CLINICAL STUDY
Effect of aspirin on late preconditioning against myocardial stunning in conscious rabbits
Ken Shinmura, MD, PhD*,
Eitaro Kodani, MD*,
Y. u-Ting Xuan, PhD*,
Buddhadeb Dawn, MD*,
Xian-Liang Tang, MD* and
Roberto Bolli, MD, FACC*,*
* Experimental Research Laboratory, Division of Cardiology, University of Louisville, and the Jewish Hospital Heart and Lung Institute, Louisville, Kentucky, USA
Manuscript received August 14, 2002;
revised manuscript received November 8, 2002,
accepted November 22, 2002.
* Reprint requests and correspondence: Dr. Roberto Bolli, Division of Cardiology, University of Louisville, Louisville, Kentucky 40292, USA.
rbolli{at}louisville.edu
 |
Abstract
|
|---|
OBJECTIVES: The goal of this study was to investigate the effect of three different doses of acetylsalicylic acid (aspirin) (ASA) on the late phase of ischemic preconditioning (PC) against myocardial stunning.
BACKGROUND: Although recent evidence indicates that the late phase of ischemic PC is mediated by cyclooxygenase-2 (COX-2), the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit COX-2 activity on late PC has not been evaluated; ASA is the most widely used NSAID. Therefore, we determined whether ASA impedes the development of late PC.
METHODS: Conscious rabbits underwent a protocol consisting of three days of six 4-min coronary occlusion/4-min reperfusion cycles.
RESULTS: Neither 5 mg/kg nor 10 mg/kg x 3 of ASA interfered with the protective effects of late PC against stunning. In contrast, the late PC effect was completely abrogated by 25 mg/kg of ASA. Low-dose (5 mg/kg) ASA effectively inhibited platelet aggregation but did not prevent the increase in COX-2 activity, whereas the highest dose (25 mg/kg) completely blocked COX-2 activity.
CONCLUSIONS: The administration of ASA either at antithrombotic doses (5 mg/kg), which are widely used to prevent cardiovascular events in patients, or at analgesic/antipyretic doses (10 mg/kg) does not interfere with the cardioprotective effects of late PC against myocardial stunning. In contrast, high doses of ASA (25 mg/kg), which are used as antirheumatic therapy, abrogate both COX-2 activity and late PC, suggesting that nonselective doses of NSAIDs should be used with caution in patients with atherosclerotic cardiovascular disease because they may deprive the heart of its innate defensive response.
|
Abbreviations and Acronyms
| | ASA | = acetylsalicylic acid (aspirin) | | COX | = cyclooxygenase | | NSAID(s) | = nonsteroidal anti-inflammatory drug(s) | | PC | = preconditioning | | PG | = prostaglandin | | WTh | = systolic wall thickening |
|
The late phase of ischemic preconditioning (PC) is an innate response to stress that renders the heart relatively resistant to ischemia/reperfusion injury (1). The development of powerful protection against myocardial stunning is one of the most consistent aspects of late PC (1–3). Recent evidence has shown that the inducible isoform of cyclooxygenase (COX), COX-2, plays an essential role in mediat- ing the cardioprotective effects of late PC (3–6). In the myocardium, COX-2 is normally expressed at low levels but is upregulated after ischemic PC leading to increased synthesis of prostaglandin (PG)E2 and PGI2 (3,6); COX-2–dependent production of these prostanoids protects against ischemia/reperfusion injury during the late phase of ischemic PC (3–6).
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit COX-1 and COX-2 activity and are widely used clinically. Acetylsalicylic acid (aspirin) (ASA) is the most commonly used NSAID for relieving pain, inflammatory symptoms, and fever (7). In addition, ASA has established efficacy for preventing cardiovascular events (7–9) and is prescribed almost universally to patients with coronary artery disease. Mounting evidence indicates that both ischemic and pharmacological PC occurs in these patients (10–14) and results in significant clinical benefits. If the mechanism involved in the development of ischemic PC in humans is similar to that in animals, an important question arises as to whether the use of ASA might affect the development of late PC. Relatively low doses (75 to 325 mg/day) of ASA are currently recommended for the prophylaxis of cardiac and cerebral ischemic events and, as mentioned above, are given to almost all patients with coronary artery disease (7). The ability of these doses of ASA to inhibit COX-1 activity is well established (7,15), but it is unknown whether these doses can also interfere with the cardioprotective effects of late PC by inhibiting COX-2 as well. In addition, it is unknown whether late PC is affected by higher doses of ASA, which are commonly used to treat fever, pain, and inflammatory states. The importance of examining the impact of COX inhibitors on myocardial ischemia is emphasized by the results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial (16), in which the rate of myocardial infarction was four times higher among patients treated with the selective COX-2 inhibitor rofecoxib as compared with patients treated with naproxen, a nonselective COX inhibitor. A recent meta-analysis has concluded that inhibition of COX-2 increases the incidence of cardiovascular events in patients with coronary artery disease (17).
