Nicorandil improves cardiac function and clinical outcome in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: Role of inhibitory effect on reactive oxygen species formation

Article Outline

• Abstract
• Methods
  • Study patients
  • Primary pci and urine sampling
  • Measurements of urinary 8-epi-PGF2α level and plasma nicorandil and brain natriuretic peptide (bnp) levels
  • Measurements of left ventricular function and hemodynamic parameters and analysis of coronary flow
  • Clinical outcomes
  • Statistical analysis
• Results
  • Comparison of clinical profiles and plasma BNP levels
  • Urinary 8-epi-PGF2α excretion
  • Plasma level of nicorandil
  • Reperfusion injury
  • Inhospital cardiac events and clinical outcomes
  • Left ventricular function
• Discussion
  • Effect of nicorandil on ROS formation
  • Role of nicorandil-induced inhibition of ROS formation in the improvement on left ventricular function and clinical outcomes
  • Comparison with previous studies
  • Study limitations
• References
• Copyright

Abstract 

Background

Early reperfusion therapy improves the clinical outcomes of patients with acute myocardial infarction (AMI), but benefits are limited by reperfusion injury in some patients. We examined the effect of nicorandil, a hybrid of K_ATP channel opener and nicotinamide nitrate, on reactive oxygen species (ROS) formation and clinical outcomes after primary percutaneous coronary intervention (PCI) for AMI.

Methods

Fifty-eight patients with AMI were randomized into control (n = 25) and nicorandil pretreatment groups (n = 33). In the nicorandil group, nicorandil (4 mg as a bolus injection followed by constant infusion at 8 mg/hour for 24 hours) was administered just after admission. ROS formation was assessed by measuring urinary excretion of 8-epi-prostaglandin F_2α (PGF_2α) and compared between the 2 groups. Cardiac function and the incidence of reperfusion injury and cardiac events were also compared.

Results

Urinary 8-epi-PGF_2α excretion was increased 2-fold at 60 to 90 minutes after PCI in the control group, whereas it was unchanged after PCI in the nicorandil group (P < .0001 between the 2 groups). The incidence of no-reflow phenomenon was lower in the nicorandil group than in the control group. Left ventricular ejection fraction and cardiac index at 6 months were greater in the nicorandil group than in controls. Plasma brain natriuretic peptide level at 6 months was lower in the nicorandil group. Incidences of inhospital cardiac events and rehospitalization were lower in the nicorandil group than in controls.

Conclusions

Nicorandil improves cardiac function and clinical outcomes in patients with AMI. Suppression of ROS formation may be involved in the mechanism.

Early reperfusion therapy of an occluded coronary artery improves survival in patients with acute myocardial infarction (AMI)¹, ²; primary percutaneous coronary intervention (PCI) is widely performed for this purpose.³, ⁴, ⁵ Although early reperfusion therapy greatly improves the outcome for patients with AMI, its benefits are limited by reperfusion injury in some.⁶ Since reactive oxygen species (ROS) have been shown to be involved in this adverse reaction, antioxidants such as superoxide dismutase and vitamins C and E have been clinically employed, but have failed to suppress reperfusion injury.⁷, ⁸, ⁹

Nicorandil is a hybrid drug of adenosine triphosphate (ATP)-sensitive K⁺ (K^ATP) channel opener and nicotinamide nitrate, and has been shown to decrease infarct size and incidence of arrhythmias after coronary artery ligation and reperfusion in experimental animals.¹⁰, ¹¹ Recent clinical studies have shown that intravenous administration of nicorandil in conjugation with reperfusion therapy in patients with AMI preserves microvascular integrity, decreases the incidence of no-reflow phenomenon, and improves myocardial viability and functional and clinical outcomes.¹², ¹³ On the other hand, nicorandil was shown to have anti–free radical and neutrophil-modulating properties¹⁴ and also to attenuate polymorphonuclear leukocyte activation induced by ischemia and reperfusion in rats.¹⁵ Thus, an antioxidant action of nicorandil was expected to occur when it was administered before primary PCI; however, there has been no clinical study that examined the effect of nicorandil on ROS formation during acute myocardial ischemia and reperfusion.

