). Using sterile surgical
techniques, the terminal aorta was exposed via a midline laparotomy. An
electromagnetic flow transducer (25C, Carolina Medical Electronic Inc)
was placed on the terminal abdominal aorta just above the iliac
bifurcation for measurement of distal aortic (hind limb) blood flow,
and two catheters (Tygon, Cardiovasc Inst) were implanted into the
terminal abdominal aorta via small arterial branches for
measurement of arterial pressure and withdrawal of
arterial blood. The abdominal incision was closed. All of
the catheters and transducer wires were run subcutaneously and
externalized near the interscapular region. The experiments were
performed on the completely recovered dogs approximately 10 days after
surgery, after the dogs were trained to lie quietly on the laboratory
table and were fully awake.
Measurement of Hemodynamics
Distal aortic blood flow was
measured from the previously placed
electromagnetic flow transducer using a square-wave electromagnetic
flowmeter (FM-501, Carolina Medical Electronic Inc), and an average
flow was derived with an 8-Hz low-pass filter. Arterial
pressure was measured by connecting the previously implanted aortic
catheter to a strain-gauge transducer (Statham P23ID), and mean
arterial pressure was derived using a 2-Hz low-pass
filter. Hind limb vascular resistance (VRLeg) was
calculated by the formula: VRLeg (mm Hg/L per minute)=mean
arterial pressure (mm Hg)/distal aortic blood flow (L/min).
Heart rate was monitored from the pressure pulse interval with a
cardiotachometer (Beckman Instruments). All signals were recorded
on an eight-channel direct-writing oscillograph (model 2800S,
Gould Instruments).
Analysis of Blood Gases and Hemoglobin and Calculation of
Oxygen Consumption
Arterial and leg venous blood samples were
withdrawn
simultaneously from the previously implanted aortic
catheter and an inserted percutaneous leg venous
catheter, respectively, on each experiment day to obtain samples, which
were analyzed immediately. Arterial and venous
blood PO2 was measured with a blood gas
analyzer (Corning 170) at 37°C. Arterial and
venous blood percent O2 saturation, %O2Hb, and
%RHb were measured with an Instrumentation Laboratories CO-Oximeter
System (model IL48O2). These instruments were calibrated daily. Blood
O2 content was calculated as 1.39x
%O2Hbxtotal hemoglobin+0.003xblood
PO2. Hind limb O2 extraction (mL%)
was calculated as arterial O2 content (mL%)
minus leg venous O2 content (mL%). Hind limb
O2 consumption (mL/min) was calculated as hindlimb
O2 extraction (mL%)xdistal aortic blood flow
(mL/min).
Effect of NLA on Hind Limb Skeletal Muscle O2
Consumption in Conscious Dogs
After the dog was lying quietly on the
laboratory table for at
least 30 minutes, hemodynamics, including distal aortic
blood flow, arterial pressure, and heart rate, were
recorded, and two control arterial and leg venous blood
samples were collected simultaneously for analysis
of blood gases, hemoglobin, and hematocrit. Then, NLA (30 mg/kg) was
administered to dogs by intravenous injection.
Arterial and venous blood samples were collected at 5, 15,
30, 60, and 90 minutes after administration of NLA, and distal aortic
blood flow, arterial blood pressure, and heart rate were
continuously recorded in all the experiments. Analyses of
blood gases, hemoglobin, and hematocrit were made from these blood
samples. We previously described the use of all of these
techniques.1 9 20
Preparation of Skeletal Muscle Tissue Slices
Muscle tissue
was isolated from the accessory head of the
triceps brachii obtained immediately from the
pentobarbital-anesthetized dogs when they were killed. The
muscle was cleansed of periadventitial fat and connective tissue and
cut into small pieces approximately 2x2x-0.5 to 1 mm
(longx
widexthick). Muscle pieces were first incubated in Krebs'
bicarbonate
buffer at 37°C for 90 to 120 minutes before conducting tissue
respiration studies. Krebs' bicarbonate buffer contained (in mmol/L):
NaCl 118, KCl 4.7, CaCl2 1.5, NaHCO3 25,
MgSO4 1.1, KH2PO4 1.2, and glucose
5.6 and was gassed with 21% O2/5%
CO2/74% N2.
Measurement of O2 Consumption by Tissue Slices
Tissue O2 uptake was measured with a Yellow Springs
Instrument Co apparatus consisting of a model 5300
biological oxygen monitor and a Clark-type electrode (model 5331)
including a 1 to 10 mL thermostated (37°C) and stirred bath model
5301, and the electrode response was recorded on a chart
recorder. Oxygen consumption is typically monitored in the oxygen
concentration range of 240 to 150 µmol/L. The initial slope of the
electrode response (O2 consumption/time) was determined and
used to calculate the nanomoles of O2 consumed per
minute per gram of tissue. The tissue O2 uptake was linear
(±1%) for 30 minutes (n=12). Tissues (50 to 80 mg) were studied
in 3
mL of air-saturated Krebs' buffer with 10 mmol/L HEPES, pH 7.4;
typically, the observation time for each dose of agent was 5 to 6
minutes, and new segments of muscle were used for each drug examined.
Cyanide (10-3 mol/L) was added at the end
of the study of each tissue segment to confirm that changes in
O2 consumption were from mitochondrial sources.
Experimental Protocols for Tissue Respiration Studies
SNAP,
CCh, BK, 8-bromo-cGMP, or PGI2 was added
to the tissue bath in an increasing cumulative
concentration-dependent manner, and their effects on oxygen
consumption were recorded. The response to the two highest doses of
CCh or BK was also examined in the presence of the receptor
antagonist atropine (10-5
mol/L) and HOE-140 (10-5 mol/L),
respectively. The responses to SNAP, CCh, and BK were studied in the
presence of 10-4 mol/L NLA, and the
response to BK was also studied in the presence of
10-7 mol/L tetrodotoxin. In studies with
DNP, it was added to the tissue bath in the presence or absence of
individual doses of SNAP, BK, 8-bromo-cGMP, and NLA, and the change
in oxygen consumption was recorded. The response to DNP plus BK was
also examined after pretreatment with NLA.