Accordingly, the aim of this study was to investigate the effect of three different doses of ASA on the late phase of ischemic PC in rabbits. All studies were conducted in conscious animals to obviate the potential confounding influence of conditions associated with open-chest animal preparations (18), particularly since COX-2 is known to be a stress-responsive enzyme (19).
|
Methods
|
|---|
The conscious rabbit model of myocardial ischemia has been described in detail previously (2,3).
Experimental protocols.
Protocol I: effect of ASA on late PC against myocardial stunning
In this protocol, rabbits underwent three consecutive days of six 4-min coronary occlusion/4-min reperfusion cycles (Fig. 1). Group I (untreated control) underwent the coronary artery occlusion/reperfusion protocol on days 1, 2, and 3 without any treatment. In group II (low ASA on day 2), rabbits underwent six 4-min coronary occlusion/4-min reperfusion cycles without any treatment on day 1. On day 2, rabbits received low-dose ASA (5 mg/kg) through a nasogastric tube 40 min before the first occlusion, whereas on day 3, rabbits underwent the six occlusion/reperfusion cycles without any treatment. In group III (high ASA on day 1), rabbits received high-dose ASA (25 mg/kg) via a nasogastric tube 40 min before the first occlusion on day 1. On days 2 and 3, rabbits underwent the six coronary occlusion/reperfusion cycles without any treatment. In group IV (high ASA on day 2), rabbits underwent the six occlusion/reperfusion cycles without any treatment on day 1. On day 2, they received 25 mg/kg of ASA 40 min before the first occlusion, and on day 3, they underwent six occlusion/reperfusion cycles without any treatment. In group V (multiple ASA), rabbits underwent the six occlusion/reperfusion cycles on day 1 and then received three doses of ASA (10 mg/kg each) every 12 h (30 min and 12 h after the sixth reperfusion on day 1 and 40 min before the first occlusion on day 2; total cumulative dose: 30 mg/kg over 24 h). On day 3, they underwent six occlusion/reperfusion cycles without any treatment; ASA was administered in 10 ml of water using a nasogastric tube, with another 10 ml of water to flush the tube (total of 20 ml of water).
View larger version (57K):
[in this window]
[in a new window]
|
Figure 1 Experimental protocols (protocol I): effect of acetylsalicylic acid (aspirin [ASA]) on late preconditioning (PC) against myocardial stunning. O = occlusion; R = reperfusion.
|
|
Protocol II: effect of ASA on platelet function
To evaluate the efficacy of ASA in inhibiting platelet function, blood samples were collected before and after the administration of ASA in group VI (low ASA) (weight: 3.0 to 3.5 kg) (Fig. 2). Ten milliliters of blood were drawn from the mid-dorsal ear artery into a syringe containing sodium citrate (final concentration 3.8%) before and 60 min after the administration of low-dose ASA (5 mg/kg) via a nasogastric tube. Platelet function in citrated whole blood samples was analyzed by a platelet function analyzer (PFA-100, Dade Behring, Inc., Deerfield, Illinois) (20) according to the manufacturer’s protocol. After determination of circulating blood cell counts, platelet function was assessed using simulated blood flow in presence of epinephrine/collagen or adenosine diphosphate/collagen agonists.
