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Institut National de la Santé et de la Recherche Médicale E9920, Rouen University Medical School, 76183 Rouen, Cedex, France
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were designed to test whether nitric oxide (NO) and peroxynitrite trigger delayed coronary endothelial protection induced by preconditioning (PC) in rats. Prolonged ischemia reperfusion markedly reduced the response of isolated coronary arteries to acetylcholine, and this was prevented by PC performed 24 h earlier. The NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) administered during PC abolished its delayed endothelial protective effect, whereas the inducible NOS inhibitor N-(3(aminomethyl)benzyl)acetaminide had no effect. Delayed endothelial PC was also abolished by the peroxynitrite scavengers selenomethionine or uric acid given during PC. In parallel, the NO/peroxynitrite donor S-morpholinosydnonimine and authentic peroxynitrite, administered 24 h before prolonged ischemia-reperfusion mimicked endothelial PC, whereas the NO donor S-nitroso-N-acetylpencillamine had no effect. This suggests that peroxynitrite is an essential trigger of the delayed coronary endothelial protection induced by PC in rat hearts.
delayed preconditioning; nitric oxide; free radicals
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THE ENDOTHELIUM, together with other organs, has the capacity to develop a delayed self-adaptation to ischemia-reperfusion injury. This phenomenon, termed delayed ischemic preconditioning (PC), has been characterized at the level of the coronary circulation by a prevention of the impaired endothelium-dependent relaxations induced by reperfusion after prolonged cardiac ischemia (11, 13). Given the well-known role of endothelial cells in the regulation of vascular tone, but also of platelet and leukocyte function, it is likely that such an endothelial protection may have many important consequences, for example, in terms of prevention of vasospasm, thrombosis, or atherosclerosis. However, at present, the exact triggers of this endothelial effect are still partly unknown. In previous experiments, we found that free radicals are necessary to initiate this endothelial protection (10). Moreover, strong evidence suggests that nitric oxide (NO) is also involved as a trigger of delayed PC at the level of cardiac myocytes (20, 25), although it is not known whether a similar role of NO exists for endothelial cells.
One possible explanation for the fact that both NO and free radicals
may be required to induce PC is that these two species react to form
other intermediates that act as triggers of the delayed protection.
Among those intermediates, peroxynitrite (ONOO
), produced
by the reaction between NO and superoxide anions (2), is
likely to be one of the species involved. In the context of PC, we can
hypothesize that the short episodes of ischemia-reperfusion (I/R) generate low levels of free radicals and subsequently low concentrations of peroxynitrite, which may act as triggers of delayed PC.
Thus we designed experiments to assess in rats the possible role of NO and peroxynitrite as triggers of the delayed coronary endothelial protection induced by ischemic PC. Specifically, we tested 1) whether inhibitors of NO synthases (NOS) or scavengers of peroxynitrite given before PC affect its delayed endothelial protective effects; 2) whether the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and S-morpholinosydnonimine (SIN-1) mimic delayed PC, taking into account that SIN-1, unlike SNAP, generates peroxynitrite in addition to NO (5, 7, 23, 24); and 3) whether peroxynitrite administration induces delayed endothelial protection in the absence of PC.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental preparation.
Male Wistar rats weighing between 350 and 400 g were assigned to
20 experimental groups (Fig. 1).
Experimentations were conducted in conformity with the "Guiding
Principles for Research Involving Animals."
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Role of NO. The role of NO as a trigger of delayed PC was assessed by administering the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg iv), 10 min before PC or sham surgery, on day 1 (groups 2, 7, and 16). The role of the inducible form of NOS (INOS) was assessed using the selective iNOS inhibitor N-(3(aminomethyl)benzyl)acetaminide (1400W) at the dose of 1 mg/kg iv 10 min before PC (group 17). This dose was previously shown to markedly inhibit iNOS-mediated responses to LPS in rats (13).
The capacity of NO to induce delayed endothelial protection in the absence of PC was tested by administering the NO donor SNAP or the NO-superoxide anions (O
1 · min1 iv;
2) a longer duration of perfusion (75 min; SNAP2) at the same dose, corresponding to the protocol used for myocyte protection (25); and 3) a higher dose of SNAP (10 µg · kg1 · min1 iv) also
perfused for 75 min (SNAP3).
Role of peroxynitrite.
The role of peroxynitrite as a trigger of delayed PC was assessed by
using the scavengers selenomethionine, which scavenges peroxynitrite
without reacting with NO, O
In vitro vascular studies.