Statistical Analysis
Data from studies in isolated skeletal
muscle in vitro were
analyzed using a one-way ANOVA to determine changes from
control. Differences before and after DNP were determined with a paired
Student's t test. All cardiac hemodynamic
values were averaged over an entire respiratory cycle. One-way and
two-way ANOVAs for repeated measures were applied to evaluate all
in vivo studies. A post hoc Scheffé's test was used to determine
differences between groups in the ANOVA. All data in the text are
expressed as mean±SE, and n in all instances is the number of
different animals studied. A value of P<.05 was considered
statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Effect of Exogenous and Endogenous Sources of NO on O2 Consumption by Isolated Skeletal Muscle
An exogenous source of NO,4 SNAP (10-7 to 10-4 mol/L), decreased tissue O2 consumption by 12±3% to 55±8%, and this effect was statistically significant at concentrations of 10-6, 10-5, and 10-4 mol/L (Fig 1a
). The
decrease in O2 consumption was completely reversible, as
respiration was not inhibited (1.2±8.6% inhibition, n=3) when
examined 5 minutes after washout of 10-4
mol/L SNAP from the tissue. CCh, a stimulus of endogenous
NO
production,3 4 5 6 7
also significantly decreased
tissue O2 consumption by 15±6% to 36±11% over the
concentrations of 10-7 to
10-4 mol/L. The reduction of tissue
O2 consumption induced by CCh at the two highest doses was
completely abolished by pretreatment with
10-5 mol/L atropine, an
antagonist of muscarinic cholinergic receptors (Fig 1b).
Bradykinin, an additional probe used for stimulation of
endogenous NO
production,3 4 5 6 7
produced
a statistically significant decrease in tissue O2
consumption by 21±5% to 42±4% at doses of
10-7 to
10-4 mol/L. Pretreatment with
10-7 mol/L tetrodotoxin, a probe used to
determine a role for neuron-derived NO, did not alter the
inhibitory effect of 10-7 to
10-4 mol/L BK (26±8% to 39±8%
inhibition, n=4). This effect of BK at the two highest doses examined
was completely abolished by pretreatment with
10-5 mol/L HOE 140, an
antagonist of B2-bradykinin receptors (Fig 1c).
Pretreatment with NLA (10-4 mol/L), a
specific inhibitor of endogenous NO
biosynthesis, had no effect on the suppression of tissue O2
consumption by SNAP (Fig 1a) but completely abolished the
inhibition of
tissue O2 consumption by CCh and BK (Fig 1b and
1c). As a
control, the endothelium-derived vasodilator
PGI2 was examined for its effect on O2
consumption, and it was found to not cause significant change over the
10-10 to
10-6 mol/L concentration range (Fig 1d).
|
Effect of DNP on O2 Consumption by Isolated Muscle in
the Presence of Exogenous or Endogenous Production
of NO
Tissue oxygen consumption was increased 90±11%
(P<.05) by 1 mmol/L DNP, an uncoupler of oxidative
phosphorylation. After pretreatment with BK
(10-5 mol/L), the effect of DNP was
reduced, and DNP increased tissue O2 consumption by only
40±11% (Fig 2a). Pretreatment with NLA did not change
the increased O2 consumption induced by DNP but attenuated
the inhibition by BK on the increased O2 consumption
induced by DNP (Fig 2a). When examined in the presence of SNAP
(10-7 to
10-4 mol/L), the effect of DNP was
significantly reduced only at concentrations of
10-5 and
10-4 mol/L (Fig 2b).
|
Effect of 8-Bromo-cGMP on O2 Consumption by
Isolated Muscle
Oxygen consumption was inhibited 10±4% to
25±6% by
10-7 to
10-4 mol/L concentrations of
8-bromo-cGMP (Fig 3a), which was significantly less
than the inhibitory effect of CCh or BK. However,
8-bromo-cGMP did not significantly alter the increased level of
O2 consumption elicited by
10-7 to
10-3 mol/L DNP (Fig 3b).
|
Effect of NLA on Hind Limb Skeletal Muscle O2
Consumption in Conscious Dogs
Intravenous infusion of NLA (30 mg/kg)
to inhibit the
endogenous biosynthesis of NO resulted in significant
increases in mean arterial pressure by 28±2.5 mm Hg and in
hind limb vascular resistance by 114±12% and a significant reduction
of blood flow by 39±3% (Table). Most important, NLA
also caused a significant elevation of tissue O2
consumption (by 55±9% at 90 minutes) in resting hind limb skeletal
muscle, associated with significant decreases in hind limb venous
PO2 (by 27±6%) and O2 saturation
(by 25±4%), and an increase in hind limb venous %RHb (by 96±26%)
(Fig 4). NLA had no effect on arterial
PO2, O2 saturation, or %RHb
(Fig 4).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The most important finding in our study was that endogenously formed NO potentially derived from the vascular endothelium can function to suppress tissue mitochondrial respiration. In the in vitro component of the present study, skeletal muscle mitochondrial O2 consumption was significantly inhibited by CCh and BK, stimulators for endogenous NO production from the vascular endothelium,3 4 5 6 7 8 9 21 and by exogenous NO released by the spontaneous decomposition of SNAP.4 When NO synthesis was blocked in vivo, there was a significant increase in hind limb O2 extraction and O2 consumption, suggesting that NO has an important physiological role in the control of skeletal muscle O2 consumption in conscious dogs. These observations are consistent with our previous study on the role of NO in O2 consumption in vivo1 and with studies that initially identified the effect of NO derived from inflammatory processes on mitochondrial respiration.10 11
Acetylcholine and BK stimulate muscarinic cholinergic and B2-bradykinin receptors, respectively, on vascular endothelial cells, and this results in the production of NO, causing endothelium-dependent relaxation of vascular smooth muscle.3 In the present study, significant reductions in tissue O2 consumption after both CCh and BK were dependent on the endogenous production of NO, as the inhibitory effect was completely abolished by blockade of NO biosynthesis with NLA, a potent inhibitor of the biosynthesis of NO from L-arginine.22 23 Although NOS has been found recently in skeletal muscle,24 25 neither muscarinic cholinergic receptors nor BK receptors have been identified in skeletal muscle, nor have they been linked to NO synthesis in this tissue. Although our in vitro study did not detect evidence that an alternative source of NO contributes to the control of respiration, conditions that promote endogenous NO biosynthesis by skeletal muscle NOS could potentially contribute to the control of respiration under other conditions. We also determined whether another endothelium-derived relaxing factor that is thought to function via cAMP, PGI2, had no effect on tissue O2 consumption at any of the doses tested. Our study suggests that NO released from capillary endothelium in skeletal muscle on activation of muscarinic cholinergic or B2-bradykinin receptors is most likely responsible for the suppression of tissue oxygen consumption in the underlying skeletal muscle.
