AJP - Heart Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 285: H392-H397, 2003. First published February 27, 2003; doi:10.1152/ajpheart.00836.2002
0363-6135/03 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
285/1/H392    most recent
00836.2002v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kojic, Z. Z.
Right arrow Articles by Decking, U. K. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kojic, Z. Z.
Right arrow Articles by Decking, U. K. M.

Endothelial NO formation does not control myocardial O2 consumption in mouse heart

Zvezdana Z. Kojic, Ulrich Flögel, Jürgen Schrader, and Ulrich K. M. Decking

1Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40001 Düsseldorf, Germany

Submitted 18 September 2002 ; accepted in final form 5 March 2003


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
To test whether endothelium-derived nitric oxide (NO) regulates mitochondrial respiration, NO was pharmacologically modulated in isolated mouse hearts, which were perfused at constant flow to sensitively detect small changes in myocardial O2 consumption (MO2). Stimulation of NO formation by 10 µM bradykinin (BK) increased coronary venous nitrite release fivefold to 58 ± 33 nM (n = 17). Vasodilatation by BK, adenosine (1 µM), or papaverine (10 µM) decreased perfusion pressure, left ventricular developed pressure (LVDP), and MO2. In the presence of adenosine-induced vasodilatation, stimulation of endothelial NO synthesis by BK had no effect on LVDP and MO2. Also, inhibition of NO formation by NG-monomethyl-L-arginine (L-NMMA, 100 µM) did not significantly alter LVDP and MO2. Similarly, intracoronary infusion of authentic NO ≤2 µM did not influence LVDP or MO2 (-1 ± 1%). Only when NO was >2 µM were contractile dysfunction and MO2 reduction observed. Because BK-induced stimulation of endothelial NO formation and basal NO are not sufficient to impair MO2 in the saline-perfused mouse heart, a tonic control of the respiratory chain by endothelial NO is difficult to conceive.

nitrite; bradykinin; nitric oxide synthase inhibition

NITRIC OXIDE (NO) is an important regulator of coronary vascular tone. It can also modulate myocardial energy metabolism and contractile function by a variety of mechanisms. Mitochondrial oxidative phosphorylation, e.g., at the level of cytochrome c oxidase, is very sensitive to blockade by NO (7). We demonstrated that arterially applied NO can induce contractile dysfunction by inhibiting O2 consumption and ATP generation (10, 26). NO has been reported to inhibit mitochondrial and cytosolic creatine kinase (18, 23) and may influence substrate utilization (5). Moreover, NO may influence contractility and energy demand by modulating {beta}-adrenergic signal transduction (e.g., see Refs. 16, 43, 46) and via cGMP-dependent and -independent effects on Ca2+ influx and cycling (3; for review, see Refs. 25, 29).

In the heart, NO is formed predominantly in the coronary endothelium by the endothelial nitric oxide synthase (eNOS). NO is also formed within cardiomyocytes (2), where ~20% of the eNOS protein resides (16). The presence of NOS within or close to cardiac mitochondria was reported in several studies and attributed to eNOS in rats (4), inducible NOS (iNOS) in pigs (14), and neuronal NOS (nNOS) in mouse heart (24). Its physiological significance is under debate (14, 24). Not only the formation of NO but also its metabolism is characterized by a high degree of compartmentalization. In the presence of O2, NO is oxidized to nitrite (), e.g., in the intravascular space. The very fast reaction of NO with oxyhemoglobin to nitrate () and methemoglobin is considered to be a major route of NO catabolism. In addition, nitrosylation of hemoglobin and other proteins binds NO (17). We have also recently shown that myoglobin contributes to intracellular NO degradation to nitrate () and is thus a potent intracellular scavenger of NO (13).