8-epi-prostaglandin F_2α (PGF_2α) is a specific, chemically stable, noninvasive marker for ROS formation in vivo.¹⁶, ¹⁷, ¹⁸ We recently demonstrated that urinary 8-epi-PGF_2α excretion was transiently increased after primary PCI for AMI, while it remained unchanged after elective PCI for stable angina.⁷ We further showed that oral administration of allopurinol, an inhibitor of enzyme-mediated ROS formation, prior to primary PCI suppressed urinary 8-epi-PGF_2α excretion and improved clinical outcomes in patients with AMI.¹⁹ In this prospective, randomized study, we examined the effects of nicorandil administered prior to primary PCI in patients with AMI. By measuring urinary 8-epi-PGF_2α excretion before and after PCI and assessing the relationships between urinary 8-epi-PGF_2α excretion and cardiac function and clinical outcomes, we investigated the role of the inhibitory effect of nicorandil on ROS formation in the improvement of cardiac function and clinical outcomes after reperfusion therapy.

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Methods 

Study patients 

The study protocol was approved by the ethics committee of our institution, and written informed consent was obtained from all patients before the study. The study was performed between May 2000 and December 2001

The subjects were 58 consecutive patients with AMI and without any of the exclusion criteria described below. Diagnosis of AMI was made by persistent chest pain typical of AMI, ST-segment elevation on more than 2 leads in an initial electrocardiogram, and abnormally elevated levels of cardiac markers such as MB fraction of creatine kinase and cardiac troponin T. Patients were randomly assigned to 1 of 2 groups by a sealed envelope method (open label, non-placebo–controlled study). In group 1 (control group, 25 patients), primary PCI was performed without pretreatment with nicorandil. In group 2 (nicorandil pretreatment group, 33 patients), primary PCI was performed with pretreatment of nicorandil: 4 mg of nicorandil (Sigmat, Chugai Pharmaceutical, Tokyo, Japan) was injected as a bolus just after admission to the emergency room and a constant infusion at 8 mg/hour was maintained for 24 hours after PCI. Aspirin (162 mg) was orally administered to all patients at the time of admission. After PCI, either angiotensin-converting enzyme inhibitor or angiotensin II-receptor blocker was administrated to all study patients. In addition to aspirin, ticlopidine was administered for 4 weeks to all patients unless there were adverse effects.

In this study, patients with cardiogenic shock; right ventricular myocardial infarction; severe liver, renal, or brain dysfunction; or other serious complications at the time of admission were excluded. Those who had taken nicorandil prior to admission were also excluded. Further, patients in whom intracoronary injection of nicorandil was performed to resolve severe no-reflow phenomenon occurring after PCI were likewise excluded.

Primary pci and urine sampling 

PCI was performed using a standard floppy guidewire and over-the-wire balloon after intravenous injection of heparin sulfate (10,000 units) and intracoronary injection of isosorbide dinitrate (2 mg). A stent was implanted at the time of primary PCI in all study patients. Intravenous heparin was continued for 48 hours after PCI to maintain activated clotting time >180 seconds. In all patients, the procedure was performed within 60 minutes after admission, and the final coronary arteriogram showed residual stenosis to be <25% of the lumen diameter.

For serial urine sampling, a balloon catheter was inserted into the bladder in all patients. Urine samples for every 30-minute period were serially obtained before PCI (baseline) and until 150 minutes after the initial PCI, and collected into polyethylene tubes containing antioxidant butylated hydroxyanisole (0.1%). Samples were kept refrigerated during the collection period and stored at −80°C until the assay.

Measurements of urinary 8-epi-PGF_2α level and plasma nicorandil and brain natriuretic peptide (bnp) levels 

Urinary 8-epi-PGF_2α level was determined as previously reported.⁷, ¹⁹ Briefly, urine samples were applied to a C-18 cartridge column, and the 8-epi-PGF_2α fraction was eluted with 5 mL of ethyl acetate containing methanol 1%. Urinary 8-epi-PGF_2α level was quantified by an enzyme immunoassay kit (Cayman Chemical Company, Ann Arbor, Mich) and corrected with the recovery rate.⁷, ¹⁶ Urinary creatinine was measured by spectrophotometry, and urinary 8-epi-PGF_2α excretion was expressed as nanogram per millimole of creatinine. To assess total urinary excretion of 8-epi-PGF_2α after PCI, the urinary 8-epi-PGF_2α level was plotted for every 30-miniute interval.