DNP, an uncoupler of mitochondrial respiration from oxidative phosphorylation, was used to distinguish between suppression of respiration by a direct inhibitory action of NO on mitochondrial electron transport versus a secondary effect caused by a NO or cGMP process that influences oxidative phosphorylation-mediated control of mitochondrial respiration through a change in the energy (ATP) consumption. The latter process is a distinct concern because NO and cGMP mechanisms have recently been shown to inhibit force generation in skeletal muscle.25 The increased O2 consumption induced by DNP was markedly inhibited by pretreatment with BK (in a NLA-reversible manner) and by SNAP, which is consistent with a direct effect of NO on mitochondrial electron transport. However, pretreatment with 8-bromo-cGMP did not inhibit respiration in the presence of DNP, suggesting that the reduction of tissue O2 consumption by cGMP-mediated signaling is not a direct effect on mitochondrial electron transport. Although the limited solubility of 8-bromo-cGMP in tissues may explain a reduced ability to suppress O2 consumption compared with NO-releasing agents, it cannot account for the inability of 8-bromo-cGMP to inhibit respiration in the presence of DNP. Thus, the effect of 8-bromo-cGMP on O2 consumption indicates the presence of a second mechanism through which cGMP (and NO) can control tissue oxygen consumption, perhaps through a process that influences the control of mitochondrial respiration through a change in the function of contractile proteins that reduces energy consumption. The concentration dependence of the inhibitory effect of SNAP on the increase in respiration caused by DNP appeared to be somewhat different from the effect of SNAP on basal respiration. In the presence of DNP, there seems to be a modest suppression of the threshold or low-dose effects of SNAP, and the shape of the curve is somewhat more sigmoidal. Based on the potent inhibitory effects of DNP on the actions of 8-bromo-cGMP, it is likely that the effects of NO derived from SNAP involve both a cGMP mechanism and a direct effect on the mitochondria, whereas only the direct mitochondrial effect is expressed in the presence of DNP. It is also likely that a similar role of cGMP also contributes to the shape of the dose-response data for the receptor-mediated agonists BK and ACh. Under the conditions of our study, the inhibition of respiration by NO was incomplete. Although this is potentially an interesting phenomenon, it is, at present, difficult to either rationalize or study because large doses of NO in an aerobic environment result in the formation of other nitrogen oxide species with actions independent of NO.26 Although these results of our study support a role for NO in the direct inhibition of mitochondrial respiration, they do not provide data to distinguish between the previously identified potential sites of action of NO,10 11 15 16 17 18 which include aconitase in the tricarboxylic acid cycle, NADH:ubiquinone oxidoreductase, succinate:ubiquinone oxidoreductase, or cytochrome oxidase in the mitochondrial electron transport chain.
The concept that NO can regulate oxygen consumption by tissues is not new.10 11 12 A number of investigators showed in the 1980s that a substance released from activated macrophages reduces oxygen consumption in bacteria and in mammalian cells.10 11 12 Other studies10 11 12 13 14 27 subsequently showed that this activity was stimulated by L-arginine and inhibited by substituted arginine molecules and could be attributed to nitrosylation of the iron-sulfur center of proteins. Although these data are consistent with NO serving as the active compound, peroxynitrite can also inhibit respiration in isolated mitochondria via its effect on aconitase.28 29 However, the inhibition of cytochrome oxidase by NO is so potent that it occurs at nanomolar concentrations,18 making it the most likely site of action of NO yet identified. The inhibition of respiration by NO also appears to occur at low oxygen tensions.17 18 Recent studies have suggested that the suppression of O2 consumption by NO may be a more universal mechanism because NO production activated by inflammatory processes or mediators can modulate mitochondrial function in rat hepatocytes,30 31 vascular smooth muscle,32 and articular chondrocytes33 in vitro. Studies by King et al2 have described a potential role for NO in the regulation of tissue oxygen consumption in skeletal muscle of anesthetized dogs. On the other hand, studies in the diaphragm muscle in situ suggested that the major action of inhibition of NO synthesis on oxygen consumption was through the alteration of vascular tone.34 Roles for NO in modulating tissue oxygen consumption have also been demonstrated in vivo in the cerebral35 and renal36 circulations. It should be noted that the mitochondrial respiratory inhibitory effects19 of the barbiturate anesthesia that was used in these studies could be a contributing factor to the conflicting results on the effects of inhibition of NO biosynthesis on tissue oxygen consumption. Thus, NO is known to both inhibit mitochondrial respiration and influence tissue oxygen consumption through mechanisms that remain to be established.
In the present study, the physiological relevance of the suppression of respiration by endothelial cell–derived NO in skeletal muscle was examined by determining the effect of NLA on hind limb O2 consumption in the absence of anesthesia in conscious dogs. There was considerable vasoconstriction in the hind limb after NLA, consistent with our other studies1 20 and indicative of the tonic production of NO in vivo. Our previous study1 showed that an increase in total tissue O2 consumption in the conscious dog after NLA appeared to be of mitochondrial origin and that it was not a consequence of the peripheral vasoconstriction or changes in sympathetic tone. Although observations from the in vitro part of the present study indicate that endothelium-derived NO can regulate respiration in skeletal muscle, additional evidence is needed to link endothelial cell function to the physiological regulation of respiration by NO observed in the conscious dog. As we have already pointed out,37 the diffusion distance from capillary endothelium to parenchymal tissue mitochondria is generally less than the diffusion distance needed for endothelium-derived NO–mediated relaxation of smooth muscle in large blood vessels. The constitutive endothelial NOS has been identified in capillary endothelium, both in isolated cells38 39 and in the microcirculation of rat skeletal muscle by immunohistochemistry (G. Kaley, unpublished observations, 1994). Furthermore, because of the large surface area of endothelial cells in capillaries, the largest of any vascular segment in the body, the capillary endothelium is likely to serve as a tremendous source of NO. Thus, endothelium-derived NO is likely to contribute to the effects of NLA on blood flow and respiration in the dog hind limb circulation.
