© 2000 American Heart Association, Inc.
Integrative Physiology |
Endogenous Nitric Oxide and Myocardial Adaptation to Ischemia
From the Abteilungen für Pathophysiologie (G.H., H.P., R.S.) and für Nieren- und Hochdruckkrankheiten (M.C.M.), Zentrum für Innere Medizin des Universitätsklinikums Essen, and the Abteilung für Kardiologie, Heinrich Heine-Universität Düsseldorf (M.K.), Germany.
Correspondence to Prof Dr Gerd Heusch, FESC, FACC, Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstraße 55, 45122 Essen, Federal Republic of Germany. E-mail gerd.heusch{at}uni-essen.de
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—Ischemic myocardium does not inevitably undergo necrosis but rather can survive through downregulation of contractile function, ie, "hibernate." To study the role of endogenous NO in this adaptation, 41 enflurane-anesthetized swine were subjected to 90 minutes of moderate left anterior descending coronary artery hypoperfusion and assigned to placebo (P), to 30 mg/kg NG-nitro-L-arginine (L-NNA) IV to inhibit NO synthase, or to aortic constriction (AO) to match the increased left ventricular pressure observed with L-NNA. During normoperfusion, a regional myocardial external work index (WI, mm Hg · mm, sonomicrometry and micromanometry) was reduced with L-NNA (from 326±27 [SEM] to 250±19, P<0.05) but increased with AO (from 321±16 to 363±19, P<0.05 versus L-NNA). At 10 minutes of ischemia, WI was lower with L-NNA (109±10, P<0.05) than P (180±22) and AO (170±11) and did not change further at 85 minutes of ischemia. Relationships between WI and transmural myocardial blood flow and oxygen consumption were shifted rightward by L-NNA versus P and AO at both 10 and 85 minutes of ischemia. The maximal increment in calcium-activated external work was not different during normoperfusion among groups but was decreased during ischemia with L-NNA. L-NNA transiently increased myocardial contractile calcium sensitivity along with systemic pressure but reduced it during ongoing ischemia. The free-energy change of ATP hydrolysis after an early ischemic decrease recovered toward baseline values in all groups, and necrosis was absent after 2 (triphenyltetrazolium chloride staining) or 8 (histology) hours of reperfusion. Thus, endogenous NO contributes to hibernation by reducing oxygen consumption and preserving calcium sensitivity and contractile function without an energy cost during ischemia. (Circ Res. 2000;87:146-152.)
Key Words: contractile function • oxygen consumption • ischemia
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Ischemic myocardium does not inevitably undergo necrosis but rather can adapt to reduced blood flow through a regulatory reduction in contractile function.1 2 Therefore, loss of contractile function in patients with coronary artery disease frequently does not indicate infarction but rather a downregulated state of myocardial "hibernation."1 A close relationship between reduced myocardial blood flow and contractile function, ie, perfusion-contraction matching, is a key feature of such hibernation in the experimental setting.3 Further characteristics of myocardial hibernation are recovery of energy metabolism during ongoing ischemia, persistence of an inotropic reserve, recovery of contractile function on reperfusion, and, almost by definition, absence of necrosis.2 No mechanism underlying myocardial hibernation other than reduced calcium responsiveness4 has thus far been identified.
Nitric oxide (NO), among its other beneficial cardiovascular effects,5 is an attractive candidate to be involved in such adaptation to ischemia, and it has been documented to be crucial in the endogenous cardioprotection by delayed preconditioning.6 The activity of the constitutive cardiovascular isoform of NO synthase (NOS III)7 and the production of NO are increased during ischemia.8 The impact of endogenous NO on myocardial function in vivo remains controversial. Inhibition of NO synthesis either has no effect on8 9 or decreases10 regional contractile function during normoperfusion and decreases it during ischemia, potentially by further decreasing ischemic blood flow.8 Apart from its ambiguous effect on regional function, NO rapidly and reversibly inhibits mitochondrial respiration,11 12 and stimulation of NO synthesis decreases oxygen consumption of isolated cardiac and skeletal muscle.13 14 During exercise, myocardial oxygen consumption for a given myocardial work is increased with inhibition of NO synthesis in conscious dogs,15 indicating improvement of the economy of oxygen use for contractile function by endogenous NO. Inhibition of NO synthesis shifts substrate metabolism from fatty acids to glucose and lactate utilization, possibly in compensation for the reduced economy of oxygen use.16
Data on the effects of endogenous NO on the interaction of myocardial contractile function, oxygen consumption, blood flow, and energetics during ischemia on the regional level, ie, the level on which coronary artery disease occurs, are lacking. We therefore investigated the consequences of systemic inhibition of NO synthesis on myocardial adaptation to ongoing ischemia by measuring regional myocardial blood flow, function, and oxygen consumption as well as contractile calcium responsiveness and myocardial energetics.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Experimental Preparation
Forty-one anesthetized Göttinger miniswine were instrumented for the measurement of left ventricular pressure and wall thickness.4 A silicon tube was passed around the descending thoracic aorta to permit its constriction. The left anterior descending coronary artery (LAD) and vein were cannulated, and the artery was perfused by an extracorporeal circuit. Heart rate was held constant by left atrial pacing.