For measurement of the plasma nicorandil level, venous blood was sampled just after the initial PCI procedure, and the plasma level was determined by high-performance liquid chromatography.²⁰

Venous blood was sampled at the 7th and 14th days and at 6 months after the onset of AMI. Plasma BNP levels were measured by radioimmunoassay.

Measurements of left ventricular function and hemodynamic parameters and analysis of coronary flow 

Approximately 30 minutes after the optimal angiographic results were obtained, cardiac index (CI) and pulmonary capillary wedge pressure (PCWP) were measured. Biplane left ventriculography was performed in the right and left anterior oblique projections, and left ventricular ejection fraction (LVEF), left ventricular end-diastolic (LVEDVI), and end-systolic volume indexes (LVESVI) were determined with the use of a Cardio 500 (Kontron Electronik, Munich, Germany). Hemodynamic study and left ventriculography were repeated 6 months after the onset of AMI. The analysis of left ventriculography was made by observers who were blinded to the patient treatment assignments.

In this study, no-reflow phenomenon was diagnosed when a reduction of 1 Thrombolysis in Myocardial Infraction (TIMI) flow grade was observed in the final angiogram relative to the angiogram immediately after PCI. If the infarct-related artery was the left anterior descending or circumflex artery, no-reflow was diagnosed when the flow in the infarct-related artery was slow compared with that in the non-infarct–related left anterior descending or circumflex artery in the final angiogram. To more quantitatively estimate coronary flow, we determined the corrected TIMI frame count, which has been shown to be a simple, reproducible, and quantitative index of coronary flow.²¹

Clinical outcomes 

Inhospital cardiac events, defined as the development of congestive heart failure, life-threatening arrhythmias, pericardial effusion, or recurrence of myocardial infarction during hospitalization, were assessed. Clinical adverse outcomes, defined as rehospitalization after discharge due to congestive heart failure or revascularization of the infarct-related coronary artery by PCI or coronary artery bypass graft surgery within 6 months after the onset of AMI, were also assessed.

Statistical analysis 

All data are expressed as mean ± SEM. Serial changes in urinary 8-epi-PGF_2αexcretion after PCI were analyzed by analysis of variance for repeated measures followed by Fisher's protected least significant difference test in each group. The percentage changes in urinary 8-epi-PGF_2α excretion from the baseline value were compared between the 2 groups by 2-way analysis of variance. Clinical characteristics, left ventricular function, and hemodynamic parameters were compared between the 2 groups by unpaired t test or χ² test. A P value <.05 was considered statistically significant.

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Results 

Comparison of clinical profiles and plasma BNP levels 

Primary PCI was successful in all patients, and there was no acute vessel closure in any of the study patients. No adverse effect was observed during nicorandil administration in group 2 patients.

There was no significant difference in age, sex, risk factors (hypertension, diabetes mellitus, smoking, and hyperlipidemia), the distribution of the infarct-related artery, and the duration from the onset of AMI to PCI between the 2 groups (Table I). Collateral vessels with grades 2 or 3 defined by Rentrop²² into the perfusion territory of the infarct-related artery were observed in 6 group 1 patients and 8 group 2 patients (P = NS). The degrees of Killip and Forrester classifications at admission were similar in both groups (P = NS). The plasma BNP levels at the 7th and 14th days and at 6 months after onset of AMI were 191 ± 36, 186 ± 39, and 102 ± 29 pg/mL, respectively, in group 1 and 107 ± 17, 93 ± 15, and 68 ± 18 pg/mL, respectively, in group 2. They were all lower in group 2 than in group 1 (all P < .05). The rate of administration of β-blocker was similar between group 1 (60%) and group 2 (67%).

Table I. Clinical and angiographic characteristics

LAD, Left anterior descending cononary artery; LCx, left circumflex artery; RCA, right coronary artery.

Variables are shown as mean ± one standard error.

Urinary 8-epi-PGF_2α excretion 

There was no significant difference in urinary 8-epi-PGF_2α excretion at baseline between the 2 groups (Figure 1). In group 1, urinary 8-epi-PG_2α excretion (ng/mmol creatinine) was 60 ± 5 at baseline, and 80 ± 7 at 0 to 30 minutes, 98 ± 9 at 30 to 60 minutes (P < .05 vs baseline), and 132 ± 13 at 60 to 90 minutes after PCI (P < .01 vs baseline). It declined to 81 ± 7 at 120 to 150 minutes after PCI. In group 2, urinary 8-epi-PGF_2α excretion was unchanged after PCI (P < .0001 vs group 1 by 2-way ANOVA), being 45 ± 3 at baseline, and 51 ± 5 at 0 to 30 minutes, 59 ± 4 at 30 to 60 minutes, 66 ± 6 at 60 to 90 minutes, 62 ± 5 at 90 to 120 minutes, and 51 ± 5 at 120 to 150 minutes after PCI.

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• Figure 1. 

  Time course of urinary 8-epi-prostaglandin F_2α (8-epi-PGF_2α) excretion in control (group 1, open bar) and nicorandil pretreatment groups (group 2, closed bar). Urinary 8-epi-PGF_2α excretion increases after primary PCI, peaks at 60 to 90 minutes and returns to the baseline value at 120 to 150 minutes in group 1, whereas it remains unchanged in group 2.

Plasma level of nicorandil 

The plasma nicorandil level just after reperfusion in group 2 was 204 ± 80 ng/mL, ranging from 112 to 418 ng/mL. Plasma nicorandil was undetected in group 1.

Reperfusion injury 

The incidences of reperfusion arrhythmia (ventricular tachycardia and ventricular fibrillation), ST elevation just after PCI, and transient hypotension (systolic blood pressure ≤80 mm Hg) immediately after PCI were similar between the 2 groups (Table II). The incidence of no-reflow phenomenon in the reperfused coronary artery was lower in group 2 than in group 1, although statistical significance was not obtained. However, corrected TIMI frame count in the infarct-related artery was smaller in group 2 than in group 1 (P = .01).

Table II. Reperfusion injury phenomena immediately after primary PCI

Reperfusion arrhythmia included ventricular tachycardia and ventricular fibrillation occurring immediately after PTCA.

Inhospital cardiac events and clinical outcomes 

There were no inhospital deaths in either group (Table III). Although there was no difference in each of the incidences of congestive heart failure, arrhythmia, pericardial effusion, and recurrence of myocardial infarction during the hospitalization, the total incidence of these cardiac events was lower in group 2 than in group 1 (P = .032). The incidence of rehospitalization due to congestive heart failure and revascularization of the infarct-related artery was also lower in group 2 than in group 1 (P = .032).

Table III. Inhospital cardiac events and clinical outcome

VT, Ventricular tachycardia; VF, ventricular fibrillation; MI, myocardial infarction.

Left ventricular function 

Mean PCWP and LVEF determined just after PCI were similar between groups 1 and 2. CI just after PCI was significantly greater in group 2 than in group 1 (P = .001) (Table IV). LVESVI just after PCI was smaller in group 2 than in group 1 (P < .05).

Table IV. Cardiac functions immediately after PCI and 6 months after the onset

LVEF, Left anterior ventricular ejetion fraction; CI, cardiac index; LVEDVI, left ventricular end-diastlic volume index; LVESVI, left ventricular end-systlic volume index.

Variables are shown as mean ± SE.

Cardiac catheterization was repeated at 6 months after the onset of AMI in 21 patients in group 1 and 29 in group 2. LVEF and CI were both significantly greater in group 2 than in group 1 (both P < .05). LVEDVI and LVESVI were both significantly smaller in group 2 than in group 1 (both P < .05).

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Discussion 

The present study shows that nicorandil pretreatment almost completely suppresses increases in urinary 8-epi-PGF_2α excretion after primary PCI in patients with AMI and results in the inhibition of no-reflow phenomenon and improved left ventricular function at 6 months after reperfusion therapy. Nicorandil improves cardiac function and clinical outcomes in patients with AMI, and suppression of ROS formation seems to be one of the mechanisms involved in the beneficial effects of nicorandil.

Effect of nicorandil on ROS formation 

In addition to its coronary artery dilating and cardioprotective effects, nicorandil has been shown to have anti–free radical effects.¹⁴ Pieper and Gross reported that nicorandil inhibits the iron-catalyzed, hydroxyl radical–mediated degradation of deoxyribose and also inhibits superoxide anion production by isolated neutrophils stimulated by phorbol myristate acetate.¹⁴ Nicorandil has also been shown to attenuate polymorphonuclear leukocyte activation induced by ischemia and reperfusion in rats via the donation of nitric oxide and the K⁺ channel-related cascade.¹⁵ Activated neutrophils are one of the major sources of ROS formation and seem to play an important role in the development of reperfusion injury in AMI.⁶ Nicorandil was therefore expected to suppress ROS formation during myocardial ischemia and reperfusion in the patients with AMI.

By measuring urinary excretion of 8-epi-PGF_2α in patients with AMI, we clearly demonstrated that ROS formation is transiently and significantly enhanced after primary PCI for AMI, which is consistent with our previous findings,⁷, ¹⁹ and pretreatment with nicorandil results in almost complete inhibition of this ROS formation. Baseline characteristics including the time from onset of AMI to reperfusion therapy, distributions of the infarct-related artery, risk factors, and the status of heart failure were similar between the patient groups with and without nicorandil pretreatment. Thus the inhibition of ROS formation after primary PCI observed in group 2 was considered to be caused by nicorandil. We have previously shown that allopurinol administered prior to primary PCI also suppresses ROS formation in patients with AMI.¹⁹

Role of nicorandil-induced inhibition of ROS formation in the improvement on left ventricular function and clinical outcomes 

Recent experimental and clinical studies have shown that K_ATP channel openers provide a cardioprotective effect against ischemia through their pharmacologic preconditioning effect, which may be mediated through mitochondrial K_ATP channels in the myocardium.²³ On the other hand, endogenous ROS generated during the acute phase of AMI play an important role in ischemia/reperfusion injury by damaging or functionally modifying contractile proteins, resulting in reduced calcium sensitivity.²⁴, ²⁵ Gao et al reported that, in isolated rat right ventricular trabeculae, exogenous ROS generated by xanthine oxidase and purine decreased systolic force by about 50% while increasing intracellular Ca²⁺ transient; they concluded that ROS mimic the effects of myocardial stunning on cardiac excitation-contraction coupling.²⁵ Since nicorandil shows anti–free radical action, it is considered to be effective in improving left ventricular contractility when superoxide-mediated myocardial stunning is involved in the pathogenesis.

The present study showed that CI measured just after PCI was greater in group 2 than in group 1, while PCWP was similar in the 2 groups, suggesting that the increase in CI is caused by the increase in the left ventricular contractility. This may be explained by the suppressive effects of nicorandil on ROS formation and the subsequent ROS-mediated myocardial stunning. Nicorandil may show 2 different effects when administered during acute myocardial ischemia and reperfusion in humans: one is a cardioprotective effect through its pharmacologic preconditioning effect and the other an inhibitory effect against ROS-mediated myocardial stunning.

This study further showed that, at 6 months after reperfusion therapy, LVEF and CI were both significantly greater in group 2 than in group 1. LVEDVI and LVESVI were both smaller in group 2 than in group 1. The incidences of inhospital cardiac events and rehospitalization were lower in group 2 than in group 1. Our findings are consistent with previous clinical findings; Ito et al reported that intravenous nicorandil before reperfusion therapy preserved microvascular integrity, decreased the incidence of no-reflow phenomenon, and improved myocardial viability and functional and clinical outcomes in patients with AMI.¹² Also, Sugimoto et al showed that nicorandil in conjugation with reperfusion therapy for AMI improved the left ventricular function especially in patients with anterior myocardial infarction and improved long-term prognosis.¹³

Patients with no-reflow phenomenon of the infarct-related artery after reperfusion therapy have been reported to have worse left ventricular function at chronic phase and worse clinical outcomes compared with those without no-reflow phenomenon.²⁶, ²⁷ In the current study, the nicorandil pretreatment group showed a lower incidence of no-reflow phenomenon, though not significantly, and a lower corrected TIMI frame count, being consistent with an earlier report.¹² The precise mechanism of the inhibitory effect of nicorandil on no-reflow phenomenon still remains unclear, but anti–free radical and neutrophil-modulating properties of the drug may be related to the improvement of coronary microvascular function and the suppression of no-reflow phenomenon. Improved left ventricular function at chronic phase observed in group 2 patients may be explained, at least in part, by the suppressive effect of nicorandil on no-reflow phenomenon. A cardioprotective effect of the drugs also seemed to participate in the improvement of left ventricular function and clinical outcomes, as reported previously.¹²

Comparison with previous studies 

The inhibitory effect of nicorandil on ROS formation in patients with AMI undergoing primary PCI was first demonstrated in this study, and the finding that the degree of inhibition of ROS formation was correlated with left ventricular function at chronic phase may account for the mechanism of the efficacy of nicorandil. The difference from earlier findings¹², ¹³ is that nicorandil improved left ventricular contractility determined just after PCI. Also, the dose of nicorandil used in this study (4 mg bolus injection followed by 8 mg/hour constant infusion for 24 hours) was larger than that in the previous studies (4 mg bolus injection followed by 6 mg/hour constant infusion for 24 hours).¹², ¹³ We showed that the mean plasma level of nicorandil just after the initial PCI was 204 ng/mL, which was shown to decrease coronary vascular resistance.²⁸ Our preliminary study using the dose of 4 mg bolus injection followed by 6 mg/hour constant infusion in patients with AMI (n = 16) showed that the mean plasma level was 161 ng/mL just after PCI. This small but certain difference in the dose and the plasma concentration may be related to the difference in left ventricular contractility during the acute phase.

Study limitations 

We analyzed urinary 8-epi-PGF_2α excretion after reperfusion as an in vivo maker of ROS formation. Although 8-epi-PGF_2α has been shown to be a specific, chemically stable marker for free radical formation,¹⁶, ¹⁷, ¹⁸ it is unclear whether the urinary 8-epi-PGF_2α level reflects total ROS generated after ischemia and reperfusion. Nicorandil also shows a cardioprotective effect through its K_ATP channel opener.¹⁰ The need for further investigations into the mechanism of the actions of nicorandil during acute myocardial ischemia and reperfusion is indicated.