Preliminary studies of freshly prepared myocardium, similar to the skeletal muscle experiments described in the present work, indicate that SNAP and BK reduced oxygen consumption,40 and this effect is observed in the presence of DNP (I.-W. Xie, T.H. Hintze, M.S. Wolin, unpublished observations, 1995). NO is also known to suppress the contraction of both skeletal muscle25 and cardiac myocytes (especially after induction of NO formation by cytokine stimulation41 42 ). Although these effects of NO on contractility have been interpreted as involving signal transduction processes that antagonize force generation, they may also be partially due to a direct suppression of mitochondrial energy metabolism by NO. Recent preliminary studies43 44 45 in the coronary circulation have observed changes in O2 consumption in the presence of inhibitors of NO biosynthesis; however, the changes observed are complex and appear to involve multiple mechanisms. Thus, endothelium-derived NO may also contribute to the physiological control of cardiac muscle respiration and, perhaps, myocardial contractility.
In summary, because the suppression of oxygen consumption by NO occurs in normal, healthy, conscious dogs and in tissues removed from these animals in which there is no purposeful activation of inflammatory NOS activity, we believe that the modulation of tissue oxygen consumption by NO is an additional physiologically important action of this molecule. The most likely source of NO in this schema is the capillary endothelial cell. A consequence of the direct inhibitory effect of NO on mitochondrial respiration in skeletal muscle is likely to be a compensatory effect on anaerobic metabolism, which remains to be defined. We have also recently shown that the regulation of tissue oxygen consumption by NO may occur during increases in metabolic demand.46 For example, at any level of external work during treadmill exercise in dogs, inhibition of NO synthesis results in a significant increase in oxygen consumption. Thus, both at rest and during increased metabolic activity, NO modulates tissue oxygen consumption. If the expressions of NOS and NO production are altered in a physiological or disease state, then the regulation of tissue metabolism may also be altered. For example, if NO production disappears in capillary endothelium, as we have shown in microvessels from the failing heart of the dog and human,47 then the restraint on mitochondrial metabolism will be lost, leading to an increase in oxygen consumption. If NOS is increased, as we have recently shown in vessels from dogs with chronic exercise,48 then NO may have an increased role in the coupling between oxygen consumption and metabolism. If there is a pathological overproduction of NO, as occurs after cytokine induction, there may be a marked reduction in energy production, resulting in decreased force generation in muscle, as occurs in cardiac muscle in sepsis, and this may contribute to cell death and organ failure.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported by grants PO1-HL-43023, HL-31069, HL-50142, and HL-53053 from the National Heart, Lung, and Blood Institute. Dr Wolin was an Established Investigator of the American Heart Association while this study was conducted.
Received January 19, 1995; revision received June 7, 1995; accepted July 24, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Shen W, Xu X, Ochoa M, Zhao G, Wolin MS, Hintze TH. Role of nitric oxide in the regulation of oxygen consumption in conscious dogs. Circ Res. 1994;75:1086-1095.
2.
King CE, Melinyshyn MJ, Mewburn JD, Curtis SE, Winn
MJ, Cain SM, Chapler CK. Canine hindlimb blood flow and
O2 uptake after inhibition of EDRF/NO synthesis.
J Appl Physiol. 1994;76:1166-1171.
3. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature (Lond). 1980;288:373-376. [Medline] [Order article via Infotrieve]
4.
Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman
AL, Kadowitz PJ, Gruetter CA. Mechanism of vascular smooth
muscle relaxation by organic nitrates, nitrites, nitroprusside and
nitric oxide: evidence for the involvement of S-nitrosothiols as active
intermediates. J Pharmacol Exp Ther. 1981;218:739-749.
5. Moncada S. The L-arginine nitric oxide pathway. Acta Physiol Scand. 1992;145:201-222. [Medline] [Order article via Infotrieve]
6. Vane J, Angarrd E, Botting R. Regulatory function of the vascular endothelium. N Engl J Med. 1990;323:27-36. [Medline] [Order article via Infotrieve]
7.
Vanhoutte PM. Endothelium and
the control of vascular function.
Hypertension. 1989;13:658-667.
8. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature (Lond). 1987;337:524-526.
9.
Shen W, Ochoa M, Xu X, Wang J, Hintze TH. Role
of EDRF/NO in parasympathetic coronary vasodilation following
carotid chemoreflex activation in conscious dogs. Am J
Physiol. 1994;267:H605-H613.
10.
Granger DL, Lehninger AL. Sites of inhibition of
mitochondrial electron transport in macrophage-injured
neoplastic cells. J Cell Biol. 1982;95:527-535.
11. Drapier JC, Hibbs JB Jr. Murine cytotoxic macrophage inhibit aconitase in tumor cells. J Clin Invest. 1986;78:790-797.
12. Marletta MA, Toon PS, Hibbs JB. Macrophage oxidation of L-arginine to nitrate and nitrite: nitric oxide is an intermediate. Biochemistry. 1988;27:8706-8711. [Medline] [Order article via Infotrieve]
13. Hibbs JB, Taintor RR, Vivrin, Rachlin EM. Nitric oxide: a cytotoxic activated macrophage effector molecule. Nature (Lond). 1991;351:714-718. [Medline] [Order article via Infotrieve]
14.
Lancaster JR, Hibbs JB. EPR demonstration of
iron-nitrosyl complex formation by cytotoxic activated
macrophage. Proc Natl Acad Sci U S A. 1990;87:1223-1227.
15. Erecinska M, Wilson DF. Inhibitors of cytochrome c oxidase. Pharmacol Ther. 1980;8:1-20.
16. Cleeter MWJ, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AH. Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. FEBS Lett. 1994;345:50-54. [Medline] [Order article via Infotrieve]
17. Schweizer M, Richter C. Nitric oxide potently and reversibly deenergizes mitochondria at low oxygen tension. Biochem Biophys Res Commun. 1994;204:169-175. [Medline] [Order article via Infotrieve]
18. Brown GC, Cooper CE. Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett. 1994;356:295-298. [Medline] [Order article via Infotrieve]
19.
