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1 Department of Anesthesiology, The effects of the NO synthase inhibitor
NG-nitro-L-arginine
methyl ester (L-NAME) and the NO
donor sodium nitroprusside (SNP) on whole body
O2 consumption
(
oxygen metabolism; sodium nitroprusside; NG-nitro-L-arginine
methyl ester; nitric oxide synthase
NITRIC OXIDE (NO) is produced in the vascular
endothelium from the amino acid
L-arginine in a reaction that
requires the constitutive enzyme NO synthase (NOS) (16).
Endothelium-derived NO (EDNO) diffuses from the vascular endothelium to
the vascular smooth muscle cell, where it stimulates guanylate cyclase
activity and the production of guanosine 3'-5'-cyclic
monophosphate, which has vasorelaxing actions. Stimulated EDNO release
is involved in the vasodilation caused by a variety of drugs, e.g.,
acetylcholine (1), and by physiological stimuli, including an increased
shear stress (1). EDNO is released tonically, as evidenced by the ability of NOS inhibitors to decrease local blood flow (and increase local vascular resistance) in peripheral tissues, e.g., skeletal muscle, as well as to increase systemic vascular resistance and aortic
pressure (16).
Studies conducted in a wide variety of isolated tissues, including
hepatocytes, skeletal muscle, and myocardium, have demonstrated that
increased NO levels can cause a reduction in
O2 use (8, 25, 29, 32). This
effect has been explained by a binding of NO to the heme moiety of
cytochrome enzymes in the mitochondrial electron-transport chain.
Studies have used NOS inhibitors to assess whether the levels of EDNO
released basally are sufficient to suppress tissue
O2 use in vivo (2-4, 11, 12,
21, 22, 26, 27). The results of these studies have been inconsistent. Whereas Shen et al. (26) demonstrated that systemic administration of a
NOS inhibitor increased whole body
O2 consumption
( The main objective of the present study was to assess the effect of the
NOS inhibitor
NG-nitro-L-arginine
methyl ester (L-NAME) on whole
body Previous findings obtained in aortic ring preparations have
demonstrated that treatment with a NOS inhibitor or denudation of the
endothelium leads to a supersensitivity to the vasorelaxing effects of
SNP (17). Whether this phenomenon has relevance at the resistance
vessel level in vivo is unknown. Accordingly, a final objective was to
evaluate how L-NAME alters the
effects of SNP on systemic vascular resistance (as well as on
O2 metabolism). In separate
studies, the cAMP phosphodiesterase inhibitor amrinone was used to
verify sensitivity of the canine preparation to calorigenic stimulation.
The present study was performed in dogs anesthetized with the clinical
anesthetics fentanyl and isoflurane; these two agents have no known
direct effects on mitochondrial activity. The use of these anesthetics
facilitated extrapolation of the findings to the operating room setting.
Canine Preparation
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O2) were assessed in 16 dogs anesthetized with fentanyl or isoflurane. Cardiac output (CO) and
mean arterial pressure (MAP) were measured with standard methods and
were used to calculate O2
and systemic vascular resistance (SVR). Data were obtained in each dog
under the following conditions: 1)
Control 1, 2) SNP (30 µg · kg
1 · min1
iv) 3) Control 2, 4)
L-NAME (10 mg/kg iv), and
5) SNP and adenosine (30 and 600 µg · kg1 · min1
iv, respectively) after L-NAME.
SNP reduced MAP by 29 ± 3% and SVR by 47 ± 3%, while it
increased CO by 39 ± 9%.
L-NAME had opposite effects; it
increased MAP and SVR by 24 ± 4% and 103 ± 11%, respectively, and it decreased CO by 37 ± 3%. Neither agent changed
O2 from the baseline value
of 4.3 ± 0.2 ml · min1 · kg1,
since the changes in CO were offset by changes in the arteriovenous O2 difference. Both SNP and
adenosine returned CO to
pre-L-NAME values, but
O2 was unaffected. We
conclude that 1) basally released endogenous NO had a tonic systemic vasodilator effect, but it had no
influence on O2;
2) SNP did not alter
O2 before or after
inhibition of endogenous NO production;
3) the inability of
L-NAME to increase
O2 was not because CO,
i.e., O2 supply, was reduced below
the critical level.