The notion of a tonic control of myocardial oxygen consumption (MO2) by NO was supported by studies that demonstrated increased MO2 after blockade of NO synthesis in both isolated hearts and dogs in vivo (5, 9), whereas enhanced endothelial NO formation decreased MO2, e.g., in myocardial tissue pieces (30, 44). On the basis of these findings, it was concluded that endothelium-derived NO regulates cardiac MO2 (42). However, increasing NO in the canine or reducing NO formation in the porcine or human heart had no effect on MO2 (8, 11, 41). The recent recognition that myocardial myoglobin is a potent scavenger of NO (13) implies a steep intracellular NO-concentration gradient, which casts further doubt on the control of mitochondrial oxidative phosphorylation by endothelium-derived NO. We have therefore tested in well-oxygenated isolated mouse hearts whether enhancing endothelium-derived NO formation by bradykinin (BK) is quantitatively sufficient to decrease MO2 and contractile function. Myocardial NO levels were also modulated by application of authentic NO or inhibition of cardiac NO synthesis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
General methods. A total of 97 hearts from C57/BL6 mice (body wt, 20–30 g) were isolated and perfused as described previously (13). In brief, hearts with a wet weight of 116 ± 11 mg were rapidly excised. The aorta was cannulated and the heart was perfused at a pressure of 100 mmHg in a nonrecirculating Langendorff mode with modified Krebs-Henseleit buffer [that contained (in mM) 116 NaCl, 4.6 KCl, 1.1 MgSO4, 24.9 NaHCO3, 2.5 CaCl2, 1.2 KH2PO4, 8.3 glucose, 2.0 pyruvate, and 0.5 EDTA] equilibrated with 95% O2-5% CO2 (pH 7.4, 37°C). Small silver electrodes were gently applied to the right atrium and cardiac apex for cardiac pacing. The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health [DHEW Publication No. (NIH) 85-23, Revised 1996, Office of Science and Health Reports, DRR/NIH, Bethesda, MD 20205].

A dedicated perfusion system (isolated heart size 1, HSE Harvard Apparatus; March-Hugstett, Germany) enabled temperature control of both inflow medium and ambient air. The following parameters were continuously recorded (Powerlab, ADInstruments; Castle Hill, NSW, Australia): coronary flow as measured by a transit-time ultrasonic flowmeter (HSE Harvard Apparatus), coronary perfusion pressure, left intraventricular pressure as assessed by a fluid-filled balloon, heart rate, and coronary venous PO2. For reliable PO2 measurements, a fraction of the coronary venous effluent (0.5 ml/min) was sucked continuously through a small-diameter tube placed in the opening of the pulmonary artery across a Clark-type PO2 electrode (model 733, Diamond General; Ann Arbor, MI) by a peristaltic pump (Minipulse 3, Gilson Medical Electronics; Villiers-le-Bel, France). For the measurement of release, coronary venous effluent was collected as well.

Protocols. After completion of the preparation, hearts were initially perfused at constant pressure (100 mmHg, 13.3 kPa) inside a water-jacketed chamber set to 37°C. Cardiac pacing (500 min-1) was initiated and continued throughout. All hearts were allowed to equilibrate for 20 min before left ventricular end-diastolic pressure was set to 5 mmHg.

Twenty minutes after the onset of cardiac pacing, the coronary perfusion rate was fixed to the steady-state flow finally attained (in general, ~1.5–2.5 ml/min) and was maintained constant thereafter by a peristaltic pump. Basal functional parameters were acquired before subjecting the hearts to the different experimental protocols. In the first set of experiments, only BK was applied. In the presence of a constant flow, BK-induced vasodilatation resulted in a decrease in perfusion pressure and contractility. To verify that the latter effect was due to vasodilatation, the effects of two other vasodilators (adenosine and papaverine) were evaluated. In the main set of experiments, maximal vasodilatation was initiated by application of adenosine (1 µM), which was continued throughout, before the different interventions under steady-state conditions were started. BK (10 µM), NG-monomethyl-L-arginine (L-NMMA, 100 µM), or authentic NO (33 nM–20 µM) was applied in the presence of 1 µM adenosine. For infusion of authentic NO, aqueous NO solutions were prepared as previously described in detail (26). At the end of the experiment, hearts were gently blotted and weighed.

Measurement of MO2. To enable the sensitive detection of even small changes in MO2, hearts were perfused at a constant arterial PO2 (~600 mmHg) and flow as previously described by others (19, 38). In brief, measurement of the coronary venous PO2 (see General methods) allowed the determination of the arteriovenous PO2 difference. Because flow was maintained constant, any change in O2 consumption translated into a considerable change in coronary venous PO2. Preliminary experiments demonstrated both the stability of the PO2 electrode signal at a given PO2 (electrode drift, <0.1 mmHg/min) as well as the ability of the setup to respond to changes in MO2: when the external Ca2+ concentration was decreased from 2.5 to 2 mM, the coronary venous PO2 increased by 16 ± 2 mmHg, which corresponds to a change in MO2 of 4% (n = 3).

release measurements. To obtain a measure of cardiac NO formation, the release of the saline-perfused hearts was determined. Measurement of release was not attempted, because it is complicated by a low- content of the arterial inflow medium due to contamination of the commonly available medium constituents. The arterial inflow and coronary venous outflow concentrations were measured by a NO analyzer (NOA, model 280; Sievers; Boulder, CO) based on the chemiluminescence method. Comparison with standards enabled quantification with the detection limit being 1 pmol. To measure reliably the low coronary concentrations, an injection volume of 500 µl was employed. For standards in the range of 1–200 nM , a linear correlation coefficient (r) of 0.98 was obtained.