Regional Myocardial Function, Blood Flow, and Metabolism
A regional myocardial external work index was calculated.
Regional myocardial blood flow was measured with microspheres,
and myocardial oxygen and lactate consumptions were
calculated.4 The cardiac respiratory quotient was
determined in 4 pigs each with
NG-nitro-L-arginine
(L-NNA) and aortic constriction.16 The free energy
change of ATP hydrolysis17 and the cGMP concentration were
determined from biopsies.
Morphology
Six transverse myocardial slices from each heart were incubated
in a triphenyl tetrazolium chloride solution. In 4 hearts, each with
L-NNA and aortic constriction, transmural tissue specimens were taken
from the ischemic and the control areas and analyzed by
histology; the area of necrotic foci was planimetered and expressed as
percentage of the analyzed area.18
Experimental Protocols
Group 1 (n=11)
After measurements of systemic hemodynamics and
regional myocardial blood flow, function, and metabolism at
baseline, LAD inflow was decreased by 45% for 90 minutes. Measurements
were repeated at 10 and 85 minutes of ischemia. Thereafter, the
myocardium was reperfused for 2 hours.
Group 2 (n=15)
After baseline measurements, 30 mg/kg IV L-NNA was infused over
30 minutes. During L-NNA infusion, LAD inflow was maintained constant.
After a further set of measurements, the protocol was identical to that
of group 1. In a subset of 4 animals, reperfusion was prolonged to 8
hours. The arterial-coronary venous nitrite
difference was measured with a flow-injection/Griess setup in 4 pigs
each of the L-NNA and aortic constriction groups,19 and
the cumulative arterial-coronary venous nitrite
difference during ischemia was calculated.
Group 3 (n=15)
After baseline measurements, the descending aorta was
constricted to increase peak left ventricular pressure by
20 to 25 mm Hg, and LAD inflow was adjusted to increase mean
coronary arterial pressure proportionately. After a
further set of measurements, the protocol was identical to that in
group 1. In a subset of 4 animals, reperfusion was prolonged to 8
hours.
In 8 swine of each group, calcium chloride was infused into the perfusion system at increasing doses to determine the contractile calcium responsiveness during normoperfusion and at 85 minutes of ischemia.4
Data Analysis and Statistics
Data are reported as mean±SEM. Statistical analysis
comprised 2-way ANOVA for repeated measures and Fisher’s least
significant difference tests when significant overall effects were
detected. Linear regression analyses between the regional
myocardial external work index and transmural blood flow or oxygen
consumption, respectively,20 were compared by ANCOVA. The
EC50 for calcium, ie, the added calcium
concentration for a 50% increase in fractional work, was
calculated.4 Cumulative
arterial-coronary venous difference of nitrite
over 90 minutes of ischemia and cardiac respiratory quotient
with L-NNA or aortic constriction were compared by t tests.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Representative original recordings from 1 animal from each of the 3 groups are shown in Figure 1A
through 1C.
|
Effectiveness of NO Synthase Blockade
L-NNA increased the cardiac respiratory quotient from
0.78±0.04 to 0.86±0.04 (P<0.05), whereas aortic
constriction did not (0.84±0.03 versus 0.83±0.03, P=NS).
Also, L-NNA abolished the bradykinin-induced decrease in mean
coronary resistance (from 5.1±1.0 [SEM] to 1.4±0.2
mm Hg · mL-1
· min-1, n=5).
With aortic constriction, there was a small net nitrite
production before ischemia
(arterial-coronary venous difference, -6±2
pmol/mL); during ischemia, there was increased nitrite
production (cumulative arterial-coronary
venous difference, -1089±478 pmol · 90
min-1 ·
mL-1). With L-NNA, in
contrast, there was net nitrite uptake before ischemia
(arterial-coronary venous difference, 3±1
pmol/mL) and during ischemia (cumulative
arterial-coronary venous difference, 342±284
pmol · 90
min-1 ·
mL-1, P<0.02
versus aortic constriction).