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References 

1. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) . Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397–402
   • View In Article
   • MEDLINE
2. ISIS-2 (Second International Study Group of Infarct Survival) collaborative group . Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet. 1988;2:349–360
   • View In Article
   • CrossRef
3. Grines CL, Browne KF, Marco J, et al.  A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med. 1993;328:673–679
   • View In Article
   • MEDLINE
   • CrossRef
4. Stone GW, Grines CL, Browne KF, et al.  Predictors of in-hospital and 6-month outcome after acute myocardial infarction in the reperfusion era: the primary angioplasty in myocardial infarction (PAMI) trial. J Am Coll Cardiol. 1995;25:370–377
   • View In Article
   • Abstract
   • Full-Text PDF (1046 KB)
   • CrossRef
5. Zijlstra F, Hoorntje JCA, de Boer MJ, et al.  Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction. N Engl J Med. 1999;341:1413–1419
   • View In Article
   • MEDLINE
   • CrossRef
6. Kloner RA. Does reperfusion injury exist in humans?. J Am Coll Cardiol. 1993;21:537–545
   • View In Article
   • Abstract
   • Full-Text PDF (892 KB)
   • CrossRef
7. Guan WP, Osanai T, Kamada T, et al.  Time course of free radical production after primary coronary angioplasty for acute myocardial infarction and the effect of vitamin C. Jpn Circ J. 1999;63:924–928
   • View In Article
   • MEDLINE
   • CrossRef
8. Klein HH, Pich S, Lindert-Heimberg S, et al.  Failure of chronic, high-dose, oral vitamin E treatment to protect the ischemic, reperfused porcine heart. J Mol Cell Cardiol. 1993;25:103–112
   • View In Article
   • Abstract
   • Full-Text PDF (389 KB)
   • CrossRef
9. Janero DR. Therapeutic potential of vitamin E against myocardial ischemic-reperfusion injury. Free Radic Biol Med. 1991;10:315–324
   • View In Article
   • MEDLINE
   • CrossRef
10. Auchampach JA, Cavero I, Gross GJ, et al.  Nicorandil attenuates myocardial dysfunction associated with transient ischemia by opening ATP-dependent potassium channels. J Cardiovasc Pharmacol. 1992;20:765–771
    • View In Article
    • MEDLINE
    • CrossRef
11. Lamping KA, Christensen CW, Pelc LR, et al.  Effect of nicorandil and nifedipine on protection of ischemic myocardium. J Cardiovasc Pharmacol. 1984;6:536–542
    • View In Article
    • MEDLINE
    • CrossRef
12. Ito H, Taniyama Y, Iwakura K, et al.  Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. J Am Coll Cardiol. 1999;33:654–660
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (158 KB)
    • CrossRef
13. Sugimoto K, Ito H, Iwakura K, et al.  Intravenous nicorandil in conjunction with coronary reperfusion therapy is associated with better clinical and functional outcomes in patients with acute myocardial infarction. Circ J. 2003;67:295–300
    • View In Article
    • MEDLINE
14. Pieper GM, Gross GJ. Anti-free-radical and neutrophil modulating properties of the nitrovasodilator, nicorandil. Cardiovasc Drugs Ther. 1992;6:225–232
    • View In Article
    • MEDLINE
    • CrossRef
15. Yasu T, Ikeda N, Ishizuka N, et al.  Nicorandil and leukocyte activation. J Cardiovasc Pharmacol. 2002;40:684–692
    • View In Article
    • MEDLINE
    • CrossRef
16. Pratico D, Lawson JA, FitzGerald GA. Cyclooxygenase-dependent formation of the isoprostane, 8-epi-prostanglandin F2a. J Biol Chem. 1995;270:9800–9808
    • View In Article
    • MEDLINE
    • CrossRef
17. Delanty N, Reilly MP, Pratico D, et al.  8-epi-prostanglandin F2a generation during cononary reperfusion: a potential quantitative marker of oxidant stress in vivo. Circulation. 1997;95:2492–2499
    • View In Article
    • MEDLINE
18. Reilly MP, Delanty N, Roy L, et al.  Increased formation of the isoprostanes IP F2a–I and 8-epi-prostanglandin F2a in acute coronary angioplasty: evidence for oxidant stress during coronary reperfusion in humans. Circulation. 1997;96:3314–3320
    • View In Article
    • MEDLINE
19. Guan WP, Osanai T, Kamada T, et al.  , Effect of allopurinol pretreatment on free radical generation after primary coronary angioplasty for acute myocardial infarction. J Cardiovasc Pharmacol. 2003;41:699–705
    • View In Article
    • MEDLINE
    • CrossRef
20. Hashimoto K, Kinoshita M, Ohbayashi Y. Cononary effects of nicorandil in comparison with nitoroglycerin in chronic conscious dogs. Cardiovasc Drugs Ther. 1991;5:131–138
    • View In Article
    • MEDLINE
    • CrossRef
21. Gibson CM, Canon CP, Daley WL, et al.  TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation. 1996;93:879–888
    • View In Article
    • MEDLINE
22. Rentrop KP, Cohen M, Blanke H, et al.  Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects. J Am Coll Cardiol. 1985;5:587–592
    • View In Article
    • Abstract
    • Full-Text PDF (2191 KB)
    • CrossRef
23. Liu Y, Sato T, O'Rourke B, et al.  Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection?. Circulation. 1998;97:2463–2469
    • View In Article
    • MEDLINE
24. MacGowan SW, Regan MC, Malone C, et al.  Superoxide radical and xanthine oxidoreductase activity in the human heart during cardiac operations. Ann Thorac Surg. 1995;60:1289–1293
    • View In Article
    • MEDLINE
    • CrossRef
25. Gao WD, Liu Y, Marban E. Selective effects of oxygen free radi-cals on excitation-contraction coupling in ventricular muscle. Implications for the mechanism of stunned myocardium. Circulation. 1996;94:2597–2604
    • View In Article
26. Lim YJ, Nanto S, Masuyama T, et al.  Myocardial salvage: its assessment and prediction by the analysis of serial myocardial contrast echocardiograms in patients with acute myocardial infarction. Am Heart J. 1994;128:649–656
    • View In Article
    • MEDLINE
    • CrossRef
27. Ito H, Maruyama A, Iwakura K, et al.  Clinical implication of the no-reflow phenomenon: a predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation. 1996;93:223–228
    • View In Article
    • MEDLINE
28. Nakae I, Matsumoto T, Horie H, et al.  Effect of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism. J Cardiovasc Pharmacol. 2000;35:919–925
    • View In Article
    • MEDLINE
    • CrossRef