Coronary endothelial function was assessed as described previously
(10, 11, 13, 21, 22). Briefly, at the end of the prolonged
reperfusion on day 2, the heart was removed and immediately
placed in cold oxygenated Krebs buffer. The left (ischemic) coronary artery was carefully dissected free, and a 1.5- to 2-mm long
segment was taken distal to the site of occlusion and mounted in a
small vessel wire myograph for isometric tension recording (JP Trading;
Aarhus, Denmark). After mounting was completed, the vessels were
allowed to equilibrate for 30 min and were then progressively stretched
and set to a normalized internal diameter, as described previously
(17). Segments with an internal diameter lower than 170 µm were excluded to avoid mechanical endothelial injury and then
unspecific dysfunction. Concentration-response curves to acetylcholine
(108 to 3.105 M) were performed in
serotonin-precontracted segments (105 M). The changes in
the relaxing responses to acetylcholine (which appear entirely mediated
by NO in this preparation) were used as a marker of endothelial
dysfunction (after I/R) or endothelial protection (after PC). Changes
in the responses to acetylcholine appear to reflect the extent of
structural injury to endothelial cells in this model (10)
Materials. Drugs were obtained from Sigma-Aldrich (France), except SIN-1 (a gift from Aventis; Paris, France), and 1400W and peroxynitrite (Alexis).
Statistical analysis. All results are expressed as means ± SE. The differences between groups were examined by ANOVA followed by a Bonferroni test. A P value <0.05 was statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of I/R and PC on coronary endothelium-dependent relaxations
to acetylcholine.
Compared with sham animals, the response to acetylcholine was markedly
reduced after I/R (Fig. 2). However, this
impairment was prevented by PC performed 24 h before (maximal
relaxation: sham, 70 ± 5%; I/R, 41 ± 5%; PC, 67 ± 6%; P < 0.05).
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Effects of NOS inhibitors on coronary endothelial protection by
delayed PC.
Figure 3 shows that the NOS inhibitor
L-NAME given before PC completely abolished its endothelial
protective effects (maximal relaxation: PC, 67 ± 6%;
L-NAME/PC, 31 ± 7%; P < 0.01; Fig.
3C). However, L-NAME did not affect the
responses in the absence of PC, either in sham-operated rats (sham,
70 ± 5%; L-NAME/sham, 67 ± 5%; Fig.
3A) or rats subjected to prolonged I/R (I/R, 41 ± 5%;
L-NAME-I/R, 41 ± 8%; Fig. 3B). In
contrast to L-NAME, the selective iNOS inhibitor 1400W
administered before PC had no effect (PC, 67 ± 6%; 1400W/PC,
65 ± 5%, Fig. 3D).
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Effects of NO donors on reperfusion-induced coronary endothelial
dysfunction.
Figure 4 shows that the administration of
the NO-peroxynitrite donor SIN-1 24 h before prolonged I/R
protected coronary endothelial function to an extent similar to that of
PC (maximal relaxation: I/R, 41 ± 5%; SIN-1-I/R, 64 ± 1%;
P < 0.05; Fig.4D), without any significant
effect in sham-operated animals (sham, 70 ± 5%; SIN-1/sham, 83 ± 4%; Fig. 4B). In contrast, the NO donor SNAP
also administered 24 h before prolonged I/R had no effect on the
endothelial dysfunction, whatever the experimental conditions used
(untreated, 41 ± 5%; SNAP1, 39 ± 8%; SNAP2, 40 ± 8%; SNAP3, 38 ± 4%; Fig. 4C). Finally, SIN-1 and
SNAP3 induced similar decreases in arterial blood pressure, when
assessed at the end of administration (data not shown).
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Effects of peroxynitrite scavengers on coronary endothelial
protection by delayed PC.
Figure 5 shows that the selective
peroxynitrite scavenger seleno-L-methionine given before PC
completely abolished its delayed coronary endothelial protective effect
(maximal relaxation: PC, 67 ± 6%;
seleno-L-methionine/PC, 41 ± 8%; P < 0.05; Fig. 5C), whereas it did not affect the responses
in the absence of PC, either in sham-operated rats (sham, 70 ± 5%, seleno-L-methionine/sham, 65 ± 1%; Fig.
5A) or rats subjected to prolonged I/R (I/R, 41 ± 5%;
seleno-L-methionine-I/R, 40 ± 5%; Fig.
5B). In contrast, methionine had no effect (PC, 67 ± 6%; methionine/PC, 64 ± 7%; Fig. 5C). In parallel,
uric acid also abolished the protective effect of delayed PC to an
extent similar to that of seleno-L-methionine (PC, 67 ± 6%; uric acid/PC, 35 ± 2%; P < 0.01; Fig.