Systemic Hemodynamics
Left ventricular pressure was increased with L-NNA and
aortic constriction during normoperfusion and at 10 minutes of
ischemia, and it was increased at 85 minutes of
ischemia compared with placebo (Table 1).
|
Regional Myocardial Function
During normoperfusion, the regional external work index was
reduced with L-NNA, also at pressure match. At 10 minutes of
ischemia, the regional external work index was again lower with
L-NNA than with placebo or pressure match. With prolongation of
ischemia to 85 minutes, the external work index did not change
further in any group (Table 1
). The maximal increment in
calcium-activated external work was not different during
normoperfusion among groups but was decreased at 85 minutes of
ischemia with L-NNA (Table 2).
With increased left ventricular peak pressure by L-NNA or
aortic constriction, the EC50 for calcium was
decreased. At 85 minutes of ischemia, when the left
ventricular peak pressure increase had subsided, the
EC50 for calcium was increased by L-NNA but
unchanged with placebo and aortic constriction (Table 2).
|
Regional Myocardial Metabolism
Regional myocardial oxygen consumption tended to increase with
aortic constriction but decreased to similar values during
ischemia in all groups (Figure 2). Myocardial lactate consumption was
reversed to net lactate production during early
ischemia but tended to recover, albeit significantly only in
the group with aortic constriction, with no differences among groups.
The free energy change of ATP hydrolysis
(
GATP) was unaffected by L-NNA or
aortic constriction. At 10 minutes of ischemia,
GATP was reduced but recovered to near
baseline values at 85 minutes of ischemia in all groups (Table 1). cGMP did not change throughout the protocol in all groups
(Table 1).
|
Relationships Between Regional Myocardial Function and Oxygen
Consumption or Blood Flow
L-NNA shifted the relationships of regional myocardial external
work versus myocardial oxygen consumption (Figure 2) or
transmural myocardial blood flow (Figure 3) rightward, also at pressure match.
Regressions with data at 85 rather than 10 minutes of ischemia
were no different.
|
Morphology
In none of the experiments was necrosis detected by
triphenyltetrazolium chloride staining.
Microinfarction, as determined by histology, averaged 1.1±1.6%
(anterior myocardium) and 2.2±2.9% (posterior
myocardium) with L-NNA and 0.6±0.4% (anterior
myocardium) and 1.3±1.1% (posterior
myocardium) with aortic constriction.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Endogenous NO increases contractile function at baseline and during moderate ischemia for any given blood flow and myocardial oxygen consumption. Obviously, endogenous NO decreases excess oxygen consumption and preserves contractile calcium sensitivity and, consequently, contractile function at no additional energy cost, thus helping the myocardium to adapt to ischemia and contributing to hibernation.
Critique of Methods
The strengths and limitations of the present model have been
discussed before.4 LAD inflow was held constant, and
constant inflow avoids hypoperfusion in the absence of the tonic
vasodilator influence of endogenous NO. It seems unlikely
that a reduction in regional myocardial function possibly seen with
L-NNA was counteracted in part by increased coronary
arterial pressure, because a Gregg or garden hose
phenomenon is not operative in this preparation.21 The
effects of L-NNA on systemic pressure were matched by a purely
mechanical increase in pressure by aortic constriction and thus
accounted for. The aortic constriction not only served to match left
ventricular afterload, as reflected by left
ventricular peak pressure, but was also associated with a
preload recruitment comparable to that seen with L-NNA, as reflected by
left ventricular end-diastolic pressure and
wall thickness (Table 1). The regional external work index used
in the present study comprises both wall excursion and the load
against which it occurs and is therefore an appropriate mechanical
counterpart to compare with myocardial oxygen consumption and
energetics. Apart from the match in loading conditions, both the L-NNA
and the aortic constriction groups had a greater percent reduction in
blood flow during ischemia; therefore, the most rigorous
comparison with respect to the role of endogenous NO is
done between the L-NNA and the aortic constriction groups.
Because of the 3D geometry of the left ventricle, we may not have detected small changes in loading conditions. However, with voluntary major changes in loading (ie, aortic constriction versus placebo), we found only small shifts in those relationships between function and flow or function and oxygen consumption; therefore, the substantial shift in those relationships with L-NNA versus aortic constriction cannot be attributed to loading.
The dose of L-NNA in the present study decreased nitrite production, increased systemic pressure, and abolished the bradykinin-induced coronary vasodilation and nitrite production; thus, L-NNA obviously reduced the activity of vascular smooth muscle soluble guanylate cyclase. In contrast, cGMP in total myocardial tissue, which reflects mostly cardiomyocytes, was, as previously described,22 not reduced, whereas myocardial oxygen consumption for a given contractile function was increased with L-NNA.
Endogenous NO, Myocardial Function, and Oxygen
Consumption
Systemic inhibition of NO synthesis in
anesthetized23 and conscious24 dogs
decreases cardiac output, and this decrease is more pronounced than
with a pressure match with phenylephrine.23 To
avoid systemic effects and altered loading conditions, other studies
used intracoronary infusion of NO synthesis
inhibitors and measured regional myocardial function;
regional myocardial function was either unchanged8 9 or
decreased.10 In previous studies with regional
ischemia in anesthetized dogs, function was decreased
along with blood flow.8 In contrast, the present study
even demonstrated a decrease in regional contractile function for any
given blood flow during both normoperfusion and ischemia.
In isolated cardiomyocytes, the positive inotropic effect of low exogenous NO concentrations was attributed to cGMP-mediated inhibition of phosphodiesterase, with a subsequently diminished breakdown of cAMP,25 or to direct activation of adenylcyclase.26 An increase in cAMP formation, possibly resulting from adrenergic drive, will increase not only contractile function but also myocardial oxygen consumption.27 Therefore, inhibition of NO synthesis is expected to lower contractile function along with myocardial oxygen consumption when its effect is mediated through reduction of cAMP formation. In the present study, however, L-NNA decreased contractile function independently from a decrease in cGMP and myocardial oxygen consumption.
In isolated rat cardiac and skeletal muscle mitochondria, low levels of exogenous NO reversibly inhibit mitochondrial respiration, in part by inhibition of cytochrome c oxidase.11 12 Consistent with this observation, the acetylcholine- and bradykinin-induced NO release also decreases oxygen consumption in isolated canine left ventricular13 and skeletal muscle,14 in left ventricular muscle of nonhuman primates,28 and in failing human hearts.29 Although the above studies agree on reduced oxygen consumption, they did not simultaneously measure contractile function and myocardial energetics. In the present study, myocardial lactate consumption and the free energy change of ATP hydrolysis were not altered by L-NNA either during normoperfusion or during ischemia. Confirming previous observations by Recchia et al,16 there was even a compensatory shift in substrate use from free fatty acids to glucose and lactate with inhibition of NO synthase by L-NNA, as indicated by the increase in the cardiac respiratory quotient. The reduction of myocardial oxygen consumption for any given contractile function by endogenous NO might therefore be even greater if it occurred with the same preferential glycolytic substrate use.
Apparently, endogenous NO reduces excess myocardial oxygen
consumption such that myocardial energetics and contractile function
are not reduced along with reduced myocardial oxygen consumption. Apart
from its effect on mitochondrial respiration, endogenous NO
appears to preserve the calcium sensitivity of the contractile
machinery during ischemia (Table 2). An initial
transient improvement in calcium sensitivity was seen with L-NNA and
pressure match and is probably related to increased
cardiomyocyte stretch30 31 ; this
stretch-related effect subsided along with the increase in pressure
during ongoing ischemia, and at 85 minutes of ischemia,
the reduction in calcium responsiveness with L-NNA becomes fully
apparent, whereas calcium responsiveness with aortic constriction is
not altered. Pharmacological calcium sensitization improves contractile
function without increasing myocardial oxygen
consumption,32 33 and therefore, the preservation of
calcium sensitivity by endogenous NO together with the
reduction of excess myocardial oxygen consumption might well explain
the improved economy of oxygen use for contractile function during
ongoing ischemia.
Endogenous NO and Myocardial Hibernation
The concept of hibernation implies a downregulation of contractile
function as an adaptation to a reduction in myocardial blood flow that
serves to permit recovery of myocardial energetics and to maintain
myocardial integrity and viability during persistent
ischemia.1 2 From the present study, it
appears that endogenous NO is not involved in the immediate
downregulation of baseline contractile function and the recovery of
myocardial energetics during ischemia, because both
perfusion-contraction matching and the recovery of the free energy
change of ATP hydrolysis also occurred with inhibition of NO synthesis
by L-NNA. At any given blood flow and oxygen consumption, however,
contractile function was lower without than with endogenous
NO. The parallel rightward shift of both the external work–blood flow
and external work–oxygen consumption relationships with L-NNA
indicates that the differences between L-NNA and aortic pressure match
at baseline are also maintained during ischemia, suggesting
that the role of NO during ischemia, even at increased
concentration, is the same as that at baseline. Thus,
endogenous NO does not appear to mediate the downregulation
of baseline contractile function during ischemia but rather to
contribute to successful myocardial adaptation to ischemia by
reducing oxygen consumption and maintaining contractile function as
high as possible without any additional energy costs, probably through
preservation of contractile calcium sensitivity.
In conclusion, we have shown, to the best of our knowledge for the first time, that (1) endogenous NO reduces myocardial oxygen consumption and thus improves regional myocardial function for any given level of myocardial blood flow, oxygen consumption, and energetics; (2) endogenous NO preserves contractile calcium sensitivity during myocardial ischemia; and (3) endogenous NO contributes to hibernation, ie, adaptation to myocardial ischemia, by preserving regional contractile function without any effect on myocardial energetics.
|
Acknowledgments |
|---|
This study was supported by the German Research Foundation (He 1320/8-3) and the IFORES program of the University of Essen Medical School.
Received May 8, 2000; accepted May 23, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Rahimtoola SH. A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation. 1985;72(suppl V):V123–V135.
2.
Heusch G. Hibernating myocardium.
Physiol Rev. 1998;78:1055–1085.
3.
Ross J Jr. Myocardial perfusion-contraction matching:
implications for coronary heart disease and hibernation.
Circulation. 1991;83:1076–1083.
4.
Heusch G, Rose J, Skyschally A, Post H, Schulz R.
Calcium responsiveness in regional myocardial short-term hibernation
and stunning in the in situ porcine heart: inotropic responses to
postextrasystolic potentiation and
intracoronary calcium. Circulation. 1996;93:1556–1566.
5.
Moncada S, Higgs A. The L-arginine-nitric
oxide pathway. N Engl J Med. 1993;329:2002–2012.
6. Bolli R, Dawn B, Tang X-L, Qiu Y, Ping P, Xuan Y-T, Jones WK, Takano H, Guo Y, Zhang J. The nitric oxide hypothesis of late preconditioning. Basic Res Cardiol. 1998;93:325–338.[Medline] [Order article via Infotrieve]
7. Depre C, Fierain L, Hue L. Activation of nitric oxide synthase by ischaemia in the perfused heart. Cardiovasc Res. 1997;33:82–87.[Medline] [Order article via Infotrieve]
8. Kitakaze M, Node K, Minamino T, Kosaka H, Shinozaki Y, Mori H, Inoue M, Hori M, Kamada T. Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs. J Am Coll Cardiol. 1996;27:1804–1812.[Abstract]
9.
Crystal GJ, Gurevicius J. Nitric oxide does not
modulate myocardial contractility acutely in in situ
canine hearts. Am J Physiol. 1996;270:H1568–H1576.
10.
Sherman AJ, Davis CA III, Klocke FJ, Harris KR,
Srinivasan G, Yaacoub AS, Quinn DA, Ahlin KA, Jang JJ. Blockade of
nitric oxide synthesis reduces myocardial oxygen consumption in vivo.
Circulation. 1997;95:1328–1334.
11. Borutaité V, Brown GC. Rapid reduction of nitric oxide by mitochondria, and reversible inhibition of mitochondrial respiration by nitric oxide. Biochem J. 1996;315:259–299.
12. Cleeter MWJ, Cooper JM, Darley-Usmar VM, Moncada S. 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]
13.
Xie Y-W, Shen W, Zhao G, Xu X, Wolin MS, Hintze TH.
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. 1996;79:381–387.
14.
Shen W, Hintze TH, Wolin MS. Nitric oxide: an important
signaling mechanism between vascular endothelium and
parenchymal cells in the regulation of oxygen consumption.
Circulation. 1995;92:3505–3512.
15.
Bernstein RD, Ochoa FY, Xu X, Forfia P, Shen W,
Thompson CI, Hintze TH. Function and production of nitric oxide
in the coronary circulation of the conscious dog during
exercise. Circ Res. 1996;79:840–848.
16.
Recchia FA, McConnell PI, Loke KE, Xu X, Ochoa M,
Hintze TH. Nitric oxide controls cardiac substrate utilization in the
conscious dog. Cardiovasc Res. 1999;44:325–332.
17.
Martin C, Schulz R, Rose J, Heusch G. Inorganic
phosphate content and free energy change of ATP hydrolysis in regional
short-term hibernating myocardium. Cardiovasc
Res. 1998;39:318–326.
18. Neumann T, Konietzka I, van de Sand A, Aker S, Schulz R, Heusch G. Identification of necrotic tissue by phase-contrast microscopy at an early stage of acute myocardial infarction. Lab Invest. 2000;80:981–982.[Medline] [Order article via Infotrieve]
19. Schulz R, Kerber S, Kelm M. Reevaluation of the Griess method for determining NO/NO2- in aqueous and protein-containing samples. Nitric Oxide. 1999;3:225–234.[Medline] [Order article via Infotrieve]
20.
Gallagher KP, Kumada T, Koziol JA, McKown MD, Kemper
WS, Ross J Jr. Significance of regional wall thickening abnormalities
relative to transmural myocardial perfusion in anesthetized
dogs. Circulation. 1980;62:1266–1274.
21.
Schulz R, Guth BD, Heusch G. No effect of
coronary perfusion on regional myocardial function within the
autoregulatory range in pigs: evidence against the Gregg phenomenon.
Circulation. 1991;83:1390–1403.
22. Csont T, Pali T, Szilvassy Z, Ferdinandy P. Lack of correlation between myocardial nitric oxide and cyclic guanosine monophosphate content in both nitrate-tolerant and -nontolerant rats. Biochem Pharmacol. 1998;56:1139–1144.[Medline] [Order article via Infotrieve]
23. Klabunde RE, Ritger RC, Helgren MC. Cardiovascular actions of inhibitors of endothelium-derived relaxing factor (nitric oxide) formation/release in anesthetized dogs. Eur J Pharmacol. 1991;199:51–59.[Medline] [Order article via Infotrieve]
24.
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.
25.
Kojda G, Kottenberg K, Nix P, Schlüter KD, Piper
HM, Noack E. Low increase in cPGM induced by organic nitrates and
nitrovasodilators improves contractile response of rat
ventricular myocytes. Circ Res. 1996;78:91–101.
26.
Vila-Petroff M, Younes A, Egan J, Lakatta EG, Sollott
SJ. Activation of distinct cAMP-dependent and cGMP-dependent pathways
by nitric oxide in cardiac myocytes. Circ Res. 1999;84:1020–1031.
27. Scholz PM, Chiu WC, Kedem J, Weiss HR. Relationship between cyclic-AMP content, regional myocardial function and O2 consumption in experimental left ventricular hypertrophy: effect of negative inotropes. Life Sci. 1993;53:1847–1858.[Medline] [Order article via Infotrieve]
28. Forfia PR, Zhang X, Knight DR, Smith AH, Doe CPA, Wolfgang EA, Flynn DM, Wolin MS, Hintze TH. NO modulates myocardial O2 consumption in the nonhuman primate: an additional mechanism of action of amlodipine. Am J Physiol. 1999;45:H2069–H2075.
29.
Loke KE, Laycock SK, Mital S, Wolin MS, Bernstein R, Oz
M, Addonizio L, Kaley G, Hintze TH. Nitric oxide modulates
mitochondrial respiration in failing human heart.
Circulation. 1999;100:1291–1297.
30.
Alvarez BV, Pérez NG, Ennis IL, de Hurtado CMC,
Cíngolani HE. Mechanisms underlying the increase in force and
Ca2+ transient that follow stretch of cardiac
muscle: a possible explanation of the anrep effect. Circ
Res. 1999;85:716–722.
31. Calaghan SC, White E. The role of calcium in the response of cardiac muscle to stretch. Prog Biophys Mol Biol. 1999;71:59–90.[Medline] [Order article via Infotrieve]
32.
Soei L, Sassen LMA, Fan DS, van Veen T, Krams R,
Verdouw PD. Myofibrillar Ca2+ sensitization
predominantly enhances function and mechanical efficiency of stunned
myocardium. Circulation. 1994;90:959–969.
33.
Senzaki H, Isoda T, Paolocci N, Ekelund U, Hare JM,
Kass DA. Improved mechanoenergetics and cardiac rest and reserve
function of in vivo failing heart by calcium sensitizer EMD-57033.
Circulation. 2000;101:1040–1048.
This article has been cited by other articles:
 |
|
 |
|
  Q. Hu, G. Suzuki, R. F. Young, B. J. Page, J. A. Fallavollita, and J. M. Canty Jr. Reductions in mitochondrial O2 consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H223 - H232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Balligand, O. Feron, and C. Dessy eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues Physiol Rev, April 1, 2009; 89(2): 481 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. R. Heinzel, P. Gres, K. Boengler, A. Duschin, I. Konietzka, T. Rassaf, J. Snedovskaya, S. Meyer, A. Skyschally, M. Kelm, et al. Inducible Nitric Oxide Synthase Expression and Cardiomyocyte Dysfunction During Sustained Moderate Ischemia in Pigs Circ. Res., November 7, 2008; 103(10): 1120 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Heusch, K. Boengler, and R. Schulz Cardioprotection: Nitric Oxide, Protein Kinases, and Mitochondria Circulation, November 4, 2008; 118(19): 1915 - 1919. [Full Text] [PDF]
|
|
|
|
 |
|
 M.-G. Ryou, J. Sun, K. N. Oguayo, E. B. Manukhina, H. F. Downey, and R. T. Mallet Hypoxic Conditioning Suppresses Nitric Oxide Production upon Myocardial Reperfusion Experimental Biology and Medicine, June 1, 2008; 233(6): 766 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Gonon, U. Widegren, A. Bulhak, F. Salehzadeh, J. Persson, P.-O. Sjoquist, and J. Pernow Adiponectin protects against myocardial ischaemia-reperfusion injury via AMP-activated protein kinase, Akt, and nitric oxide Cardiovasc Res, April 1, 2008; 78(1): 116 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.W. Merx and C. Weber Sepsis and the Heart Circulation, August 14, 2007; 116(7): 793 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Martin, R. Schulz, H. Post, K. Boengler, M. Kelm, P. Kleinbongard, P. Gres, A. Skyschally, I. Konietzka, and G. Heusch Microdialysis-based analysis of interstitial NO in situ: NO synthase-independent NO formation during myocardial ischemia Cardiovasc Res, April 1, 2007; 74(1): 46 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Rassaf, L. W. Poll, P. Brouzos, T. Lauer, M. Totzeck, P. Kleinbongard, P. Gharini, K. Andersen, R. Schulz, G. Heusch, et al. Positive effects of nitric oxide on left ventricular function in humans Eur. Heart J., July 2, 2006; 27(14): 1699 - 1705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
H. Post and B. Pieske Arginase: a modulator of myocardial function Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1747 - H1748. [Full Text] [PDF]
|
|
|
|
|
|
E. B. Manukhina, H. F. Downey, and R. T. Mallet Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia. Experimental Biology and Medicine, April 1, 2006; 231(4): 343 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zong, J. D. Tune, and H. F. Downey Mechanisms of Oxygen Demand/Supply Balance in the Right Ventricle Experimental Biology and Medicine, September 1, 2005; 230(8): 507 - 519. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Suzuki, T.-C. Lee, J. A. Fallavollita, and J. M. Canty Jr Adenoviral Gene Transfer of FGF-5 to Hibernating Myocardium Improves Function and Stimulates Myocytes to Hypertrophy and Reenter the Cell Cycle Circ. Res., April 15, 2005; 96(7): 767 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch, R. Schulz, and S. H. Rahimtoola Myocardial hibernation: a delicate balance Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H984 - H999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Martinez, S. Setty, P. Zong, J. D. Tune, and H. F. Downey Nitric oxide contributes to right coronary vasodilation during systemic hypoxia Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1139 - H1146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Westerhof Nitric oxide and efficiency of the right heart Cardiovasc Res, December 1, 2004; 64(3): 379 - 380. [Full Text] [PDF]
|
|
|
|
|
|
S. Setty, J. D. Tune, and H. F. Downey Nitric oxide contributes to oxygen demand-supply balance in hypoperfused right ventricle Cardiovasc Res, December 1, 2004; 64(3): 431 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Nordhaug, T. Steensrud, E. Aghajani, C. Korvald, and T. Myrmel Nitric oxide synthase inhibition impairs myocardial efficiency and ventriculo-arterial matching in acute ischemic heart failure Eur J Heart Fail, October 1, 2004; 6(6): 705 - 713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kupatt, C. Dessy, R. Hinkel, P. Raake, G. Daneau, C. Bouzin, P. Boekstegers, and O. Feron Heat Shock Protein 90 Transfection Reduces Ischemia-Reperfusion-Induced Myocardial Dysfunction via Reciprocal Endothelial NO Synthase Serine 1177 Phosphorylation and Threonine 495 Dephosphorylation Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1435 - 1441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schulz, M. Kelm, and G. Heusch Nitric oxide in myocardial ischemia/reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 402 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A Gorog, M. Tanno, X. Cao, M. Bellahcene, R. Bassi, A. M.N Kabir, K. Dighe, R. A Quinlan, and M. S Marber Inhibition of p38 MAPK activity fails to attenuate contractile dysfunction in a mouse model of low-flow ischemia Cardiovasc Res, January 1, 2004; 61(1): 123 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Post, C. d'Agostino, V. Lionetti, M. Castellari, E. Y Kang, M. Altarejos, X. Xu, T. H Hintze, and F. A Recchia Reduced Left Ventricular Compliance and Mechanical Efficiency after Prolonged Inhibition of NO Synthesis in Conscious Dogs J. Physiol., October 1, 2003; 552(1): 233 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Z. Kojic, U. Flogel, J. Schrader, and U. K. M. Decking Endothelial NO formation does not control myocardial O2 consumption in mouse heart Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H392 - H397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Martin, R. Schulz, H. Post, P. Gres, and G. Heusch Effect of NO synthase inhibition on myocardial metabolism during moderate ischemia Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2320 - H2324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Wright, J. J. Higgin, R. T. Raines, C. Steenbergen, and E. Murphy Activation of the Prolyl Hydroxylase Oxygen-sensor Results in Induction of GLUT1, Heme Oxygenase-1, and Nitric-oxide Synthase Proteins and Confers Protection from Metabolic Inhibition to Cardiomyocytes J. Biol. Chem., May 23, 2003; 278(22): 20235 - 20239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J M Cotton, M T Kearney, and A M Shah Nitric oxide and myocardial function in heart failure: friend or foe? Heart, December 1, 2002; 88(6): 564 - 566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch and R. Schulz Hibernating Myocardium: New Answers, Still More Questions! Circ. Res., November 15, 2002; 91(10): 863 - 865. [Full Text] [PDF]
|
|
|
|
|
|
H. Degenhardt, J. Jansen, R. Schulz, D. Sedding, R. Braun-Dullaeus, and K.-D. Schluter Mechanosensitive release of parathyroid hormone-related peptide from coronary endothelial cells Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1489 - H1496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Rassaf, P. Kleinbongard, M. Preik, A. Dejam, P. Gharini, T. Lauer, J. Erckenbrecht, A. Duschin, R. Schulz, G. Heusch, et al. Plasma Nitrosothiols Contribute to the Systemic Vasodilator Effects of Intravenously Applied NO: Experimental and Clinical Study on the Fate of NO in Human Blood Circ. Res., September 20, 2002; 91(6): 470 - 477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Gres, R. Schulz, J. Jansen, C. Umschlag, and G. Heusch Involvement of endogenous prostaglandins in ischemic preconditioning in pigs Cardiovasc Res, August 15, 2002; 55(3): 626 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Thielmann, H. Dorge, C. Martin, S. Belosjorow, U. Schwanke, A. van de Sand, I. Konietzka, A. Buchert, A. Kruger, R. Schulz, et al. Myocardial Dysfunction With Coronary Microembolization: Signal Transduction Through a Sequence of Nitric Oxide, Tumor Necrosis Factor-{alpha}, and Sphingosine Circ. Res., April 19, 2002; 90(7): 807 - 813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Sawyer and J. Loscalzo Myocardial Hibernation: Restorative or Preterminal Sleep? Circulation, April 2, 2002; 105(13): 1517 - 1519. [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. Post, R. Schulz, P. Gres, and G. Heusch No involvement of nitric oxide in the limitation of beta -adrenergic inotropic responsiveness during ischemia Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2392 - H2397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch Nitroglycerin and Delayed Preconditioning in Humans : Yet Another New Mechanism for an Old Drug? Circulation, June 19, 2001; 103(24): 2876 - 2878. [Full Text] [PDF]
|
|
|
|
|
|
R. Schulz, H. Post, T. Neumann, P. Gres, H. Luss, and G. Heusch Progressive loss of perfusion-contraction matching during sustained moderate ischemia in pigs Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H1945 - H1953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schulz, P. Gres, and G. Heusch Role of endogenous opioids in ischemic preconditioning but not in short-term hibernation in pigs Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2175 - H2181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R Schulz and G Heusch Hibernating myocardium Heart, December 1, 2000; 84(6): 587 - 594. [Full Text]
|
|
|
|
|
|
J. M. Canty Jr. Nitric Oxide and Short-Term Hibernation : Friend or Foe? Circ. Res., July 21, 2000; 87(2): 85 - 87. [Full Text] [PDF]
|
|
|
|
|
|
M. Thielmann, H. Dorge, C. Martin, S. Belosjorow, U. Schwanke, A. van de Sand, I. Konietzka, A. Buchert, A. Kruger, R. Schulz, et al. Myocardial Dysfunction With Coronary Microembolization: Signal Transduction Through a Sequence of Nitric Oxide, Tumor Necrosis Factor-{alpha}, and Sphingosine Circ. Res., April 19, 2002; 90(7): 807 - 813. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||