View larger version (46K):
[in this window]
[in a new window]
|
Figure 2 Experimental protocols (protocols II and III): effect of acetylsalicylic acid (aspirin [ASA]) on platelet function. COX = cyclooxygenase; O = occlusion; R = reperfusion.
|
|
Protocol III: effect of ASA on COX-2 protein expression and activity
As shown in Figure 2, group VII (control) did not receive any treatment or ischemic PC. In groups VIII (PC), IX (high ASA on day 1), X (low ASA on day 2), and XI (high ASA on day 2), rabbits underwent six cycles of 4-min occlusion/4-min reperfusion without ASA on day 1. In group IX (high ASA on day 1), rabbits received high-dose ASA (25 mg/kg) 40 min before the first occlusion on day 1. In groups X and XI, rabbits received low-dose (5 mg/kg) or high-dose (25 mg/kg) ASA 40 min before euthanasia on day 2. Twenty-four hours later (on day 2), myocardial samples were obtained from the ischemic-reperfused and nonischemic region (posterior left ventricular wall) and stored at –140°C until used.
Measurements.
Regional myocardial function was assessed as systolic thickening fraction using a Doppler probe (21). The total deficit of systolic wall thickening (WTh) (an integrative assessment of the overall severity of postischemic dysfunction) was calculated as described (2,3). The expression of COX-2 was assessed by standard sodium dodecyl sulfate-polyacrylamide gel electrophoresis Western immunoblotting techniques using monoclonal anti-COX-2 antibodies (Transduction Laboratories, Lexington, Kentucky) (3,6). The myocardial content of PGE2 and 6-keto-PGF1 was determined using enzyme immunoassay kits as described (3,6).
Statistical analysis.
Data are reported as means ± SEM. For intragroup comparisons, hemodynamic variables and WTh were analyzed by a one-way analysis of variance, followed by Student t tests for paired data with the Bonferroni correction. For intergroup comparisons, data were analyzed by either a one-way or a two-way repeated measures analysis of variance (time and group), as appropriate, followed by Student t tests for unpaired data with the Bonferroni correction.
|
Results
|
|---|
Exclusions.
A total of 73 rabbits were used. Of the 40 rabbits instrumented for protocol I (studies of myocardial stunning), three were excluded because the WTh signal was lost on day 2 (one each in groups II, IV, and V), and two died of ventricular fibrillation during the coronary occlusion on day 2 (one each in groups II and III). Thus, seven rabbits completed the study in group I, seven in group II, eight in group III, eight in group IV, and five in group V. Of the eight rabbits assigned to protocol II (platelet function), three were excluded because of difficulty in obtaining blood samples for the analysis of platelet function after the administration of ASA; thus, five rabbits completed protocol II. All of the 25 rabbits assigned to protocol III (COX-2 expression and activity) completed the study.
Protocol I: effect of ASA on late PC against myocardial stunning
There were no appreciable differences in heart rate throughout the experimental protocol among the five groups (Table 1). There were also no differences in thickening fraction at baseline and just before coronary occlusion (Table 2). As shown in Table 3, the left ventricular weight and the size of the occluded-reperfused vascular bed (area-at-risk) did not differ significantly among the five groups.
As expected (2,3), in control rabbits (group I), the recovery of WTh during the 5-h reperfusion period was improved on days 2 and 3 compared with day 1 (Fig. 3), resulting in a significant decrease in the total deficit of WTh after the sixth reperfusion on days 2 and 3, respectively, compared with day 1 (p < 0.05 for both) (Fig. 4). This indicates the development of late PC against stunning. Similar results were obtained in rabbits given low-dose ASA on day 2 (group II) (Figs. 4 and 5A). Thus, 5 mg/kg of ASA given on day 2 did not abrogate late PC against stunning.
View larger version (28K):
[in this window]
[in a new window]
|
Figure 3 Systolic thickening fraction in group I (control). Illustrated is thickening fraction at baseline, just before the first occlusion (Pre-O), 3 min into each coronary occlusion (O), 3 min into each reperfusion (R), and at selected times during the 5-h reperfusion period after the sixth occlusion. Thickening fraction is expressed as a percentage of baseline values. The two comparisons performed at each time-point from 5 min to 4 h of reperfusion were adjusted with the Bonferroni correction. Data are means ± SEM.
|
|
View larger version (35K):
[in this window]
[in a new window]
|
Figure 4 Total deficit of systolic wall thickening after the sixth reperfusion. The total deficit of systolic wall thickening was measured in arbitrary units, as described in the text. The two comparisons performed in each group were adjusted by the Bonferroni correction. Data are means ± SEM. ASA = acetylsalicylic acid.