INTRODUCTION
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ABSTRACT
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METHODS
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DISCUSSION
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O2), thus implying
that EDNO tonically suppresses mitochondrial use of
O2, King et al. (11) showed no
effect. Furthermore, although most studies have indicated no effect of
NOS inhibition on basal O2 use in
individual tissues, e.g., myocardium and skeletal muscle (2-4, 12,
21, 22), some have demonstrated decreases (27) and others increases
(11). The variability in these previous in vivo findings has been
attributed to the ability of barbiturate anesthetics, e.g.,
pentobarbital sodium, to block NO-induced inhibition of mitochondrial
O2 use (9, 20, 26) and to the
decreases in blood flow, i.e., O2
delivery, that frequently accompany inhibition of EDNO (11).
O2. Intravenous infusions of adenosine were used to normalize cardiac output after L-NAME administration. A second
objective was to evaluate the effect of the NO donor sodium
nitroprusside (SNP) (7) on whole body
O2. Findings during
equihypotensive infusions of adenosine served as a reference for
evaluating the effects of SNP.
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DISCUSSION
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1 · h1)
was used to facilitate mechanical ventilation and to prevent muscle
fasciculations. Core body temperature was monitored and was maintained
at 38°C with a heating pad, warmed intravenous fluids, and warming lights.
A polyethylene catheter was implanted in the thoracic aorta for measurements of mean arterial pressure and heart rate and for collection of samples of arterial blood. A multiport catheter with a thermister was introduced into the right jugular vein, and was flow directed into the pulmonary artery by using pressure monitoring for guidance. This catheter was used to obtain measurements of cardiac output by thermodilution and to collect samples of mixed venous blood. The values for cardiac output were obtained in triplicate and averaged. Cardiac output was normalized according to body weight in kilograms. A continuous record of mean arterial pressure was obtained on a physiological recorder (model 2800S, Gould, Cleveland, OH). Systemic vascular resistance was calculated by dividing mean arterial pressure by cardiac output.
Measurements of Whole Body
O2
O2 were calculated from the
product of cardiac output and the arteriovenous
O2 difference (Fick equation).
O2 content was measured in 1-ml
samples of arterial and mixed venous blood. Hemoglobin concentration
and percent hemoglobin O2
saturation for the blood samples were determined with a CO-oximeter
(model 482, Instrumentation Laboratories) and were used to calculate
O2 bound to hemoglobin, assuming
an O2-carrying capacity for
hemoglobin of 1.39 ml O2/g. The
O2 dissolved in the blood was
calculated (O2 dissolved = 0.003 ml O2 · 100 ml1 · Torr1)
and was added to the bound component to compute total
O2 content.
Experimental Protocols
Series 1. Effects of L-NAME and
SNP on whole body O2.
The dogs of series 1 were divided into
three groups on the basis of the anesthetic technique employed.
Anesthesia was induced in group 1 (n = 6) with a bolus injection of
fentanyl and midazolam (40 µg/kg and 2 mg/kg iv, respectively), in
group 2 (n = 6) with a bolus
injection of thiopental sodium (15 mg/kg iv), and in
group 3 (n = 4) with a bolus injection of
ketamine hydrochloride (30 mg/kg iv). In group
1, anesthesia was maintained with a continuous infusion
of fentanyl and midazolam (12 µg · kg1 · h1
and 0.6 mg · kg1 · h1
iv, respectively). In groups 2 and
3, anesthesia was maintained with 1 MAC (minimum alveolar concentration) of isoflurane (1.4%) in the
inspired gas. In group 2, bolus iv
injections of fentanyl were made, as necessary, to reduce baseline
heart rate to ~100 beats/min. The dogs were permitted to stabilize
for at least 30 min after surgical preparation before values for whole
body O2 and hemodynamic
parameters were obtained under the following conditions: 1) Control 1, 2) SNP (infused intravenously at
dose of 30 µg · kg1 · min1),
3) Control 2, 4) adenosine (infused at a dose of
600 µg · kg1 · min1
iv), 5) Control 3, and
6)
L-NAME (10 mg/kg iv).