Hafeti A. Flavoproteins of the electron
transport system and the site of action of amytal, rotenone and
piercidin A. Proc Natl Acad Sci U S A. 1968;60:733-740.
20.
Shen W, Lundborg M, Wang J, Stewart JM, Xu X, Ochoa M,
Hintze TH. Role of EDRF in the regulation of regional blood flow
and vascular resistance at rest and during exercise in conscious
dogs. J Appl Physiol. 1994;77:165-172.
21. Seyedi N, Gerritsen M, Burke-Wolin T, Wolin MS, Hintze TH. Nitrite release from microvessels of the left ventricle and large coronary arteries in the normal dog heart. FASEB J. 1992;6:1822. Abstract.
22. Moore PK, Al-Swayeh OA, Chong NWS, Evans RA, Gibson A. L-NG-Nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilatation in vitro. Br J Pharmacol. 1990;99:408-412. [Medline] [Order article via Infotrieve]
23. Mulsch A, Busse R. NG-Nitro-L-arginine (N5-[imino(nitroamino)methyl]-L-ornithine) impairs endothelium-dependent dilations by inhibiting cytosolic nitric oxide synthesis from L-arginine. Naunyn Schmiedebergs Arch Pharmacol. 1990;341:143-147. [Medline] [Order article via Infotrieve]
24. Nakane M, Schmidt HH, Pollock JS, Forstermann U, Murad F. Cloned human brain nitric oxide synthase is highly expressed in skeletal muscle. FEBS Lett. 1993;316:175-180. [Medline] [Order article via Infotrieve]
25. Kobzik L, Reid MB, Bredt DS, Stamler JS. Nitric oxide in skeletal muscle. Nature (Lond). 1994;372:546-548. [Medline] [Order article via Infotrieve]
26. Gross SS, Wolin MS. Nitric oxide: pathophysiological mechanisms. Annu Rev Physiol. 1995;57:737-769. [Medline] [Order article via Infotrieve]
27. Drapier JC, Hibbs JB. Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondria iron-sulfur enzymes in the macrophage effector cell. J Immunol. 1988;140:2829-2838. [Abstract]
28.
Castro L, Rodriguez M, Radi R. Aconitase is
readily inactivated by peroxynitrite, but not by its
precursor, nitric oxide. J Biol Chem. 1994;269:29409-29415.
29.
Hausladen A, Fridovich I. Superoxide and
peroxynitrite inactivate aconitase, but nitric oxide does
not. J Biol Chem. 1994;269:29405-29408.
30.
Stadler J, Billiar TR, Curran RD, Struehr DJ, Ochoa JB,
Simmons RL. Effect of exogenous and endogenous
nitric oxide on mitochondria respiration of rat
hepatocytes. Am J Physiol. 1991;260:C910-C916.
31.
Stadler J, Curran RD, Ochoa JB, Harbrecht BG, Hoffman
RA, Simmons RL, Billiar TR. Effect of endogenous
nitric oxide on mitochondrial respiration of rat
hepatocytes in vitro and in vivo. Arch
Surg. 1991;126:186-191.
32.
Geng YJ, Hansson GK, Holme E.
Interferon-gamma and tumor necrosis factor synergize to induce
nitric oxide production and inhibit mitochondrial respiration
in vascular smooth muscle cells. Circ Res. 1992;71:1268-1276.
33. Stefanovic-Racic M, Stadler J, Georgescu HI, Evans CH. Nitric oxide and energy production in articular chondrocytes. J Cell Physiol. 1994;159:274-280. [Medline] [Order article via Infotrieve]
34.
Chang HY, Ward ME, Hussain SNA. Regulation of
diaphragmatic oxygen uptake by endothelium-derived
relaxing factor. Am J Physiol. 1993;265:H123-H130.
35.
Iwamoto J, Yang SP, Yoshinaga M, Krasney E, Krasney
J. N-Nitro-L-arginine influences cerebral metabolism
in awake sheep. J Appl Physiol. 1992;73:2233-2240.
36. Brezis M, Heyman SN, Dinour D, Epstein FH, Rosen S. Role of nitric oxide in renal medullary oxygenation. J Clin Invest. 1991;88:390-395.
37. Hintze TH, Shen W, Seyedi N, Zhao G. Potential roles for changes in coronary and myocyte nitric oxide production in the development of heart failure. Heart Failure. 1994;10:116-125.
38. Suschek C, Fehsel C, Kroncke K-D, Sommer A, Kolb-Bachofen V. Primary cultures of rat islet endothelium: constitutive and cytokine-inducible macrophage-like nitric oxide synthases are expressed and activities regulated by glucose concentration. Am J Pathol. 1994;145:685-695. [Abstract]
39. Wiemer G, Popp R, Scholkens BA, Gogelein H. Enhancement of cytosolic calcium, prostacyclin and nitric oxide by bradykinin and the ACE inhibitor ramiprilat in porcine brain capillary endothelial cells. Brain Res. 1994;638:261-266. [Medline] [Order article via Infotrieve]
40. Xie I-W, Shen W, Hintze TH, Wolin MS. Nitric oxide inhibits oxygen consumption in isolated canine myocardial muscle. FASEB J.. 1995;9:A557. Abstract.
41. Balligand JL, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, Smith TW. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest. 1993;91:2314-2319.
42.
Brady AJB, Warren JB, Poole-Wilson PA, Williams TJ,
Harding SE. Nitric oxide attenuates cardiac myocyte
contraction. Am J Physiol. 1993;265:H176-H182.
43. Davis CA, Harris KR, Quinn DA, Ahlin KA, Klocke FJ. Blockade of EDRF synthesis with L-NAME reduces myocardial O2 consumption and coronary blood flow at comparable levels of double and triple product. Circulation. 1994;90(suppl I):I-104. Abstract.
44. Bernstein R, Shen W, Xu X, Hintze TH. Nitro-L-arginine decreases myocardial oxygen consumption in response to isoproterenol infusion in awake dogs. Circulation. 1994;90(suppl I):I-104. Abstract.
45. Bernstein R, Xu X, Ochoa M, Hintze TH. Nitric oxide differentially modulates myocardial oxygen consumption in response to isoproterenol and norepinephrine in awake dogs. FASEB J.. 1995;9:A842. Abstract.
46. Shen W, Zhang XP, Zhao G, Wolin MS, Sessa W, Hintze TH. Nitric oxide production and NO synthase gene expression contribute to vascular regulation during exercise. Med Sci Sports Exerc. 1995;27;1125-1134.
47.
Wang J, Seyedi N, Xu XB, Wolin MS, Hintze
TH. Defective endothelium-mediated control
of the coronary circulation in conscious dogs after heart
failure. Am J Physiol. 1994;266:H670-H680.
48.
Sessa WC, Pritchard K, Seyedi N, Wang J, Hintze
TH. Chronic exercise in dogs increases coronary vascular
nitric oxide production and endothelial cell
nitric oxide synthase gene expression. Circ
Res. 1994;74:349-353.
This article has been cited by other articles:
 |
|
 |
|
  C. J. Ray and J. M. Marshall Nitric oxide (NO) does not contribute to the generation or action of adenosine during exercise hyperaemia in rat hindlimb J. Physiol., April 1, 2009; 587(7): 1579 - 1591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Yamin, O. Amir, M. Sagiv, E. Attias, Y. Meckel, N. Eynon, M. Sagiv, and R. E. Amir ACE ID genotype affects blood creatine kinase response to eccentric exercise J Appl Physiol, December 1, 2007; 103(6): 2057 - 2061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Erusalimsky and S. Moncada Nitric Oxide and Mitochondrial Signaling: From Physiology to Pathophysiology Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2524 - 2531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Brown and V. Borutaite Nitric oxide and mitochondrial respiration in the heart Cardiovasc Res, July 15, 2007; 75(2): 283 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Mortensen, J. Gonzalez-Alonso, R. Damsgaard, B. Saltin, and Y. Hellsten Inhibition of nitric oxide and prostaglandins, but not endothelial-derived hyperpolarizing factors, reduces blood flow and aerobic energy turnover in the exercising human leg J. Physiol., June 1, 2007; 581(2): 853 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Cooper and C. Giulivi Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology Am J Physiol Cell Physiol, June 1, 2007; 292(6): C1993 - C2003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-J. Kim, X. Zhang, X. Xu, A. Chen, J. B. Gonzalez, S. Koul, K. Vijayan, G. J. Crystal, S. F. Vatner, and T. H. Hintze Evidence for enhanced eNOS function in coronary microvessels during the second window of protection Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2152 - H2158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lapointe, M. Roy, I. St-Pierre, S. Kimmins, D. Gauvreau, L. A. MacLaren, and J.-F. Bilodeau Hormonal and Spatial Regulation of Nitric Oxide Synthases (NOS) (Neuronal NOS, Inducible NOS, and Endothelial NOS) in the Oviducts Endocrinology, December 1, 2006; 147(12): 5600 - 5610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shibata, K. Qin, S. Ichioka, and A. Kamiya Vascular wall energetics in arterioles during nitric oxide-dependent and -independent vasodilation J Appl Physiol, June 1, 2006; 100(6): 1793 - 1798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Monnet, B. Ghaleh, L. Lucats, P. Colin, R. Zini, L. Hittinger, and A. Berdeaux Phenotypic adaptation of the late preconditioned heart: Myocardial oxygen consumption is reduced Cardiovasc Res, May 1, 2006; 70(2): 391 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. S Hopkinson, K. I Eleftheriou, J. Payne, A. H Nickol, E. Hawe, J. Moxham, H. Montgomery, and M. I Polkey +9/+9 Homozygosity of the bradykinin receptor gene polymorphism is associated with reduced fat-free mass in chronic obstructive pulmonary disease. Am. J. Clinical Nutrition, April 1, 2006; 83(4): 912 - 917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Parent, N. Leblanc, and M. Lavallee Nitroglycerin reduces myocardial oxygen consumption during exercise despite vascular tolerance Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1226 - H1234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. McMahon and A. Doctor Extrapulmonary effects of inhaled nitric oxide: role of reversible s-nitrosylation of erythrocytic hemoglobin. Proceedings of the ATS, January 1, 2006; 3(2): 153 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shibata, S. Ichioka, and A. Kamiya Nitric oxide modulates oxygen consumption by arteriolar walls in rat skeletal muscle Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2673 - H2679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Grassi, M. C Hogan, K. M Kelley, R. A Howlett, and L. B. Gladden Effects of nitric oxide synthase inhibition by L-NAME on oxygen uptake kinetics in isolated canine muscle in situ J. Physiol., November 1, 2005; 568(3): 1021 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kinugawa, J. Zhang, E. Messina, E. Walsh, H. Huang, P. M. Kaminski, M. S. Wolin, and T. H. Hintze gp91phox-containing NAD(P)H oxidase mediates attenuation of nitric oxide-dependent control of myocardial oxygen consumption by ANG II Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H862 - H867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Utz, J. Jordan, T. Niendorf, M. Stoffels, F. C. Luft, R. Dietz, and M. G. Friedrich Blood Oxygen Level-Dependent MRI of Tissue Oxygenation: Relation to Endothelium-Dependent and Endothelium-Independent Blood Flow Changes Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1408 - 1413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kinugawa, H. Huang, Z. Wang, P. M. Kaminski, M. S. Wolin, and T. H. Hintze A Defect of Neuronal Nitric Oxide Synthase Increases Xanthine Oxidase-Derived Superoxide Anion and Attenuates the Control of Myocardial Oxygen Consumption by Nitric Oxide Derived From Endothelial Nitric Oxide Synthase Circ. Res., February 18, 2005; 96(3): 355 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Williams, S. S. Dhamrait, P. T. E. Wootton, S. H. Day, E. Hawe, J. R. Payne, S. G. Myerson, M. World, R. Budgett, S. E. Humphries, et al. Bradykinin receptor gene variant and human physical performance J Appl Physiol, March 1, 2004; 96(3): 938 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Li, T. Jue, J. Edwards, X. Wang, and T. H. Hintze Changes in NO bioavailabilty regulate cardiac O2 consumption: control by intramitochondrial SOD2 and intracellular myoglobin Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H47 - H54. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. TSAI, P. C. JOHNSON, and M. INTAGLIETTA Oxygen Gradients in the Microcirculation Physiol Rev, July 1, 2003; 83(3): 933 - 963. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, J. H. Traverse, M. Hou, Y. Li, R. Du, and R. J. Bache Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1513 - H1520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hillig, P. Krustrup, I. Fleming, T. Osada, B. Saltin, and Y. Hellsten Cytochrome P450 2C9 plays an important role in the regulation of exercise-induced skeletal muscle blood flow and oxygen uptake in humans J. Physiol., January 1, 2003; 546(1): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Brodsky, S. Gao, H. Li, and M. S. Goligorsky Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2130 - H2139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chen, J. H. Traverse, R. Du, M. Hou, and R. J. Bache Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart Circulation, July 9, 2002; 106(2): 273 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Kim, Y.-K. Kim, G. Takagi, C.-H. Huang, Y.-J. Geng, and S. F. Vatner Enhanced iNOS function in myocytes one day after brief ischemic episode Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H423 - H428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Borutaite, A. Matthias, H. Harris, S. Moncada, and G. C. Brown Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2256 - H2260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
H. E. De Wardener The Hypothalamus and Hypertension Physiol Rev, October 1, 2001; 81(4): 1599 - 1658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Paxinou, M. Weisse, Q. Chen, J. M. Souza, C. Hertkorn, M. Selak, E. Daikhin, M. Yudkoff, G. Sowa, W. C. Sessa, et al. Dynamic regulation of metabolism and respiration by endogenously produced nitric oxide protects against oxidative stress PNAS, September 13, 2001; (2001) 201293198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Setty, X. Bian, J. D. Tune, and H. F. Downey Endogenous nitric oxide modulates myocardial oxygen consumption in canine right ventricle Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H831 - H837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
N J Edmunds and J. M Marshall Vasodilatation, oxygen delivery and oxygen consumption in rat hindlimb during systemic hypoxia: roles of nitric oxide J. Physiol., April 1, 2001; 532(1): 251 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-P. Wang, H. Xu, K. Mizoguchi, M. Oe, and H. Maeta Intestinal ischemia induces late preconditioning against myocardial infarction: a role for inducible nitric oxide synthase Cardiovasc Res, February 1, 2001; 49(2): 391 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
Y. Chen, R. Du, J. H. Traverse, and R. J. Bache Effect of sildenafil on coronary active and reactive hyperemia Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2319 - H2325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Zhao, X. Zhang, X. Xu, M. S. Wolin, and T. H. Hintze Depressed modulation of oxygen consumption by endogenous nitric oxide in cardiac muscle from diabetic dogs Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H520 - H527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch, H. Post, M. C. Michel, M. Kelm, and R. Schulz Endogenous Nitric Oxide and Myocardial Adaptation to Ischemia Circ. Res., July 21, 2000; 87(2): 146 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 E. Sato, K. L. Simpson, M. B. Grisham, S. Koyama, and R. A. Robbins Reactive Nitrogen and Oxygen Species Attenuate Interleukin- 8-induced Neutrophil Chemotactic Activity in Vitro J. Biol. Chem., April 6, 2000; 275(15): 10826 - 10830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. P. Gavin, D. A. Spector, H. Wagner, E. C. Breen, and P. D. Wagner Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise J Appl Physiol, April 1, 2000; 88(4): 1192 - 1198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tatsumi, S. Matoba, A. Kawahara, N. Keira, J. Shiraishi, K. Akashi, M. Kobara, T. Tanaka, M. Katamura, C. Nakagawa, et al. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes J. Am. Coll. Cardiol., April 1, 2000; 35(5): 1338 - 1346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. T. Murray, M. E. Wylam, and J. G. Umans Nitric Oxide and Septic Vascular Dysfunction Anesth. Analg., January 1, 2000; 90(1): 89 - 89. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 E. Sato, K. L. Simpson, M. B. Grisham, S. Koyama, and R. A. Robbins Effects of reactive oxygen and nitrogen metabolites on MCP-1-induced monocyte chemotactic activity in vitro Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L543 - L549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S.R. Baker, O. Rimoldi, P. G. Camici, E. Barnes, M. R. Chacon, T. Y. Huehns, D. O. Haskard, J. M. Polak, and R. J.C. Hall Repetitive myocardial stunning in pigs is associated with the increased expression of inducible and constitutive nitric oxide synthases Cardiovasc Res, August 15, 1999; 43(3): 685 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Sato, K. L. Simpson, M. B. Grisham, S. Koyama, and R. A. Robbins Effects of Reactive Oxygen and Nitrogen Metabolites on RANTES- and IL-5-Induced Eosinophil Chemotactic Activity in Vitro Am. J. Pathol., August 1, 1999; 155(2): 591 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Crystal, X. Zhou, A. A. Halim, S. Alam, M. El-Orbany, and M. R. Salem Nitric oxide does not modulate whole body oxygen consumption in anesthetized dogs J Appl Physiol, June 1, 1999; 86(6): 1944 - 1949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. Forfia, X. Zhang, D. R. Knight, A. H. Smith, C. P. A. Doe, E. A. Wolfgang, D. M. Flynn, M. S. Wolin, and T. H. Hintze NO modulates myocardial O2 consumption in the nonhuman primate: an additional mechanism of action of amlodipine Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H2069 - H2075. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Han, Z. Ming, and W. W. Lautt Shear stress-induced nitric oxide antagonizes adenosine effects on intestinal metabolism Am J Physiol Gastrointest Liver Physiol, May 1, 1999; 276(5): G1227 - G1234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Loke, P. I. McConnell, J. M. Tuzman, E. G. Shesely, C. J. Smith, C. J. Stackpole, C. I. Thompson, G. Kaley, M. S. Wolin, and T. H. Hintze Endogenous Endothelial Nitric Oxide Synthase–Derived Nitric Oxide Is a Physiological Regulator of Myocardial Oxygen Consumption Circ. Res., April 16, 1999; 84(7): 840 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Clementi, G. C. Brown, N. Foxwell, and S. Moncada On the mechanism by which vascular endothelial cells regulate their oxygen consumption PNAS, February 16, 1999; 96(4): 1559 - 1562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. Motterlini, H. Kerger, C. J. Green, R. M. Winslow, and M. Intaglietta Depression of endothelial and smooth muscle cell oxygen consumption by endotoxin Am J Physiol Heart Circ Physiol, September 1, 1998; 275(3): H776 - H782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Takano, S. Manchikalapudi, X.-L. Tang, Y. Qiu, A. Rizvi, A. K. Jadoon, Q. Zhang, and R. Bolli Nitric Oxide Synthase Is the Mediator of Late Preconditioning Against Myocardial Infarction in Conscious Rabbits Circulation, August 4, 1998; 98(5): 441 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Suto, A. Mikuniya, T. Okubo, H. Hanada, N. Shinozaki, and K. Okumura Nitric oxide modulates cardiac contractility and oxygen consumption without changing contractile efficiency Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H41 - H49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Laycock, T. Vogel, P. R. Forfia, J. Tuzman, X. Xu, M. Ochoa, C. I. Thompson, A. Nasjletti, and T. H. Hintze Role of Nitric Oxide in the Control of Renal Oxygen Consumption and the Regulation of Chemical Work in the Kidney Circ. Res., June 29, 1998; 82(12): 1263 - 1271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-W. Xie, P. M. Kaminski, and M. S. Wolin Inhibition of Rat Cardiac Muscle Contraction and Mitochondrial Respiration by Endogenous Peroxynitrite Formation During Posthypoxic Reoxygenation Circ. Res., May 4, 1998; 82(8): 891 - 897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gheorghiade and R. O. Bonow Chronic Heart Failure in the United States : A Manifestation of Coronary Artery Disease Circulation, January 27, 1998; 97(3): 282 - 289. [Full Text] [PDF]
|
|
|
|
|
|
J. M. Hare, M. M. Givertz, M. A. Creager, and W. S. Colucci Increased Sensitivity to Nitric Oxide Synthase Inhibition in Patients With Heart Failure : Potentiation of ß-Adrenergic Inotropic Responsiveness Circulation, January 20, 1998; 97(2): 161 - 166. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Poderoso, J. G. Peralta, C. L. Lisdero, M. C. Carreras, M. Radisic, F. Schopfer, E. Cadenas, and A. Boveris Nitric oxide regulates oxygen uptake and hydrogen peroxide release by the isolated beating rat heart Am J Physiol Cell Physiol, January 1, 1998; 274(1): C112 - C119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Gow, S. R. Thom, and H. Ischiropoulos Nitric oxide and peroxynitrite-mediated pulmonary cell death Am J Physiol Lung Cell Mol Physiol, January 1, 1998; 274(1): L112 - L118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bolli, S. Manchikalapudi, X.-L. Tang, H. Takano, Y. Qiu, Y. Guo, Q. Zhang, and A. K. Jadoon The Protective Effect of Late Preconditioning Against Myocardial Stunning in Conscious Rabbits Is Mediated by Nitric Oxide Synthase : Evidence That Nitric Oxide Acts Both as a Trigger and as a Mediator of the Late Phase of Ischemic Preconditioning Circ. Res., December 19, 1997; 81(6): 1094 - 1107. [Abstract] [Full Text]
|
|
|
|
|
|
M. J. Joyner and N. M. Dietz Nitric oxide and vasodilation in human limbs J Appl Physiol, December 1, 1997; 83(6): 1785 - 1796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Balligand and P. J. Cannon Nitric Oxide Synthases and Cardiac Muscle : Autocrine and Paracrine Influences Arterioscler. Thromb. Vasc. Biol., October 1, 1997; 17(10): 1846 - 1858. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. SAULEDA, F. GARCÍA-PALMER, R. J. WIESNER, S. TARRAGA, I. HARTING, P. TOMÁS, C. GÓMEZ, C. SAUS, A. PALOU, and A. G. N. AGUSTÍ Cytochrome Oxidase Activity and Mitochondrial Gene Expression in Skeletal Muscle of Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., May 1, 1997; 157(5): 1413 - 1417. [Abstract] [Full Text]
|
|
|
|
|
|
A. J. Sherman, C. A. Davis III, F. J. Klocke, K. R. Harris, G. Srinivasan, A. S. Yaacoub, D. A. Quinn, K. A. Ahlin, and J. J. Jang Blockade of Nitric Oxide Synthesis Reduces Myocardial Oxygen Consumption In Vivo Circulation, March 4, 1997; 95(5): 1328 - 1334. [Abstract] [Full Text]
|
|
|
|
|
|
Y.-W. Xie and M. S. Wolin Role of Nitric Oxide and Its Interaction With Superoxide in the Suppression of Cardiac Muscle Mitochondrial Respiration: Involvement in Response to Hypoxia/Reoxygenation Circulation, November 15, 1996; 94(10): 2580 - 2586. [Abstract] [Full Text]
|
|
|
|
|
|
R. D. Bernstein, F. Y. Ochoa, X. Xu, P. Forfia, W. Shen, C. I. Thompson, and T. H. Hintze Function and Production of Nitric Oxide in the Coronary Circulation of the Conscious Dog During Exercise Circ. Res., October 1, 1996; 79(4): 840 - 848. [Abstract] [Full Text]
|
|
|
|
|
|
R. A. Kelly, J.-L. Balligand, and T. W. Smith Nitric Oxide and Cardiac Function Circ. Res., September 1, 1996; 79(3): 363 - 380. [Full Text]
|
|
|
|
|
|
Y.-W. Xie, W. Shen, G. Zhao, X. Xu, M. S. Wolin, and T. H. Hintze Role of Endothelium-Derived Nitric Oxide in the Modulation of Canine Myocardial Mitochondrial Respiration In Vitro: Implications for the Development of Heart Failure Circ. Res., September 1, 1996; 79(3): 381 - 387. [Abstract] [Full Text]
|
|
|
|
|
|
E. Paxinou, M. Weisse, Q. Chen, J. M. Souza, C. Hertkorn, M. Selak, E. Daikhin, M. Yudkoff, G. Sowa, W. C. Sessa, et al. Dynamic regulation of metabolism and respiration by endogenously produced nitric oxide protects against oxidative stress PNAS, September 25, 2001; 98(20): 11575 - 11580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Setty, J. D. Tune, and H. F. Downey Nitric oxide modulates right ventricular flow and oxygen consumption during norepinephrine infusion Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H696 - H703. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||