|
|
View larger version (31K):
[in this window]
[in a new window]
|
Figure 5 Systolic thickening fraction in group II (low acetylsalicylic acid [aspirin {ASA}] on day 2) (A) and in group III (high ASA on day 1) (B). Same format as Figure 3. In both groups II and III, the two comparisons performed at each time-point from 5 min to 4 h of reperfusion were adjusted with the Bonferroni correction. Data are means ± SEM. Pre-O = before first occlusion; O/R = occlusion/reperfusion.
|
|
In group III (high ASA on day 1), the total deficit of WTh on day 1 did not differ from that measured on day 1 in groups I, II, IV, and V (p = 0.46) (Fig. 4), demonstrating that the administration of high-dose ASA (25 mg/kg) did not affect the severity of myocardial stunning in nonpreconditioned myocardium. These results are consistent with previous reports in vivo (22) and suggest that, in the absence of a PC stimulus, endogenous biosynthesis of prostanoids does not modulate the severity of myocardial stunning. On days 2 and 3, the recovery of WTh was significantly improved compared with day 1 (Fig. 5B), and the total deficit of WTh was significantly decreased (Fig. 4), indicating that a single high dose of ASA (25 mg/kg) given on day 1 did not block the development of late PC against stunning on day 2.
In group IV (high ASA on day 2), the recovery of WTh on day 2 was essentially indistinguishable from that on day 1 (Fig. 6A), and the total deficit of WTh was similar to that on day 1 (Fig. 4), indicating that the administration of high-dose (25 mg/kg) ASA on day 2 completely abrogated late PC against stunning. On day 3, the recovery of WTh was significantly improved (Fig. 6A), and the total deficit of WTh was attenuated to the same extent as in groups I, II, III, and V (Fig. 4), indicating a late PC effect against stunning.
View larger version (33K):
[in this window]
[in a new window]
|
Figure 6 Systolic thickening fraction in group IV (high acetylsalicylic acid [aspirin {ASA}] on day 2) (A) and in group V (multiple ASA) (B). Same format as Figure 3. In both groups IV and V, the two comparisons performed at each time-point from 5 min to 4 h of reperfusion were adjusted with the Bonferroni correction. Data are means ± SEM. Pre-O = before first occlusion; O/R = occlusion/reperfusion.
|
|
In group V (multiple ASA), the total deficit of WTh on day 1 was similar to that measured on day 1 in groups I, II, III, and IV (Fig. 4). On days 2 and 3, the recovery of WTh was significantly improved compared with day 1 (Fig. 6B), resulting in a marked decrease in the total deficit of WTh versus day 1 (Fig. 4). Therefore, administration of multiple doses of ASA (10 mg/kg x 3) during the 24-h interval before the six occlusion/reperfusion cycles on day 2 did not block the development of late PC against stunning on day 2.
Protocol II: effect of ASA on platelet function
In the five rabbits studied in group VI (low ASA), there were no significant differences in the number of white blood cells and platelets before and after the administration of ASA. The number of red blood cells decreased slightly but significantly after ASA administration, probably due to the previous blood sampling (Table 4). Platelet aggregation in response to epinephrine/collagen was suppressed by low-dose (5 mg/kg) ASA; in contrast, platelet aggregation in response to ADP/collagen was unchanged after ASA (Table 4). Thus, the inhibitory effect of ASA (5 mg/kg) on platelet aggregation in rabbits is similar to the effect of low-dose ASA in humans (7,20).
Protocol III: effect of ASA on COX-2 protein expression and activity
Representative examples of Western immunoblotting analysis of COX-2 in membranous fractions are illustrated in Figure 7. A weak COX-2 signal was detected in control hearts (group VII). When rabbits were preconditioned with six 4-min occlusion/4-min reperfusion cycles (group VIII), the expression of COX-2 in the ischemic-reperfused region increased markedly 24 h later (Fig. 7, left panel), in keeping with our previous observations (3,6). The administration of high-dose ASA (25 mg/kg) before ischemic PC failed to abolish the upregulation of COX-2 protein 24 h later (group IX) (Fig. 7, left panel). There was no change in COX-2 protein expression in the nonischemic region among the three groups (Fig. 7, right panel).