5D).
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Effects of peroxynitrite on reperfusion-induced coronary
endothelial dysfunction.
Figure 6 shows that the administration of
authentic peroxynitrite 24 h before prolonged I/R protected
coronary endothelial function to an extent similar to that of PC
(maximal relaxation: I/R, 41 ± 5%; peroxynitrite-I/R, 70 ± 7%; P < 0.05; Fig. 6A). This effect was
only attributable to peroxynitrite and not to its solvent KOH, because
endothelial dysfunction observed after I/R was not reversed by KOH
administration 24 h before (I/R, 41 ± 5%; KOH-I/R, 39 ± 6%; Fig. 6B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of this study show that 1) the endothelial protective effect of delayed PC was abolished by the NOS inhibitor L-NAME and by the peroxynitrite scavengers seleno-L-methionine and uric acid; 2) the delayed endothelial protection by PC was mimicked by SIN-1, a mixed NO-peroxynitrite donor, and by authentic peroxynitrite, but not by the pure NO donor SNAP. Taken together, these data demonstrate for the first time that peroxynitrite triggers potent endothelial-adaptive mechanisms resulting in a delayed resistance of these cells against I/R injury and may be an important trigger of ischemic PC.
Involvement of NO in delayed endothelial PC. Previous studies have demonstrated that NO triggers delayed myocardial protection induced by PC (3, 20). The present study shows that NO is also involved in the endothelial effects of PC. Moreover, the nonselective NOS inhibitor, but not the selective iNOS inhibitor, abolished the protection, suggesting that NO acts as a trigger through its production by constitutive NOS (presumably endothelial NOS, eNOS). In rabbits, an increase in calcium-dependent NOS activity (assessed by the measurement of the arginine-citrulline conversion) is observed immediately after the brief episodes of I/R (27). Although this has not been fully tested, this rapid activation of eNOS may be due to the transient increase of shear stress occurring during reperfusion (secondary to reactive hyperemia).
To further assess the possibility that NO triggers delayed endothelial protection, we tried to mimic PC by administering the NO donor SNAP 24 h before prolonged I/R. Initially, we administered SNAP at the dose of 2.5 µg · kg1 · min1,
previously shown to induce myocardial protection (25), and chose to perfuse SNAP for 22 min, which corresponded to the duration of
PC. Because we found that this protocol failed to induce endothelial protection and to rule out that this could be due to a too short duration of perfusion, we repeated the experiments by using the same
dose but a longer duration of perfusion (75 min), which corresponded to
the one shown to induce myocardial protection (25). Again, this protocol failed to induced delayed endothelial protective effects.
Thus finally, to rule out that this was due to a too low dose of SNAP,
we repeated the same protocol with a higher dose of SNAP (10 µg · kg1 · min1 iv).
Thus, SNAP, even when administered at a dose four times higher than
that previously shown to trigger delayed myocyte protection, failed to
induce endothelial protective effects. Moreover, the capacity of SNAP
to release NO in this context was supported by the fact that it
significantly reduced blood pressure. Thus, although we cannot fully
exclude this hypothesis, it is unlikely that this lack of endothelial
effect was due to an insufficient dose of NO donor.
In contrast to the lack of effect of the "pure" NO donor SNAP, we
found that the mixed NO-superoxide donor SIN-1 prevented coronary
endothelial dysfunction induced by prolonged I/R. These results suggest
that NO alone (administered in the absence of I/R, i.e., in the absence
of elevated levels of superoxide anions) is not sufficient to induce a
delayed endothelial protection and that both NO and free radicals are
necessary. This is also supported by our previous experiments, which
showed that administration of free radical scavengers during PC fully
prevented its delayed coronary endothelial protective effects
(11).
Involvement of peroxynitrite in delayed endothelial PC. The fact that both NO (current study) and free radicals (11) are necessary to trigger delayed endothelial PC, together with the fact that the mixed NO-superoxide donor SIN-1 mimics its protective effects, suggest that these two radical species react to form intermediates that act as triggers of the protection. Among those intermediates, the most likely candidate is peroxynitrite, which is produced by the reaction of NO and superoxide anions (2). To test the possible role of peroxynitrite, we first assessed whether the endothelial effects of PC were affected by seleno-L-methionine, which scavenges peroxynitrite, but, unlike other scavengers of peroxynitrite such as ebselen, does not possess any peroxidase activity (23, 24) and also does not scavenge some other potential triggers of PC, i.e., NO and superoxide anions (23, 24). Thus the fact that seleno-L-methionine given during PC abolished endothelial protection suggests that peroxynitrite indeed triggers endothelial PC. It must be noted, however, that the selectivity of seleno-L-methionine was so far tested mostly in vitro. Whether this compound is selective for peroxynitrite in our experimental conditions is still partly unknown. However, we observed in pilot experiments that seleno-L-methionine administration did not affect blood pressure and did not affect the hypotensive effect of SNAP, suggesting that seleno-L-methionine also does not scavenge NO in our model.
As with all thiol-containing molecules, seleno-L-methionine may possibly act through scavenging of hydroxyl radicals. To rule out such a possible role, we compared the effects of seleno-L-methionine to those of methionine, which also scavenges hydroxyl radicals but is a weak scavenger of peroxynitrite (19, 24). The fact that methionine, administered at the same dose as seleno-L-methionine, does not affect PC rules out a major role of hydroxyl radical scavenging in the effect of seleno-L-methionine. To further test the role of peroxynitrite, we also assessed the effect of uric acid. Indeed, uric acid has been shown to have potent inhibitory effects on peroxynitrite-induced tyrosine nitration (12, 23) and dihydrorhodamine 123 oxidation (8), without affecting NO production (9). In our experiments, uric acid abolished the endothelial protective effects of PC, reinforcing the hypothesis that peroxynitrite is a trigger of delayed endothelial PC. The fact that peroxynitrite triggers endothelial protection is also supported by the observation that authentic peroxynitrite given 24 h before prolonged I/R mimicked endothelial PC. To the best of our knowledge, this is the first study that reports a direct delayed protective effect of peroxynitrite against I/R injury. Peroxynitrite is generally considered to be deleterious for endothelial cells. However, its effects may be dependent on its concentration (7). In some conditions, peroxynitrite generates S-nitrosothiols, which then release NO (16). However, because we found that the NO donor SNAP does not mimic PC, it is unlikely that the delayed endothelial protective effect observed after administration of peroxynitrite resulted from a secondary conversion of this species into NO. Several studies already assessed the antiischemic effect of peroxynitrite, administered immediately before or during prolonged I/R, or its role as a mediator of PC. Indeed, peroxynitrite given during prolonged ischemia inhibits leukocyte adhesion to endothelial cells (14), limits infarct size, and prevents coronary endothelial dysfunction (18), although other studies suggest that peroxynitrite is deleterious (15). Moreover, peroxynitrite also is a mediator of "classic" PC in isolated rat hearts (1). These studies, however, markedly differ from ours, because they addressed the protective role of peroxynitrite given during prolonged ischemia, whereas our study is the first to address the delayed (i.e., 24 h after administration) protective mechanisms of peroxynitrite and to demonstrate that peroxynitrite triggers (rather than mediate) PC. Our data suggest that peroxynitrite (either produced during PC or resulting from exogenous administration) acts as a cellular messenger responsible for a cascade of events leading to delayed coronary endothelial protection. However, the exact cellular mechanisms ultimately leading to delayed endothelial protection are still mostly unknown. One likely possibility is that peroxynitrite triggers the synthesis of various protective proteins, especially antioxidant enzymes (e.g., SOD) and NOS. This would lead to delayed increase in NO production, together with a decreased production of oxygen-derived free radicals during reperfusion after prolonged ischemia, ultimately leading to endothelial protection. Although such possible effects of peroxynitrite have not been tested, other oxygen radical species such as hydrogen peroxide or even NO have been shown to induced delayed increases in the expression of eNOS (4, 6) or of extracellular SOD (8). Further experiments are required to assess whether this also occurs with peroxynitrites, especially in the context of PC. In conclusion, our results demonstrate that peroxynitrite is an essential trigger of the endothelial protective effects of delayed PC. This suggests the existence of a previously unknown role of peroxynitrite, i.e., the capacity to trigger a delayed resistance of endothelial cells against I/R injury.| |
ACKNOWLEDGEMENTS |
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K. Laude was supported by a grant from the French Society of Pharmacology.
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FOOTNOTES |
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Present address of K. Laude: Division of Cardiology, Dept. of Medicine, Emory University School of Medicine, Atlanta, GA 30322.
Address for reprint requests and other correspondence: Vincent Richard, INSERM E9920, Faculté de Médecine, 22 Bd Gambetta, 76183 Rouen CEDEX, France (E-mail Vincent.Richard{at}univ-rouen.fr).
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.
June 13, 2002;10.1152/ajpheart.00375.2002
Received 25 February 2002; accepted in final form 12 June 2002.
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REFERENCES |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05 vs.
PC.