Chemicals. BK, L-NMMA, and urethane were obtained from Sigma (Deisenhofen, Germany), and heparin was purchased from Hoffmann-LaRoche (Grenzau, Germany). All other reagents were obtained from Merck (Darmstadt, Germany). NO gas was obtained from AGA gas (Hamburg, Germany).

Data analysis. To compare control or basal values with those obtained during the different interventions, Student's t-test or one-way ANOVA followed by post hoc tests [least-significant difference (LSD) and Bonferroni as indicated] were employed as appropriate. A P value of <0.05 was considered to indicate a significant difference. All results are expressed as means ± SD.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Isolated hearts of C57/BL6 mice were initially perfused at a pressure of 100 mmHg. The flow attained at the end of the equilibration period was fixed and maintained constant for the rest of the experiment. Therefore, any change in O2 consumption resulted directly in a change in coronary venous PO2. Hearts were paced (500 min-1) and developed a left ventricular pressure (LVDP) of 81 ± 18 mmHg at a myocardial perfusion of 16.8 ± 3.4 ml · min-1 · g-1. This resulted in a coronary venous PO2 of 119 ± 44 mmHg, which translates into a MO2 of 10.7 ± 3.1 µmol O2 · min-1 · g-1.

In this model, coronary vasodilatation does not affect coronary flow (which is held constant) but results in a fall in coronary perfusion pressure. This is associated with a decrease in LVDP (the garden-hose phenomenon) and a decline in MO2 that is independent of the mechanism of action of the vasodilator: adenosine-induced maximal vasodilatation (1 µM, n = 17) caused a rapid decrease in LVDP (-34 ± 9%) and an increase in coronary venous PO2 by >30 mmHg due to a decrease in MO2 by 10.1 ± 3.6% (see Fig. 1). Similarly, intracoronary infusion of BK (10 µM, n = 17) caused a drop in coronary perfusion pressure (-49%) that was associated with significant decreases in LVDP (-22%) and MO2 (-6%). Finally, papaverine (10 µM, n = 8) also decreased LVDP and MO2 to a comparable extent (-34 ± 18% and -10.6 ± 4.2%, respectively).



View larger version (24K):
[in this window]
[in a new window]
  		Fig. 1. Lack of effect of bradykinin (BK, 10 µM) on coronary venous PO2 (cvPO2), O2 consumption (MO2), left ventricular developed pressure (LVDP), and coronary perfusion pressure (CPP) in presence of maximal vasodilatation induced by adenosine (1 µM). *P < 0.05, **P < 0.01 vs. basal (ANOVA, least-significant difference); n = 12.

 

To eliminate this confounding factor, all further experiments were conducted in the presence of maximal vasodilatation (1 µM adenosine). As can be seen in Fig. 1, under these conditions, additional application of BK (n = 12) had no further effect on coronary venous PO2 (-6 ± 6 mmHg compared to adenosine) and thus O2 consumption. Neither did BK induce any additional changes in LVDP and coronary perfusion pressure.

To quantify the increase in NO formation induced by BK (10 µM) in our experimental model, coronary venous release was determined. Basal coronary venous concentration was 22.8 ± 12.6 nM (Fig. 2). After correction for the arterial inflow (13 nM), basal myocardial release was calculated to be 192 pmol · min-1 · g-1. BK induced a fivefold increase in release to 960 pmol · min-1 · g-1, which translates into a coronary venous effluent concentration of 66 nM (Fig. 2).



View larger version (12K):
[in this window]
[in a new window]
  		Fig. 2. Nitrite concentrations in the arterial inflow medium and the coronary venous effluent measured in presence of adenosine (1 µM) under basal conditions and during application of BK. BK venous-outflow samples were obtained 2 min after start of BK infusion. **P < 0.01 vs. basal; n = 17.