View larger version (30K):
[in this window]
[in a new window]
|
Figure 7 (Upper panel) Representative Western immunoblots showing the expression of cyclooxygenase (COX-2) protein in the membranous fraction in the ischemic/reperfused region. (Lower panels) Densitometic analysis of COX-2 protein signals in the membranous fraction in the ischemic/reperfused region (anterior left ventricular [LV] wall) (left) and in the nonischemic region (posterior LV wall) (right). In all samples, the densitometric measurements of COX-2 immunoreactivity were expressed as a percentage of the average value measured in the corresponding LV wall of control rabbits. The two comparisons performed in each panel were adjusted by the Bonferroni correction. Data are means ± SEM. ASA = acetylsalicylic acid (aspirin); PC = preconditioning.
|
|
Previous studies in this conscious rabbit model have demonstrated that the two main products of enhanced COX-2 activity during late PC are PGE2 and 6-keto-PGF1 (the stable metabolite of PGI2) (3,6). Consistent with these prior studies, we found that ischemic PC (group VIII) resulted in a significant increase in both PGE2 and 6-keto-PGF1 levels in the ischemic region 24 h later (Fig. 8). The myocardial levels of PGE2 and 6-keto-PGF1 were lower in groups IX (high ASA on day 1) and X (low ASA on day 2) than in group VIII (PC), indicating that administration of high-dose ASA on day 1 or low-dose ASA on day 2 produced partial inhibition of COX-2 activity; nevertheless, PGE2 and 6-keto-PGF1 were significantly higher in groups IX and X than in group VII (controls), indicating that COX-2 activity was still upregulated in these two groups (Fig. 8). In contrast, in group XI (high ASA on day 2) the myocardial levels of PGE2 and 6-keto-PGF1 were indistinguishable from controls (Fig. 8), indicating that the enhanced COX-2 activity induced by ischemic PC was completely abrogated by the administration of high-dose ASA on day 2.
View larger version (30K):
[in this window]
[in a new window]
|
Figure 8 Myocardial levels of prostaglandin (PG)E2 and 6-keto-PGF1 (measured by enzyme immunoassay). The three intergroup comparisons performed in each panel were adjusted by the Bonferroni correction. Data are means ± SEM. ASA = acetylsalicylic acid (aspirin); PC = preconditioning.
|
|
|
Discussion
|
|---|
The late phase of PC plays an important role in enhancing the tolerance of the heart to stress (1). To our knowledge, this is the first report to evaluate the effect on late PC of ASA, an NSAID that is widely used to prevent cardiovascular events. The present study provides three major findings: 1) the administration of a low dose of ASA (5 mg/kg), which is sufficient to inhibit platelet aggregation, does not prevent the increase in COX-2 activity and does not ablate the cardioprotective effects of late PC; 2) multiple higher doses of ASA, in the range used for analgesic/antipyretic effects (10 mg/kg x 3 over 24 h), also do not block late PC; and 3) in contrast, a very high dose of ASA, in the range used for antirheumatic therapy (25 mg/kg), abrogates COX-2 activity and the cardioprotection afforded by late PC. These results suggest that, in patients taking NSAIDs, the ability of the myocardium to shift to a preconditioned phenotype is not impaired so long as these drugs are given in doses that are selective for COX-1; however, doses of NSAIDs that completely block COX-2 can deprive the heart of its innate defensive response.
Effect of escalating doses of ASA on late PC.
In clinical practice, ASA is used at three different dosage levels, with each dose reflecting the relative ASA sensitivity of different target cells (7); ASA acts as an antithrombotic (60 to 325 mg per day), as an analgesic/antipyretic (650 mg), or as an antirheumatic agent (3,000 to 6,000 mg). We chose 5 mg/kg as the low dose because this dosage is comparable to that used to prevent cardiovascular events in patients (7). We found that this dose of ASA inhibited platelet aggregation (a COX-1-dependent phenomenon) (Table 4) but had no effect on late PC against stunning (a COX-2-dependent phenomenon) (Figs. 4 and 5A) and did not prevent the increase in cardiac COX-2 activity (although it exerted a partial inhibition) (Fig. 8). We also evaluated a dosage of aspirin that is commonly used for its analgesic/antipyretic effects (10 mg/kg every 12 h). Even after three doses (total cumulative dose of 30 mg/kg over 24 h), late PC against stunning was not blocked (Figs. 4 and 6B). Taken together, these results indicate that doses of ASA commonly given to patients (5 to 10 mg/kg) do not interfere with late PC.