Measurements for whole body
O2 were obtained after mean
arterial pressure was stable for 15 min during SNP or adenosine. At
least 20 min were permitted for recovery after the hypotensive drug
infusion. The order of SNP and adenosine was randomized. Measurements
of whole body O2 were
obtained 60 min after the injection of
L-NAME.
O2 were repeated during iv
infusions of SNP and adenosine (using the same doses and protocol as
described above) after L-NAME.
Series 2. Effect of high-dose amrinone on whole body
O2.
The four dogs in series 2 were
anesthetized with isoflurane, as described above for
group 2 in series
1. Measurements of whole body
O2 and hemodynamic
parameters were evaluated under control conditions and during amrinone
(1 mg/kg bolus, 20 mg · kg1 · min1
iv for 15 min). This dose of amrinone had been demonstrated in pilot
studies to cause an increase in whole body
O2.
Statistical Analyses
The Student's t-test for paired samples was used to evaluate the effects of SNP, adenosine, L-NAME, and amrinone alone (33). An analysis of variance for repeated measures, in conjunction with the Student-Newman-Keuls test (33), was used to evaluate the effects of L-NAME alone and during adenosine or SNP.| |
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Table 1 presents the changes in whole body
O2 (and its determinants), as
well as in systemic hemodynamic parameters, during SNP, adenosine, and
L-NAME in fentanyl-anesthetized
dogs (group 1). SNP caused decreases in mean
arterial pressure and systemic vascular resistance, accompanied by
increases in cardiac output. Whole body
O2 did not change, because
the increases in cardiac output were accompanied by proportional
decreases in the arteriovenous O2
difference. The findings during adenosine were similar to those during
SNP. L-NAME caused increases in
mean arterial pressure and systemic vascular resistance but decreases
in cardiac output. Whole body
O2 did not change, because
the decreases in cardiac output were balanced by increases in the
arteriovenous O2 difference.
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Tables 2 and
3 show that SNP, adenosine, and
L-NAME also had no effect on
whole body O2 in dogs
anesthetized with isoflurane (groups 2 and
3), and the drugs caused hemodynamic
changes that were essentially similar to those in dogs anesthetized
with fentanyl.
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After administration of L-NAME,
adenosine and SNP had similar effects in the fentanyl and isoflurane
groups. Thus these findings were pooled (Table
4). Both adenosine and SNP reduced mean
arterial pressure and systemic vascular resistance from the
L-NAME-induced increased level,
which returned cardiac output to the control level; however, whole body
O2 was not altered. It was
noteworthy that L-NAME augmented
the decreases in systemic vascular resistance during SNP and adenosine
to the same extent (Fig. 1).
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Amrinone caused proportional increases in whole body
O2 and cardiac output (Table
5).
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Critique of Methods
Responses to equihypotensive infusions of adenosine were used as a reference to evaluate the effects of SNP. Adenosine was chosen for this purpose for the following three reasons. 1) It does not, like SNP, depend on release of NO for its vasodilating action. 2) It has been shown to cause a rapidly induced and easily maintained hypotension. 3) It has been demonstrated (confirmed in the present study) to have no effect on whole bodyO2 (18, 19, 28).
The doses for SNP and adenosine were chosen on the basis of preliminary
studies that demonstrated that they caused relatively modest (~25%),
readily reversible decreases in mean arterial pressure. Higher doses of
the vasodilators were not used to avoid the decreases in cardiac
output, i.e., whole body O2
delivery, which complicate interpretation of changes in whole body
O2. The dose of
L-NAME was adopted from previous
studies (27).
The amrinone findings (Table 5) verified that our canine preparation was sensitive to calorigenic stimulation.
Metabolic and Hemodynamic Effects of NO
Our three main findings were as follows. 1) Inhibition of NO production with L-NAME increased arterial pressure and reduced cardiac output, but it did not change whole bodyO2.