 

To test whether the basal formation of NO contributed to a tonic inhibition of MO2, NO synthesis was blocked by L-NMMA (100 µM) again in the presence of maximal vasodilatation (1 µM adenosine). Under these conditions, L-NMMA induced small increases in coronary perfusion pressure (46.3 ± 3.6 vs. 44.6 ± 3.3 mmHg) and pressure development (43.8 ± 5.0 vs. 41.5 ± 3.8 mmHg) but had no effect on coronary venous PO2 and thus O2 consumption values, which were 10.97 ± 2.15 µmol · min-1 · g-1 before and 10.74 ± 2.23 µmol·min-1·g-1 after NOS blockade by L-NMMA (n = 6).

To finally obtain insight into the NO concentration necessary to significantly inhibit mitochondrial oxidative phosphorylation and depress cardiac contractile function and MO2, a concentration-response curve for exogenously applied authentic NO was obtained again in the presence of adenosine. As shown in Fig. 3, in the concentration range <2 µM, NO had no effect on either contractile function or MO2 (n = 9). Only at concentrations >2 µM did NO impair contractile function and decrease MO2 in a concentration-dependent manner (n = 6).



View larger version (14K):
[in this window]
[in a new window]
  		Fig. 3. Effect of arterially applied NO on LVDP and MO2 in presence of adenosine (1 µM). *P < 0.05, **P < 0.01 vs. basal (ANOVA, Bonferroni); n = 6–9 for each concentration.

 


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study clearly demonstrates that in the well-oxygenated saline-perfused mouse heart, neither the basal levels of NO nor a fivefold rise in endothelial NO formation induced by BK influence MO2. When modulating NO levels by arterial application of authentic NO, concentrations >2 µM NO were required to induce a decrease in MO2, which is a concentration three orders of magnitude higher than basal release. Thus endogenous endothelial NO formation does not regulate O2 consumption in this model.

This conclusion is at variance with the postulate that endothelium-derived NO tonically controls MO2 (42). This view was initially based on studies demonstrating (e.g., in dog hearts in vivo) an increase in MO2 upon blockade of NOS (39). It was subsequently supported by studies in myocardial tissue pieces (wet weight, 40 mg), in which a reduction in MO2 on BK addition was consistently observed (30, 31, 45). What could be the reason for this discrepancy?

Insufficient stimulation of NO formation by BK in the present study can be excluded: the BK concentration employed was 10-fold higher than the maximally effective vasodilatory concentration in mice (13) and was similar to that used in other studies (30). Moreover, in the present study, the BK-induced increase in release (+400%), which is a commonly used index of cardiac NO formation, by far exceeded that seen in guinea pig hearts (27) or canine coronary microvessels (33), the latter being sufficient to profoundly affect the MO2 of neighboring myocardial tissue pieces (33). Moreover, the basal release of was similar to the and release measured in vivo (5).

An important difference, however, may have been the degree of tissue oxygenation: the saline-perfused mouse heart as established in our laboratory was well oxygenated. This is indicated by a high creatine phosphate concentration and low Pi and adenosine release, as well as its free energy of ATP hydrolysis (-63 kJ/mol; Refs. 12, 15). Its high rate of O2 consumption (10 µmol · min-1 · g-1) is in line with the high murine heart rate (500 min-1 in the present study). Although the coronary venous PO2 in this model was significantly higher than values in vivo, already a moderate decrease in O2 supply results in a substantial decrease in myocardial function and oxygenation (32), which indicates near-physiological conditions. In contrast, when studying O2 consumption in mouse myocardial tissue pieces, values of <0.2 µmol · min-1 · g-1 were reported (30, 33). This was possibly due to insufficient oxygenation at least in the tissue core, which would have rendered the pieces especially vulnerable to an increase in NO, because the inhibitory action of NO at cytochrome c oxidase is competitive with regard to O2 (28).

A BK-induced decrease in O2 consumption due to enhanced eNO formation has not been seen in the heart in vivo to the best of our knowledge. The lack of effect of BK in the present study under well-controlled conditions despite a fivefold increase in endothelial NO formation therefore strongly suggests that endothelial NO does not regulate MO2. One decisive factor for the observed dissociation of endothelial NO formation and mitochondrial oxidative phosphorylation is most likely the presence of high concentrations of the potent NO scavenger myoglobin (13) in cardiac tissue. This is a major player in the spatial confinement of NO formed by different isoforms (3) and constitutes a safeguard to protect mitochondria from endothelial NO. Myoglobin-mediated NO inactivation not only diminishes the bio-activity of endothelium-derived NO in the control of mitochondrial respiration, it is most likely also this degradation pathway that made the application of very high arterial NO concentrations necessary to induce contractile dysfunction and a decline in MO2 in the present and previous studies (10, 26). It cannot be excluded that extracellular degradation of NO, facilitated by the relatively high capillary PO2, results in a small decrease in the effectively applied NO concentration (see Ref. 26). The intracellular myoglobin-mediated NO inactivation may also explain why high levels of myocardial iNOS overexpression increased release but had little effect on contractile function in a recent study (20). In vivo, the intravascular degradation of NO by hemoglobin will even further reduce the myocardial effects of endothelium-derived NO.

In the present study, blockade of myocardial NO formation by L-NMMA did not increase MO2. The concentration of L-NMMA employed (100 µM) increased perfusion pressure (13), decreased the deleterious effects of NO in reperfusion (12), and increased O2 consumption in the guinea pig heart (9) in previous studies of our group, excluding insufficient enzyme inhibition. In fact, much lower concentrations were employed by others in the field (35). The lack of effect of L-NMMA was in line with previous studies in wild-type murine myocytes (24) and tissue pieces (30). Also in humans and pigs, NOS blockade had no effect on MO2 (41). In canine hearts, contradictory effects were reported (5, 8, 39, 40), whereas in guinea pigs, inhibition of NO formation consistently increased MO2 (9). The recent observation that enhanced expression of NOS in mitochondria [from dystrophin-deficient (mdx) mice] reduces cellular O2 consumption (24) may shed some light on these potential species differences. We would like to suggest that the species-dependent level of mitochondrial NO formation governs the relative importance of NO in the control of mitochondrial respiration. In fact, the low activity of NOS in porcine mitochondria recently reported (14) is fully consistent with the lack of effect of NOS inhibition in pigs (11), whereas the functionally active presence of NOS in guinea pig myocardial mitochondria (22) complements our previous observation of enhanced MO2 following NOS blockade in guinea pig hearts (9).

The study of the role of NO in the regulation of MO2 is complicated by the fact that NO may influence energy demand and O2 consumption not only on the level of the respiratory chain. NO modulates substrate uptake in vivo thereby resulting either in decreased glucose uptake and metabolism (36) or reduced fatty acid uptake (37). Although this NO-mediated effect would either increase or decrease O2 consumption, it does not play a role in the present study: glucose and pyruvate were the only substrates provided, and pyruvate will inhibit the mitochondrial metabolism of endogenous fatty acids. NO may modulate myocardial contractile efficiency by unknown mechanisms (21, 40). Furthermore, NO may influence {beta}-adrenergic signal transduction (1, 16, 46; see also 34, 43), the directional effect being dependent on the extent of the adrenergic stimulation. This results in modulation of Ca2+ entry via voltage-gated Ca2+ channels and of Ca2+ release from the sarcoplasmic reticulum. Whether NO exerts a positive or negative inotropic effect in vivo appears to be influenced also by the local NO concentration (29), and the subcellular localization of NOS isoforms will play a significant role in this regard (3). However, the physiological relevance of these effects is still under debate (6, 43). The lack of a functional effect of increasing the endothelial production of NO or blocking NO formation in this study indicates a minor role of these regulatory pathways in the present model. It is thus well suited for studying the control of mitochondrial oxidative phosphorylation by endothelium-derived NO in the intact heart.

In the well-oxygenated saline-perfused murine heart, we found no evidence for the control of cardiac respiration by endothelium-derived NO. In view of the subcellular localization of different NOSs in the myocardium (e.g., see Ref. 3) and the potent inactivation of NO by myoglobin (13), a direct endothelial control of the mitochondrial oxidative phosphorylation of the myocytes appears to be highly unlikely. We propose that the sometimes contradictory effects of NOS inhibition on MO2 reported in the literature do not only reflect a variability of endothelial NO formation but may be also be due to differences in substrate selection and local NO formation, e.g., in the vicinity of sarcoplasmic reticula or caveolae or in mitochondria.


   ACKNOWLEDGMENTS
 
The authors thank T. Rassaf and M. Kelm for providing the NO solutions, G. Grosse and D. Haubs for excellent technical assistance, and A. Gödecke for helpful discussions.

This work was supported by the Deutsche Forschungsgemeinschaft (DFG De 487/4-1) and the Center for Biological and Medical Research (Biomedizinisches Forschungszentrum) of the Heinrich-Heine-University Düsseldorf.


   FOOTNOTES
 

Address for reprint requests and other correspondence: U. Decking, Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, Postfach 10 10 07, 40001 Düsseldorf, Germany (E-mail: decking{at}uni-duesseldorf.de).

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. Section 1734 solely to indicate this fact.

Present address of Z. Z. Kojic: Department of Physiology, School of Medicine, University of Belgrade, Visegradska 26/II, 11000 Belgrade, Serbia.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Abi-Gerges N, Szabo G, Otero AS, Fischmeister R, and Mery PF. NO donors potentiate the {beta}-adrenergic stimulation of ICa,L and the muscarinic activation of IK,ACh in rat cardiac myocytes. J Physiol 540: 411-424, 2002.[Abstract/Free Full Text]
  2. Balligand JL, Kobzik L, Han X, Kaye DM, Belhassen L, O'Hara DS, Kelly RA, Smith TW, and Michel T. Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (type III) nitric oxide synthase in cardiac myocytes. J Biol Chem 270: 14582-14586, 1995.[Abstract/Free Full Text]
  3. Barouch LA, Harrison RW, Skaf MW, Rosas GO, Cappola TP, Kobeissi ZA, Hobai IA, Lemmon CA, Burnett AL, O'Rourke B, Rodriguez ER, Huang PL, Lima JA, Berkowitz DE, and Hare JM. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 416: 337-339, 2002.[Medline]
  4. Bates TE, Loesch A, Burnstock G, and Clark JB. Mitochondrial nitric oxide synthase: a ubiquitous regulator of oxidative phosphorylation? Biochem Biophys Res Commun 218: 40-44, 1996.[ISI][Medline]
  5. Bernstein RD, Ochoa FY, Xu X, Forfia P, Shen W, Thompson CI, and Hintze TH. Function and production of nitric oxide in the coronary circulation of the conscious dog during exercise. Circ Res 79: 840-848, 1996.[Abstract/Free Full Text]
  6. Bers DM. Cardiac excitation-contraction coupling. Nature 415: 198-205, 2002.[Medline]
  7. Brown GC. Nitric oxide regulates mitochondrial respiration and cell functions by inhibiting cytochrome oxidase. FEBS Lett 369: 136-139, 1995.[ISI][Medline]
  8. Crystal GJ and Gurevicius J. Nitric oxide does not modulate myocardial contractility acutely in in situ canine hearts. Am J Physiol Heart Circ Physiol 270: H1568-H1576, 1996.[Abstract/Free Full Text]
  9. Decking UKM, Flesche CW, Gödecke A, and Schrader J. Endotoxin-induced contractile dysfunction in guinea pig hearts is not mediated by nitric oxide. Am J Physiol Heart Circ Physiol 268: H2460-H2465, 1995.[Abstract/Free Full Text]
  10. Decking UKM, Williams JP, Dahmann R, Stumpe T, Kelm M, and Schrader J. The nitric oxide-induced reduction in cardiac energy supply is not due to inhibition of creatine kinase. Cardiovasc Res 51: 313-321, 2001.[Abstract/Free Full Text]
  11. Duncker DJ, Stubenitsky R, Tonino PA, and Verdouw PD. Nitric oxide contributes to the regulation of vasomotor tone but does not modulate O2 consumption in exercising swine. Cardiovasc Res 47: 738-748, 2000.[Abstract/Free Full Text]
  12. Flögel U, Decking UKM, Gödecke A, and Schrader J. Contribution of NO to ischemia-reperfusion injury in the saline-perfused heart: a study in endothelial NO synthase knockout mice. J Mol Cell Cardiol 31: 827-836, 1999.[ISI][Medline]
  13. Flögel U, Merx MW, Gödecke A, Decking UKM, and Schrader J. Myoglobin: a scavenger of bioactive NO. Proc Natl Acad Sci USA 98: 735-740, 2001.[Abstract/Free Full Text]
  14. French S, Giulivi C, and Balaban RS. Nitric oxide synthase in porcine heart mitochondria: evidence for low physiological activity. Am J Physiol Heart Circ Physiol 280: H2863-H2867, 2001.[Abstract/Free Full Text]
  15. Gödecke A, Decking UKM, Ding Z, Hirchenhain J, Bidmon HJ, Gödecke S, and Schrader J. Coronary hemodynamics in endothelial NO synthase knockout mice. Circ Res 82: 186-194, 1998.[Abstract/Free Full Text]
  16. Gödecke A, Heinicke T, Kamkin A, Kiseleva I, Strasser RH, Decking UKM, Stumpe T, Isenberg G, and Schrader J. Inotropic response to {beta}-adrenergic receptor stimulation and anti-adrenergic effects of ACh in endothelial NO synthase-deficient mouse hearts. J Physiol 532: 195-204, 2001.[Abstract/Free Full Text]
  17. Gow AJ, Luchsinger BP, Pawloski JR, Singel DJ, and Stamler JS. The oxyhemoglobin reaction of nitric oxide. Proc Natl Acad Sci USA 96: 9027-9032, 1999.[Abstract/Free Full Text]
  18. Gross WL, Bak MI, Ingwall JS, Arstall MA, Smith TW, and Balligand JL. Nitric oxide inhibits creatine kinase and regulates rat heart contractile reserve. Proc Natl Acad Sci USA 93: 5604-5609, 1996.[Abstract/Free Full Text]
  19. Gustafson LA and Van Beek JHGM. Measurement of the activation time of oxidative phosphorylation in isolated mouse hearts. Am J Physiol Heart Circ Physiol 279: H3118-H3123, 2000.[Abstract/Free Full Text]
  20. Heger J, Gödecke A, Flögel U, Merx MW, Molojavyi A, Kühn-Velten WN, and Schrader J. Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. Circ Res 90: 93-99, 2002.[Abstract/Free Full Text]
  21. Heusch G, Post H, Michel MC, Kelm M, and Schulz R. Endogenous nitric oxide and myocardial adaptation to ischemia. Circ Res 87: 146-152, 2000.[Abstract/Free Full Text]
  22. Hotta Y, Otsuka-Murakami H, Fujita M, Nakagawa J, Yajima M, Liu W, Ishikawa N, Kawai N, Masumizu T, and Kohno M. Protective role of nitric oxide synthase against ischemia-reperfusion injury in guinea pig myocardial mitochondria. Eur J Pharmacol 380: 37-48, 1999.[ISI][Medline]
  23. Kaasik A, Minajeva A, De Sousa E, Ventura-Clapier R, and Veksler V. Nitric oxide inhibits cardiac energy production via inhibition of mitochondrial creatine kinase. FEBS Lett 444: 75-77, 1999.[ISI][Medline]
  24. Kanai AJ, Pearce LL, Clemens PR, Birder LA, VanBibber MM, Choi SY, de Groat WC, and Peterson J. Identification of a neuronal nitric oxide synthase in isolated cardiac mitochondria using electrochemical detection. Proc Natl Acad Sci USA 98: 14126-14131, 2001.[Abstract/Free Full Text]
  25. Kelly RA, Balligand JL, and Smith TW. Nitric oxide and cardiac function. Circ Res 79: 363-380, 1996.[Free Full Text]
  26. Kelm M, Schaefer S, Dahmann R, Dolu B, Perings S, Decking UKM, Schrader J, and Strauer BE. Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation. Cardiovasc Res 36: 185-194, 1997.[ISI][Medline]
  27. Kelm M and Schrader J. Control of coronary vascular tone by nitric oxide. Circ Res 66: 1561-1575, 1990.[Abstract/Free Full Text]
  28. Koivisto A, Matthias A, Bronnikov G, and Nedergaard J. Kinetics of the inhibition of mitochondrial respiration by NO. FEBS Lett 417: 75-80, 1997.[ISI][Medline]
  29. Kojda G and Kottenberg K. Regulation of basal myocardial function by NO. Cardiovasc Res 41: 514-523, 1999.[Free Full Text]
  30. Loke KE, McConnell PI, Tuzman JM, Shesely EG, Smith CJ, Stackpole CJ, Thompson CI, Kaley G, Wolin MS, and Hintze TH. Endogenous endothelial nitric oxide synthase-derived nitric oxide is a physiological regulator of myocardial oxygen consumption. Circ Res 84: 840-845, 1999.[Abstract/Free Full Text]
  31. Loke KE, Messina EJ, Mital S, and Hintze TH. Impaired nitric oxide modulation of myocardial oxygen consumption in genetically cardiomyopathic hamsters. J Mol Cell Cardiol 32: 2299-2306, 2000.[ISI][Medline]
  32. Merx MW, Flögel U, Stumpe T, Gödecke A, Decking UKM, and Schrader J. Myoglobin facilitates oxygen diffusion. FASEB J, published online (10.1096/fj.00–0497fje) Feb. 5, 2001.
  33. Pittis M, Zhang X, Loke KE, Mital S, Kaley G, and Hintze TH. Canine coronary microvessel NO production regulates oxygen consumption in ecNOS knockout mouse heart. J Mol Cell Cardiol 32: 1141-1146, 2000.[ISI][Medline]
  34. Post H, Schulz R, Gres P, and Heusch G. No involvement of nitric oxide in the limitation of {beta}-adrenergic inotropic responsiveness during ischemia. Am J Physiol Heart Circ Physiol 281: H2392-H2397, 2001.[Abstract/Free Full Text]
  35. Prendergast B, Sci BM, Sagach V, and Shah AM. Basal release of nitric oxide augments the Frank-Starling response in the isolated heart. Circulation 96: 1320-1329, 1997.[Abstract/Free Full Text]
  36. Recchia FA, Osorio JC, Chandler MP, Xu X, Panchal AR, Lopaschuk GD, Hintze TH, and Stanley WC. Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs. Am J Physiol Endocrinol Metab 282: E197-E206, 2002.[Abstract/Free Full Text]
  37. Rottman JN, Bracy D, Malabanan C, Yue Z, Clanton J, and Wasserman DH. Contrasting effects of exercise and NOS inhibition on tissue-specific fatty acid and glucose uptake in mice. Am J Physiol Endocrinol Metab 283: E116-E123, 2002.[Abstract/Free Full Text]
  38. Saupe KW, Spindler M, Tian R, and Ingwall JS. Impaired cardiac energetics in mice lacking muscle-specific isoenzymes of creatine kinase. Circ Res 82: 898-907, 1998.[Abstract/Free Full Text]
  39. Shen W, Xu X, Ochoa M, Zhao G, Wolin MS, and Hintze TH. Role of nitric oxide in the regulation of oxygen consumption in conscious dogs. Circ Res 75: 1086-1095, 1994.[Abstract/Free Full Text]
  40. Sherman AJ, Davis CA, Klocke FJ, Harris KR, Srinivasan G, Yaacoub AS, Quinn DA, Ahlin KA, and Jang JJ. Blockade of nitric oxide synthesis reduces myocardial oxygen consumption in vivo. Circulation 95: 1328-1334, 1997.[Abstract/Free Full Text]
  41. Shinke T, Takaoka H, Takeuchi M, Hata K, Kawai H, Okubo H, Kijima Y, Murata T, and Yokoyama M. Nitric oxide spares myocardial oxygen consumption through attenuation of contractile response to {beta}-adrenergic stimulation in patients with idiopathic dilated cardiomyopathy. Circulation 101: 1925-1930, 2000.[Abstract/Free Full Text]
  42. Trochu JN, Bouhour JB, Kaley G, and Hintze TH. Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism: implications in health and disease. Circ Res 87: 1108-1117, 2000.[Abstract/Free Full Text]
  43. Vandecasteele G, Eschenhagen T, Scholz H, Stein B, Verde I, and Fischmeister R. Muscarinic and {beta}-adrenergic regulation of heart rate, force of contraction and calcium current is preserved in mice lacking endothelial nitric oxide synthase. Nat Med 5: 331-334, 1999.[ISI][Medline]
  44. Xie YW, Shen W, Zhao G, Xu X, Wolin MS, and Hintze TH. Role of endothelium-derived nitric oxide in the modulation of canine myocardial mitochondrial respiration in vitro. Circ Res 79: 381-387, 1996.[Abstract/Free Full Text]
  45. Zhao G, Zhang X, Xu X, Wolin MS, and Hintze TH. Depressed modulation of oxygen consumption by endogenous nitric oxide in cardiac muscle from diabetic dogs. Am J Physiol Heart Circ Physiol 279: H520-H527, 2000.[Abstract/Free Full Text]
  46. Ziolo MT, Katoh H, and Bers DM. Positive and negative effects of nitric oxide on Ca2+ sparks: influence of {beta}-adrenergic stimulation. Am J Physiol Heart Circ Physiol 281: H2295-H2303, 2001.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
S. M. Davidson and M. R. Duchen
Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance
Cardiovasc Res, July 1, 2006; 71(1): 10 - 21.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
X. Zhao, G. He, Y.-R. Chen, R. P. Pandian, P. Kuppusamy, and J. L. Zweier
Endothelium-Derived Nitric Oxide Regulates Postischemic Myocardial Oxygenation and Oxygen Consumption by Modulation of Mitochondrial Electron Transport
Circulation, June 7, 2005; 111(22): 2966 - 2972.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
285/1/H392    most recent
00836.2002v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kojic, Z. Z.
Right arrow Articles by Decking, U. K. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kojic, Z. Z.
Right arrow Articles by Decking, U. K. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the American Physiological Society.