The ability of ASA to prevent platelet aggregation and, thereby, prevent cardiac and cerebral ischemia, results from inhibition of COX-1 due to irreversible acetylation of the protein at serine 530 (7,15); ASA also inhibits COX-2 in a similar manner but exhibits less potency for COX-2 than for COX-1 (23) because the substrate channel of COX-2 is larger and more flexible than that of COX-1 (24). These considerations provide a plausible explanation for our finding that 5 mg/kg and 10 mg/kg of ASA inhibited platelet aggregation but failed to affect late PC.
In contrast with the effects of antithrombotic and analgesic/antipyretic doses of ASA, administration of an antirheumatic dose of ASA (25 mg/kg) completely ablated the beneficial actions of late PC on myocardial stunning (Figs. 4 and 6A) and the attending increase in COX-2 activity (Fig. 8), indicating loss of COX-1 selectivity. Interestingly, although this dose of ASA (25 mg/kg) blocked the beneficial effects of late PC on day 2, it failed to exacerbate postischemic dysfunction on day 1 in nonpreconditioned hearts (Figs. 4 and 5A), indicating that endogenous biosynthesis of prostanoids does not modulate the severity of myocardial stunning in the absence of a PC stimulus. This finding reveals a heretofore unrecognized difference in the response of the myocardium to COX inhibitors; that is, inhibition of COX-2 (or COX-1) activity has no effect in the unstressed (nonpreconditioned) state, where COX-2 is not upregulated, but exacerbates ischemia/reperfusion injury in the stressed (preconditioned) state, where COX-2 is upregulated.
Effect of ASA on COX-2 protein induction.
The impetus to examine the effect of high-dose ASA on COX-2 induction in protocol III was provided by the recent demonstration that, besides inhibiting COX activity, some NSAIDs can also suppress the transcription of inflammation-related genes via inhibition of transcriptional activators (25). Among these, nuclear factor-kappaB plays a major role in controlling the transcription of the COX-2 gene (26) and also in the development of the late PC phenotype (1). In noncardiac cells studied in vitro, ASA has been found to inhibit nuclear factor-kappaB activation (27,28), and Xu et al. (9) have reported that it blocks COX-2 transcription. In the present study, however, neither the induction of COX-2 protein (Fig. 7) nor the development of a late PC effect 24 h later (on day 2) (Figs. 4 and 5B) was affected by the administration of 25 mg/kg of ASA on day 1 (before ischemic PC), demonstrating that even very high doses of ASA fail to block upregulation of COX-2 in response to a sublethal ischemic stress in the heart. There are several possible explanations for the apparent discrepancy between our results and those of Xu et al. (9). Aside from the obvious differences in experimental models (in vivo vs. in vitro), stimuli for COX-2 induction (ischemia vs. nonischemic stimuli), and cell types examined (cardiac tissue vs. noncardiac cells), it is plausible that multiple transcription factors are involved in the induction of cardiac COX-2 after ischemic PC (1), so that inhibition of one factor might not suffice to suppress COX-2 gene transcription in this setting.
Our measurements of tissue prostanoid levels (Fig. 8) demonstrate that COX-2 activity was partially inhibited by 5 mg/kg of ASA given on day 2 and 25 mg/kg of ASA given on day 1. In the former case, this most likely reflects the limited selectivity of ASA for COX-1 vis-à-vis COX-2 (8,23). In the latter case, it may reflect irreversible inhibition of constitutive or induced COX-2 protein that was present in the heart in the first few hours after administration of ASA on day 1. The fact that in both cases the late PC response was intact indicates that the upregulation of COX-2 during late PC is somewhat redundant; that is, COX-2-dependent biosynthesis of prostanoids is sufficient to confer cardioprotection even when it is partially inhibited, implying that complete blockade of COX-2 activity is necessary to block late PC.
Conclusions and clinical implications.