2) Hypotensive infusions of SNP or
adenosine did not affect whole body
O2, either before or after
L-NAME.
3) Pretreatment with
L-NAME enhanced the decreases in
systemic vascular resistance caused by SNP and adenosine to the same extent.
Shen et al. (26) reported that inhibition of EDNO increased whole body
O2 in conscious dogs; this
implies that endogenous NO provides a tonic "braking" influence
on mitochondrial O2 use. However,
the present study and previous studies (11, 26) that have used
anesthetized dogs have failed to demonstrate this effect. The previous
investigators explained their negative findings by the ability of
barbiturates, such as pentobarbital sodium (the agent used for general
anesthesia in the studies), to inhibit NADH+ dehydrogenase (complex I) in
the mitochondrial respiratory chain (9, 20). In group
2 of series 1, we used
another barbiturate, thiopental sodium, as an induction agent, i.e., a
single bolus injection was made at the beginning of each study.
Thiopental sodium has a short duration of action in the central nervous
system (5-10 min), because it is rapidly redistributed away from
active, highly perfused tissues, such as the brain, into other tissues, including fat and muscle. However, data from pharmacokinetic studies in
humans have shown that the elimination half-life for thiopental sodium
may be as long as 12 h (30). Thus it cannot be ruled out that a
persistent inhibitory action of thiopental sodium on tissue
mitochondria may have prevented NO-mediated effects on oxidative
metabolism in group 2 of our study.
However, this mechanism cannot explain the lack of effect of NO in our
other studies in series 1, all of
which were performed in the absence of a barbiturate.
Taken together, the findings to date suggest that general anesthesia per se may prevent NO-induced inhibition of mitochondrial function. Because the anesthetics employed have such different molecular structures [fentanyl and isoflurane in the present study, and pentobarbital sodium in the previous studies (11, 26)], this effect would likely be nonspecific, e.g., due to depression of tissue metabolic activity.
The work of Schumaker and Cain (24) has demonstrated that the
relationship between whole body O2
delivery and O2 is biphasic. At normal or high levels of O2
delivery, O2 is constant and independent of O2 delivery. As
O2 delivery is gradually reduced, an increase in O2 extraction
maintains O2. Eventually,
a critical point is reached at which
O2 extraction cannot increase
adequately. Below this threshold, the so-called "critical
O2 delivery," the level of
O2 is limited by
O2 delivery. In the present study, we considered the possibility that a critical decrease in cardiac output (and thus O2 delivery) may
have prevented the increase in whole body
O2 after
L-NAME. However, the findings
during the infusion of adenosine after
L-NAME indicate that this was not the case. Adenosine restored cardiac output (presumably via reduction in afterload), but
O2 remained at the baseline level.
The infusions of SNP had no effect on whole body
O2 whether before or after
L-NAME. Under both conditions,
the induced increases in cardiac output were accompanied by
proportional decreases in the arteriovenous
O2 difference. The inability of
SNP to affect whole body O2
in dogs with intact vascular endothelium was in keeping with findings
obtained in pentobarbital-anesthetized dogs by Fan et al. (6). Although
Michenfelder and Theye (15) found that SNP caused appreciable
reductions (>30%) in whole body
O2 in dogs anesthetized with
halothane and nitrous oxide, these responses were accompanied by severe
decreases (70%) in cardiac output; this suggested that tissue
O2 use may have been limited by
O2 delivery. The lack of effect of
SNP on whole body O2 after
L-NAME was apparently
not because an increase in whole body
O2 (secondary to the
restoration of cardiac output) masked a direct depressive effect of NO
on oxidative metabolism. If that were the case, adenosine infusion
after L-NAME would have caused
an increase in whole body O2,
and it did not.
The values for whole body O2
are an aggregate of the O2
consumed by the individual body tissues. Thus the lack of change in
whole body O2 during
L-NAME or SNP does not
necessarily indicate that O2
in all vascular beds remained stable, i.e., it cannot be ruled out that
small increases in O2 in some
beds were balanced by small decreases in others. However, the present
findings would seem to preclude a generalized effect of NO (either
endogenously released under basal conditions or provided by SNP) on
tissue O2.
The present findings pertain only to the levels of endogenous NO associated with normal basal release from the vascular endothelium via constitutive NOS. Another form of NOS (so-called inducible NOS) can become expressed in a variety of cell types, e.g., neutrophils and vascular smooth muscle, after induction by immunological stimuli, such as cytokines and endotoxin (16). The inducible NOS pathway can produce higher concentrations of NO over extended periods of time. Results obtained in isolated tissues have demonstrated that the higher concentrations of NO associated with activation of inducible NOS are capable of inhibiting mitochondrial respiration (8, 29). Recent studies have shown that the inhibitory metabolic action of NO is greatly enhanced when it combines with superoxide anion to form peroxynitrite, such as during hypoxia-reoxygenation and ischemia-reperfusion (14, 23, 31).
The decreases in cardiac output caused by systemic NOS inhibition in the fentanyl- and isoflurane-anesthetized dogs of the present study have been shown previously in conscious dogs (5) and in dogs anesthetized with pentobarbital sodium (13). The decreases were associated with large increases in systemic vascular resistance accompanied by more modest increases in mean arterial pressure. The systemic vasoconstricting effect of L-NAME reflects a basal release of EDNO, which maintains the peripheral vasculature in a dilated state.
The infusions of either SNP or adenosine reversed the increases in arterial pressure and systemic vascular resistance, as well as the decreases in cardiac output caused by L-NAME. This implies that the L-NAME-induced decrease in cardiac output was related to the peripheral vasoconstrictor effect rather than to a direct inhibitory action of L-NAME on myocardial contractility. Our experimental design did not permit a determination of whether the decrease in cardiac output was due to an augmented afterload per se, to a baroreceptor-mediated withdrawal of sympathetic drive to the heart, or to a combination of these factors. The finding of Huang et al. (10), that the ganglion blocker hexamethonium had no effect on the L-NAME-induced changes in cardiac output and mean arterial pressure in anesthetized rats, provides support for the former mechanism.
Previous studies that used isolated aortic rings have demonstrated enhanced relaxation by SNP after denudation of the endothelium or treatment with a NOS inhibitor (17). This has been explained by the ability of the removal of NO in the vasculature to cause upregulation of its receptor in soluble guanylate cyclase. The present findings do not provide support for this mechanism in vivo at the level of the resistance vessels, i.e., arterioles. Although L-NAME augmented the decreases in systemic vascular resistance caused by SNP (Fig. 1), it did the same to the responses during adenosine. This suggests that this effect of L-NAME was nonspecific and likely was due to its ability to increase the baseline level of vasomotor tone.
In conclusion, we have demonstrated the following in normal, healthy
dogs anesthetized with fentanyl or isoflurane.
1) Endogenous NO released basally
did not affect whole body
O2, although it was important
in maintaining the peripheral vasculature in a dilated state. This
latter effect reduced left ventricular afterload, thus facilitating
cardiac ejection. 2) A moderately
hypotensive infusion of SNP did not affect whole body
O2.
3) Blockade of endogenous NO did not
sensitize the peripheral vasculature to the dilating effects of SNP or
cause the emergence of an inhibitory action of SNP on tissue oxidative
metabolism. Whether the present findings reflect a relative lack of
responsiveness of the mitochondria in parenchymal cells (compared with
vascular smooth muscle) to NO, a restricted access of NO to the
mitochondria or a combination of these factors remains to be ascertained.
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ACKNOWLEDGEMENTS |
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We appreciate the expert technical assistance of Derrick L. Harris.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. J. Crystal, Dept. of Anesthesiology, Illinois Masonic Medical Center, Univ. of Illinois College of Medicine, 836 West Wellington Ave., Chicago, IL (E-mail: George.J.Crystal{at}uic.edu).
Received 6 May 1998; accepted in final form 18 February 1999.
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SVR) by sodium
nitroprusside (SNP) and adenosine before and after
NG-nitro-L-arginine methyl ester
(L-NAME). * Significant
difference vs. before L-NAME,
P < 0.05.