In summary, using a conscious animal model, we found that administration of ASA either at antithrombotic doses (5 mg/kg), which are widely used to prevent cardiovascular events in patients, or at analgesic/antipyretic doses (10 mg/kg) does not interfere with the cardioprotective effects of late PC against myocardial stunning. In contrast, high doses of ASA (25 mg/kg), which are used as antirheumatic therapy, abrogate COX-2 activity as well as late PC, suggesting that they should be used with caution in patients with atherosclerotic cardiovascular disease because they may deprive the heart of its innate defensive response. Given the ubiquitous use of ASA and other NSAIDs and the increasing use of selective COX-2 inhibitors, the present findings have potential clinical reverberations. Recent studies indicate that COX-2 inhibitors increase the incidence of cardiovascular events (16,17), possibly because they inhibit late PC (a COX-2-dependent phenomenon) without inhibiting platelet aggregation (a COX-1-dependent phenomenon) (4). Because many NSAIDs, such as ibuprofen and indomethacin, are less COX-1 selective than ASA (8), they may interfere with late PC at relatively lower doses. Our results suggest that the actions of NSAIDs in patients with atherosclerosis are more complex than heretofore appreciated, and that when NSAIDs are given in doses sufficient to block COX-2, inhibitions of the PC response may offset the benefits deriving from inhibition of platelet aggregation.
|
Footnotes
|
|---|
Supported, in part, by NIH grants R01 HL-43151, HL-55757, and HL-68088 to Dr. Bolli, and HL-65660 to Dr. Xuan.
|
References
|
|---|
1. Bolli R. The late phase of preconditioning. Circ Res. 2000;87:972–983[Abstract/Free Full Text]
2. Bolli R, Manchikalapudi S, Tang XL, et al. The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase. Circ Res. 1997;81:1094–1107[Abstract/Free Full Text]
3. Shinmura K, Tang XL, Wang Y, et al. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci USA. 2000;97:10197–10202[Abstract/Free Full Text]
4. Bolli R, Shinmura K, Tang X, et al. Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res. 2002;55:506[Abstract/Free Full Text]
5. Guo Y, Bao W, Wu WJ, Shinmura K, Tang XL, Bolli R. Evidence for an essential role of cyclooxygenase-2 as a mediator of the late phase of ischemic preconditioning in mice. Basic Res Cardiol. 2000;95:479–484[CrossRef][Medline]
6. Shinmura K, Xuan YT, Tang XL, et al. Inducible nitric oxide synthase modulates cyclooxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning. Circ Res. 2002;90:602–608[Abstract/Free Full Text]
7. Calverley D, Roth G. Aspirin, prostaglandins and platelet function: pharmacology and thrombosis prevention. Rao G. Handbook of Platelet Physiology and Pharmacology. Norwell, MA: Kluwer Academic Publishers; 1999. p. 478–494
8. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104:413–421[CrossRef][Medline]
9. Xu XM, Sansores-Garcia L, Chen XM, Matijevic-Aleksic N, Du M, Wu KK. Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate. Proc Natl Acad Sci USA. 1999;96:5292–5297[Abstract/Free Full Text]
10. Kloner RA, Shook T, Przyklenk K, et al. Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning? Circulation. 1995;91:37–45[Abstract/Free Full Text]
11. Leesar MA, Stoddard M, Ahmed M, Broadbent J, Bolli R. Preconditioning of human myocardium with adenosine during coronary angioplasty. Circulation. 1997;95:2500–2507[Abstract/Free Full Text]
12. Leesar MA, Stoddard MF, Dawn B, Jasti VG, Masden R, Bolli R. Delayed preconditioning-mimetic action of nitroglycerin in patients undergoing coronary angioplasty. Circulation. 2001;103:2935–2941[Abstract/Free Full Text]
13. Yellon DM, Dana A. The preconditioning phenomenon: a tool for the scientist or a clinical reality? Circ Res. 2000;87:543–550[Abstract/Free Full Text]
14. Heusch G. Nitroglycerin and delayed preconditioning in humans: yet another new mechanism for an old drug? Circulation. 2001;103:2876–2878[Free Full Text]
15. Wu KK. Aspirin and salicylate: an old remedy with a new twist. Circulation. 2000;102:2022–2023[Free Full Text]
16. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis: VIGOR Study Group. N Engl J Med. 2000;343:1520–1528[Abstract/Free Full Text]
17. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954–959[Abstract/Free Full Text]
18. Li XY, McCay PB, Zughaib M, Jeroudi MO, Triana JF, Bolli R. Demonstration of free radical generation in the "stunned" myocardium in the conscious dog and identification of major differences between conscious and open-chest dogs. J Clin Invest. 1993;92:1025–1041[Medline]
19. Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem. 1996;271:33157–33160[Free Full Text]
20. Kundu SK, Heilmann EJ, Sio R, Garcia C, Davidson RM, Ostgaard RA. Description of an in vitro platelet function analyzer—PFA-100. Semin Thromb Hemost. 1995;21:106–112[Medline]
21. Bolli R, Zhu WX, Myers ML, Hartley CJ, Roberts R. Beta-adrenergic stimulation reverses postischemic myocardial dysfunction without producing subsequent functional deterioration. Am J Cardiol. 1985;56:964–968[CrossRef][Medline]
22. Rose J, Ehring T, Sakka SG, Skyschally A, Heusch G. Aspirin does not prevent the attenuation of myocardial stunning by the ACE inhibitor ramiprilat. J Mol Cell Cardiol. 1996;28:603–613[CrossRef][Medline]
23. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci USA. 1993;90:11693–11697[Abstract/Free Full Text]
24. Kurumbail RG, Stevens AM, Gierse JK, et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996;384:644–648[CrossRef][Medline]
25. Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest. 2001;107:135–142[Medline]
26. Schmedtje JF Jr., Ji YS, Liu WL, DuBois RN, Runge MS. Hypoxia induces cyclooxygenase-2 via the NF-kappaB p65 transcription factor in human vascular endothelial cells. J Biol Chem. 1997;272:601–608[Abstract/Free Full Text]
27. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994;265:956–959[Abstract/Free Full Text]
28. Weber C, Erl W, Pietsch A, Weber PC. Aspirin inhibits nuclear factor-kappa B mobilization and monocyte adhesion in stimulated human endothelial cells. Circulation. 1995;91:1914–1917[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
J. N. Peart and J. P. Headrick
Clinical cardioprotection and the value of conditioning responses
Am J Physiol Heart Circ Physiol,
June 1, 2009;
296(6):
H1705 - H1720.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Wang, V. V. Patel, E. Ricciotti, R. Zhou, M. D. Levin, E. Gao, Z. Yu, V. A. Ferrari, M. M. Lu, J. Xu, et al.
Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function
PNAS,
May 5, 2009;
106(18):
7548 - 7552.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Sato, R. Bolli, G. D. Rokosh, Q. Bi, S. Dai, G. Shirk, and X.-L. Tang
The cardioprotection of the late phase of ischemic preconditioning is enhanced by postconditioning via a COX-2-mediated mechanism in conscious rats
Am J Physiol Heart Circ Physiol,
October 1, 2007;
293(4):
H2557 - H2564.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Salinas, U. C. Rangasetty, B. F. Uretsky, and Y. Birnbaum
The Cycloxygenase 2 (COX-2) Story: It's Time to Explain, Not Inflame
Journal of Cardiovascular Pharmacology and Therapeutics,
June 1, 2007;
12(2):
98 - 111.
[Abstract]
[PDF]
|
|
|
|
|
|
|
Y. Birnbaum, Y. Lin, Y. Ye, J. D. Martinez, M.-H. Huang, C. Y. Lui, J. R Perez-Polo, and B. F. Uretsky
Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin
Am J Physiol Heart Circ Physiol,
June 1, 2007;
292(6):
H2891 - H2897.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Nishino, T. Miura, T. Miki, J. Sakamoto, Y. Nakamura, Y. Ikeda, H. Kobayashi, and K. Shimamoto
Ischemic preconditioning activates AMPK in a PKC-dependent manner and induces GLUT4 up-regulation in the late phase of cardioprotection
Cardiovasc Res,
February 15, 2004;
61(3):
610 - 619.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Abbate, G. G. L. Biondi-Zoccai, A. Maria Leone, A. Baldi, and F. Crea
Cyclooxygenase-2 in myocardial ischemia: is it really a friend?
J. Am. Coll. Cardiol.,
November 5, 2003;
42(9):
1714 - 1714.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods