HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ito, H. Articles by Minamino, T. Search for Related Content PubMed PubMed Citation Articles by Ito, H. Articles by Minamino, T.

CLINICAL STUDIES

Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction

Hiroshi Ito, MD^*, Yoshiaki Taniyama, MD^*, Katsuomi Iwakura, MD^*, Nagahiro Nishikawa, MD^*, Tohru Masuyama, MD, Tsunehiko Kuzuya, Masatsugu Hori, MD, Yorihiko Higashino, MD^*, Kenshi Fujii, MD^* and Takazo Minamino, MD^*

^* Division of Cardiology, Sakurabashi Watanabe Hospital, Osaka, Japan
First Department of Medicine, Osaka University School of Medicine, Osaka, Japan

Manuscript received July 21, 1998; revised manuscript received September 17, 1998, accepted November 5, 1998.

Reprint requests and correspondence: Dr. Hiroshi Ito, The Division of Cardiology, Sakurabashi Watanabe Hospital, 2-4-32 Umeda, Kita-ku, Osaka 530-0001, Japan
itomd{at}osk4.3web.ne.jp

	Abstract

Top Abstract Methods Results Discussion References

 
OBJECTIVES

We assessed whether the intravenous administration of nicorandil, an adenosine triphosphate (ATP)-sensitive K⁺ channel opener, exerts beneficial effect on microvascular function and functional and clinical outcomes in patients with acute myocardial infarction (AMI).

BACKGROUND

Experimental studies documented that ATP-sensitive K⁺ channel opener exerts cardioprotection after prolonged ischemia.

METHODS

We randomly divided 81 patients with a first anterior AMI into two groups, nicorandil (n = 40) and control groups (n = 41). All patients received successful coronary angioplasty within 12 h after the symptom onset and underwent myocardial contrast echcardiography (MCE) with the intracoronary injection of sonicated microbubbles. In the nicorandil group, we injected 4 mg of nicorandil followed by the infusion at 6 mg/h for 24 h and by oral nicorandil (15 mg/day).

RESULTS

The improvement in regional left ventricular function, wall motion score and regional wall motion was significantly better in the nicorandil group then in the control group. Intractable congestive heart failure, malignant ventricular arrhythmia and pericardial effusion were more frequently found in the control group than in the nicorandil group (15% vs. 37%, 5% vs. 20% and 8% vs. 37%, p < 0.05, respectively). The frequency of sizable MCE no reflow phenomenon was significantly lower in the nicorandil group than in the control group (15% vs. 33%, p < 0.05).

CONCLUSIONS

Intravenous nicorandil in conjunction with coronary angioplasty is associated with better functional and clinical outcomes compared to angioplasty alone in patients with an anterior AMI. Myocardial contrast echocardiography findings imply that an improvement in microvascular function with nicorandil may be attributable to this better outcome.

Abbreviations and Acronyms   AMI = acute myocardial infarction   ANOVA = analysis of variance   ATP = adenosine triphosphate   CHF = congestive heart failure   ECG = electrocardiography   LV = left ventricular   LVEDVI = left ventricular end-diastolic volume index   MCE = myocardial contrast echocardiography   TIMI = Thrombolysis in Myocardial Infarction

The goal of this study is to assess the effect of intravenous nicorandil on the functional improvement, left ventricular morphology, in-hospital complications and survival in patients with reperfused anterior wall AMI. We chose intravenous rather than intracoronary injection, because this approach is easy and can be widely accepted in clinical settings. To assess its mechanism of cardioprotection, we also studied its effect on coronary microvasculature with myocardial contrast echocardiography (MCE).

	Methods

Top Abstract Methods Results Discussion References

 
Study population.   From February 1994 through November 1996, 90 patients who were admitted to the Coronary Care Unit of the Sakurabashi Watanabe Hospital for their first myocardial infarction of the anterior wall and presented Thrombolysis in Myocardial Infarction (TIMI) grade 0 or 1 flow (12) at initial coronary angiography were considered study population. The diagnosis of AMI was made on the basis of chest pain of 30 min duration, ST segment elevation of 2 mm in two contiguous electrocardiographic (ECG) leads and more than threefold increase in serum creatine kinase activities. Nine patients were excluded from analysis because of: inadequate image quality (four patients) and coronary stenosis >90% in another coronary artery (five patients). Therefore, this report is based on the remaining 81 patients. All patients underwent percutaneous transluminal coronary angioplasty and achieved successful coronary reflow (TIMI grade 2 or 3) within 12 h after the symptom onset. An investigator obtained written informed consent from each patient. The study protocol was approved by the hospital’s Ethics Committee.

Protocol.   Just after the diagnosis of AMI, we randomly divided patients into two groups, nicorandil and control groups. After the bolus injection of nicorandil (4 mg) (Sigmat, Chugai), it was continuously injected at 6 mg/h for 24 h followed by oral nicorandil 15 mg/day until the discharge (a mean of 28 days) in the nicorandil group. Other protocols were the same between the two groups. All patients underwent cardiac catheterization with the use of the femoral approach after the injection of 100 U/kg heparin. After the injection of 0.3 mg of nitroglycerine into the left coronary artery, we performed the coronary angiography and left ventriculography. Then, we injected 2 ml of sonicated ioxaglate (Hexabrix-360, Tanabe) containing microbubbles (mean size, 12 µm) into the left coronary artery for MCE as previously described (13,14). We used a mechanical sector scanner (model SAL-38B, Toshiba; carrier frequency, 3.5 MHz or SONOS 100, Hewlett-Packard; carrier frequency, 2.5 MHz). We initiated imaging of the apical long-axis view about 10 s before the contrast injection and continued it for an average of 30 s with constant gain setting. Myocardial contrast echocardiography images were recorded on 1.25-cm videotape with a S-VHS recorder (model AG-7350, Panasonic). We repeated MCE with the contrast injection into the right coronary artery. We also performed MCE a mean of 16 min (10 to 24 min) after angioplasty.

After angioplasty, heparin was continued for 48 h and was adjusted to maintain the activated clotting time to >180 s. All patients were maintained on a regimen of aspirin or ticlopidine and coumadine. If required, oral nitrates, calcium antagonists, beta-adrenergic blocking agents diuretics and/or angiotensin-converting enzyme inhibitors were added and continued until the late stage examination. We continuously monitored a lead V₅-equivalent ECG until a mean of 7 days after the infarction (range, 3 to 10 days) for detecting arrhythmia. We performed the two-dimensional echocardiography on admission and at days 2, 3, 7 and 21 of the AMI with a commercially available electrical sector scanner (SONOS 1500 or 2500, Hewlett-Packard, carrier frequency of 2.5 or 3.75 MHz) and recorded the images on 1.25-cm videotape with the same S-VHS recorder. The presence or absence of pericardial effusion was also evaluated. We repeated coronary angiography and left ventriculography at a mean of 25 days after the AMI (range, 24 to 29 days) by use of the right brachial approach.

Analysis of echocardiographic data.   We analyzed echocardiograms with a commercially available off-line computer system (Color Cardiology Workstation, TomTec Imaging). The details of analysis were described elsewhere (13–15). In brief, an operator who did not know patients’ data selected echocardiographic images with the best delineation between contrast-enhanced and nonenhanced myocardium to determine risk area which was determined to be an area showing contrast defect in the prereflow MCE images. Only when the endocardial length of contrast perfusion defect after angioplasty exceeded a quarter of that of the risk area was myocardial reperfusion in the corresponding segment considered incomplete (MCE no reflow). Areas showing contrast defects were always successfully defined, and measurements of the size of the residual contrast defects were highly reproducible (13). Left ventricular wall motion was evaluated at baseline and at follow-up (day 21) according to the previously reported method (13). We scored 17 segments of the left ventricle using the following system: 3, dys/akinetic; 2, severely hypokinetic; 1, hypokinetic; 0, normal. We defined a sum of segmental scores as wall motion score. Two independent observers who did not know clinical data determined the segmental score, and a third observer established consensus in cases of disagreement.

Analysis of catheterization data.   An angiographer blinded to patient’ data analyzed the cinefilms in a random sequence. The right anterior oblique view of left ventriculograms at acute and convalescent stages was analyzed. End-diastolic volume and ejection fraction were measured with the area-length method. The regional wall motion (standard deviation/chord) of the territory of the left anterior descending coronary artery was analyzed with the centerline method (16). The percent diameter stenosis after angioplasty and at follow-up study was measured. Collateral channels were graded following Rentrop classification (17).

In-hospital data collection.   We followed up the patients for the occurrence of complications until the time of hospital discharge. We carefully collected data on clinically relevant in-hospital events (death from any cause and reinfarction) in the study forms. The type and frequency of ventricular arrhythmias were evaluated from monitor ECG in the catheter laboratory and in the Coronary Care Unit. Malignant ventricular arrhythmia was defined as ventricular tachycardia (a minimum of three consecutive beats of ventricular origin at a rate of >100 beat/min) and ventricular fibrillation found within 24 h after angioplasty. Congestive heart failure (CHF) was diagnosed based on the same clinical criteria as previously reported (18). Early postinfarction angina was defined as angina pectoris observed within 7 days after the onset of the AMI. Late postinfarction angina was defined by angina pectoris found beyond 7 days after the AMI and was evaluated mainly by symptom-limited bicycle ergometer exercise test performed at a mean of 25 days after the AMI (range, 24 to 27 days). Pericardial effusion and cardiac tamponade were diagnosed based on clinical and echocardiographic findings.

Statistical analysis.   All data are expressed as mean ± SD. Univariate analyses of differences between control and nicorandil groups were performed with one-way analysis of variance (ANOVA) (Scheffé F test) for continuous outcome variables and by chi-square tests or Fisher exact test for discrete outcome variables. Statistical analysis of temporal changes in certain variables was computed by ANOVA and Scheffé F test for repeated measures. Differences were considered significant at p < 0.05.

	Results

Top Abstract Methods Results Discussion References

 
Forty patients received the intravenous and oral nicorandil, and were designated as the nicorandil group. The other 41 patients were served as the control group. There were no differences in age, gender, culprit lesion, time from the symptom onset to reperfusion, heart rate, blood pressure, frequency of non–Q wave AMI, collateral grade or risk factors between the two groups (Table 1). There were also no differences in the in-hospital medications other than nicorandil between the two groups.

View this table: [in this window] [in a new window]   Table 5 Functional Outcomes (Cases of Onset–Reperfusion Time 6 h)

View larger version (31K): [in this window] [in a new window]   Figure 1 Comparison of frequency of MCE no reflow between nicorandil and control groups. Frequency of MCE no reflow was significantly lower in the nicorandil group than in the control group. Relative risk for MCE no reflow with nicorandil was 0.34. Abbreviations: CI = confidence interval; MCE = myocardial contrast echocardiography.

	Discussion

Top Abstract Methods Results Discussion References

Frequency of either pericardial effusion or cardiac tamponade was significantly lower in the nicorandil group than in the control group. Frequency of malignant ventricular arrhythmia was also significantly lower in the nicorandil group than in the control group. In the previous study, we also reported that the frequencies of pericardial effusion, cardiac tamponade and reperfusion arrhythmia are significantly higher in patients with MCE no reflow than in those with MCE reflow. The broad and extensive myocardial damage in cases of MCE no reflow may contribute to the occurrence of malignant ventricular arrhythmia, pericarditis or oozing rupture (18). Thus, the lower frequencies of post-AMI complications in the nicorandil group should be explained by the lower incidence of MCE no reflow of this group.

Left ventricular remodeling is sometimes observed during the early convalescent period of AMI. Although this dilation appears to represent a compensatory mechanism for suppressed LV function, it sometimes profoundly damages LV function and affects patient prognoses. Although coronary reperfusion per se might have a beneficial effect of preventing LV dilation, a substantial population (19% to 42%) of patients still manifest significant LV dilation (22–24). Among patients with reperfused AMI, we previously reported that MCE no flow can strongly discriminate patients with LV dilation from those with MCE reflow. This is because the sizable no reflow phenomenon indicates the presence of greater size of AMI.

In this study, LVEDVI decreased from acute to late stage of AMI in the nicorandil group, whereas it increased in the control group. This finding was more evident in patients who underwent angioplasty within 6 h after the symptom onset. This result may be explained by the lower frequency of MCE no reflow in the nicorandil group. In addition to the possible smaller size of AMI in the nicorandil group, success of coronary perfusion at microcirculation may enhance the healing process of infarct tissue. Reduction of LV load with nicorandil may play an additional role in the prevention of LV dilation, although the hemodynamic variables were not different between the two groups.

Comparison with previous studies.   In the previous study (5), we injected verapamil into the infarct-related artery after angioplasty in patients with AMI. We observed a decrease in size of the no reflow phenomenon and an increase in contrast peak intensity, which imply improvement in the microvascular function. This was associated with better improvement in LV function than angioplasty alone. Recently, Sakata et al. reported that the single administration of intracoronary nicorandil after angioplasty improves microvascular function, which was associated with better recovery of postischemic myocardial function in patients with AMI (4). In these studies, verapamil or nicorandil was injected directly into the coronary artery only after the presence or absence of no reflow phenomenon was judged with MCE. In contrast with these studies, we continuously injected nicorandil intravenously in the present study, but a similar salutary effect was demonstrated.

This may be explained by the difference in the onset and duration of the drug administration. We initiated the intravenous nicorandil just after the diagnosis of AMI was established, and it was at least 30 min before angioplasty. This was because we considered it hard to deliver nicorandil into the whole risk area, once the no reflow phenomenon is established. In an experimental study, Villanueva et al. (25) documented that the size of no reflow is minimal at the moment of coronary reperfusion, and it increases until 15 min after reperfusion, at which point we usually evaluate the presence or absence of this phenomenon in the clinical setting. This result indicates that myocardial blood flow may once be present even in no reflow zone. In such an instance, nicorandil may be effectively delivered to the postischemic microvascular beds on the blood flow at reperfusion. Additionally, nicorandil may also be delivered to the risk area by collateral flow before coronary reperfusion.

We continued the intravenous injection of nicorandil at least 24 h followed by the oral administration. Several studies have demonstrated that the no reflow phenomenon may progress for several hours after coronary reperfusion (26,27). The continuous infusion of nicorandil may restrain the progression of microvascular damages.

Possible mechanisms.   Several mechanisms were postulated to explain the direct cardioprotective effect of nicorandil. First, opening of the K_ATP channel in the ischemic myocardium shortens the duration of the action potential and inhibits voltage-dependent Ca²⁺ channels and Na⁺/Ca²⁺ exchange. Because Ca²⁺ overload in myocyte causes cellular damage, the inhibition of these routes for Ca²⁺ influx may largely contribute to cardioprotection. Second, nicorandil reduces neutrophil infiltration into the ischemic myocardium (8,10). It also attenuates the activity of neutrophil in a concentration-dependent manner (28). This reduction may attenuate microvascular injury caused by neutrophil, leading to an increase in myocardial blood flow. The attachment and migration of neutrophil through inflamed vessels is dependent on shear rate, and an increase in shear rate due to an increase in microvascular flow may also reduce neutrophil recruitment. An increase in blood flow can enhance the functional improvement of stunned myocardium (29). Third, this may be related to the hemodynamic effect that is characterized by a reduction of preload and/or afterload. Finally, the vessels <100 µm are more sensitive to nicorandil than other size vessels (30).

The characteristic of nicorandil to reduce infarct size when given after coronary occlusion is not shared by other K_ATP channel openers. In fact, bimakalim exerts its protective effects so long as it is given before the onset of ischemia, whereas it has no beneficial effect when administrated only during the reperfusion period (31–33). The difference between nicorandil and bimakalim can be explained only by supporting that a mechanism other than K_ATP channel opening is responsible for the cardioprotective effect of nicorandil. This may be in part explained by its nitrates activity.

Limitations.   We selected the maximal intravenous dose allowed for the treatment of unstable angina pectoris and the oral dose routinely used in patients with angina pectoris. The optimal dose and protocol of nicorandil may be different from the protocol of this study. Our analysis was based on a comparison of in-hospital complications and functional outcomes only; survival and quality of life in a longer follow-up period were not taken into consideration. The salutary effect of intravenous nicorandil has not been established in patients with an inferior or posterior wall AMI or a recurrent AMI.

Myocardial contrast echocardiography data should be considered in light of several limitations. First, our method depends on image quality. Second, contrast intensity is influenced by many factors, including the size and number of microbubbles, factors altering ultrasonic reflection such as gain setting, depth of penetration, incident angle, axial and lateral resolution, gray scale compression and the nonlinearity of echo amplitude signals.

Clinical implications.   Assessment of microvascular perfusion with MCE seems to be essential in gaining further understanding of patients’ outcome and of the relation between intervention and outcome, since MCE is a useful method available for assessment of microvascular integrity. The prompt assessment of both coronary anatomy and the quality of microvascular perfusion and hence myocardial viability may aid in decision making in individual patients. Our results indicated that the intravenous nicorandil partially restrains ischemic microvascular damages and, thereby, augments myocardial blood flow. This was associated with better functional and clinical outcomes than angioplasty alone. Thus, we should achieve and maintain not only the patency of the epicardial coronary artery but also that of coronary microvasculature with pharmacologic intervention to achieve an optimal myocardial salve in AMI. Myocardial contrast echocardiograhy provides a useful method to promptly evaluate the salutary effect of these drugs on coronary microcirculation.

	Acknowledgments

 
We greatly acknowledge the excellent technical assistance of Yuzo Sakagami, Yoshiki Jonishi, Hideshi Shimokawa and Masakazu Ueda and the excellent secretarial assistance of Hideko Masuda.

	References

Top Abstract Methods Results Discussion References

 

1. Hillis LD, Former S, Braunwald E. Risk stratification before thrombolytic therapy in patients with acute myocardial infarction. J Am Coll Cardiol. 1990;16:313–315[Abstract]
2. Gruppo Italiano per lo Studio Della Streptokinesi Nell’ Infarcto Micardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;i:397–401
3. Kennedy JW, Ritchie JL, Davis KB, Fritz JK. Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction. N Engl J Med. 1983;309:1477–1482[Abstract]
4. Sakata Y, Kodama K, Momamura K, et al. Salutary effect of adjunctive intracoronary nicorandil administration on restoration of myocardial blood flow and functional improvement in patients with acute myocardial infarction. Am Heart J. 1997;133:616–621[CrossRef][Medline]
5. Taniyama Y, Ito H, Iwakura K, et al. Beneficial effect of intracoronary verapamil on microvascular and myocardial salvage in patients wtih acute myocardial infarction. J Am Coll Cardiol. 1997;30:1193–1199[Abstract]
6. Mahaffey KW, Puma JA, Barbagelata A, et al. Does adenosine in conjunction with thrombolysis reduce infarct size? Results from the controlled, randomized AMISTAD trial. Circulation. 1997;96(Suppl I):I-206
7. Auchampach JA, Cavero I, Gross GJ. Nicorandil attenuates myocardial dysfunction associated with transient ischemia by opening ATP-dependent pottasium channels. J Cardiovasc Pharmacol. 1992;20:765–771[Medline]
8. Mizunuma T, Nithipatikom K, Gross GJ. Effects of nicorandil and glyveryl trinitrate on infarct size, adenosine release, and neutrophil infiltration in the dog. Cardiovasc Res. 1995;29:482–489[CrossRef][Medline]
9. Klein HH, Pich S, Lindert-Heimberg S, Shade-Brittinger C, Maisch B, Nebendahl K. Comparative study on the effects of intracoronary nicorandil and nitroglycerin in ischaemic, reperfused porcine hearts. Eur Heart J. 1995;16:603–609[Abstract/Free Full Text]
10. Galie N, Guarnieri C, Ussia GP, et al. Limitation of myocardial infarct size by nicorandil after sustained ischemia in pigs. J Cardiovasc Pharmacol. 1995;26:477–484[Medline]
11. Kitakaze M, Minamino T, Node K, et al. Role of activation of ectopic 5'-nucleotidase in the cardioprotection mediated by opening K⁺ channels. Am J Physiol. 1996;270:H1744–H1756
12. Cheesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I: A comparison between intravenous plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation. 1987;76:142–154[Abstract/Free Full Text]
13. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation. 1992;85:1699–1705[Abstract/Free Full Text]
14. Ito H, Iwakura K, Oh H, et al. Recovery of coronary microcirculation after coronary reflow in patients with anterior wall acute myocardial infarction: its correlates to myocardial viability. Circulation. 1995;91:656–662[Abstract/Free Full Text]
15. Ito H, Tomooka T, Sakai N, et al. Time course of functional improvement in stunned myocardium in risk area in patients with reperfused anterior infarction. Circulation. 1993;87:355–362[Abstract/Free Full Text]
16. Sheehan FH, Bolson EL, Dodge HT, Mathey DG, Schofer J, Woo H-W. Advantages and applications of the centerline method for characterizing regional ventricular function. Circulation. 1986;74:293–305[Abstract/Free Full Text]
17. Cohen M, Rentrop KP. Limitation of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study. Circulation. 1986;74:469–476[Abstract/Free Full Text]
18. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of ‘no reflow’ phenomenon: a predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation. 1996;93:223–228[Abstract/Free Full Text]
19. Kloner RA, Ganote CE, Jennings RB. The "no reflow" phenomenon after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496–1508[Medline]
20. Kloner RA, Rude RE, Carlson N, Maroko PR, DeBoer LWV, Braunwald E. Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: which comes first? Circulation. 1980;62:945–952[Abstract/Free Full Text]
21. Johnson WB, Malone SA, Pantely GA, Anselone CG, Bristow JD. No reflow and extent of infarction during maximal vasodilation in the porcine heart. Circulation. 1988;78:462–472[Abstract/Free Full Text]
22. Erlebacher JA, Weiss JL, Weisfeldt ML, Bulkley MB. Early dilation of the infarcted segment in acute transmural myocardial infarction: role of infarct expansion in acute ventricular enlargement. J Am Coll Cardiol. 1984;4:201–208[Abstract]
23. Hochman JS, Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation. 1987;75:299–306[Abstract/Free Full Text]
24. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81:1161–1172[Abstract/Free Full Text]
25. Villaneuva FS, Glasheen WP, Sklenar J, Kaul S. Characterization of spatial patterns of flow within the reperfused myocardium by myocardial contrast echocardiography. Implication in determining extent of myocardial salvage. Circulation. 1993;88:2596–2606[Abstract/Free Full Text]
26. Ambrosio G, Weisman HF, Mnnisi JA, Becker LC. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation. 1989;80:1841–1861
27. Jeremy RW, Links JM, Becker CC. Progressive failure of coronary flow during reperfusion of myocardial infarction: documentation of the no reflow phenomenon with positron emission tomography. J Am Coll Cardiol. 1990;16:695–704[Abstract]
28. Pieper GM, Gross GJ. Anti-free-radical and neutrophil-modulating properties of the nitrovasodilator, nicorandil. Cardiovasc Drugs Ther. 1992;2:225–232
29. Stahl LD, Aversano TR, Becker LC. Selective enhancement of function of stunned myocardium by increased flow. Circulation. 1986;74:843–851[Abstract/Free Full Text]
30. Akai K, Wang Y, Sato K, et al. Vasodilatory effect of nicorandil on coronary arterial microvessels: its dependency on vessel size and the involvement of the ATP-sensitive potassium channels. J Cardiovasc Pharmacol. 1995;26:541–547[Medline]
31. Yao Z, Gross GJ. Effects of KATP channel opener bimakalim on coronary blood flow, monophasic action potential duration, and infarct size in dogs. Circulation. 1994;89:1769–1775[Abstract/Free Full Text]
32. Rohmann S, Weygandt H, Chelling P, et al. Effect of bimakalim, an opener of ATP sensitive potassium channels, on infarct size, coronary blood flow, regional wall motion, and oxygen consumption in swine. Cardiovasc Res. 1994;28:858–863[Abstract/Free Full Text]
33. Mizumura T, Nithipatikom K, Gross GJ. Bimakalim, an ATP-sensitive potassium channel opener, mimics the effect of ischemic preconditioning to reduce infarct size, adenosine release, and neutrophil function in dogs. Circulation. 1995;92:1236–1245[Abstract/Free Full Text]

This article has been cited by other articles:

				A. Okamura, H. Ito, K. Iwakura, T. Kurotobi, Y. Koyama, M. Date, Y. Higuchi, K. Inoue, and K. Fujii Clinical Implications of Distal Embolization During Coronary Interventional Procedures in Patients With Acute Myocardial Infarction: Quantitative Study With Doppler Guidewire J. Am. Coll. Cardiol. Intv., June 1, 2008; 1(3): 268 - 276. [Abstract] [Full Text] [PDF]

				P. A. Grayburn and J. W. Choi Advances in the assessment of no-reflow after successful primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: now that we can diagnose it, what do we do about it? J. Am. Coll. Cardiol., February 5, 2008; 51(5): 566 - 568. [Full Text] [PDF]

				S. A. Hayat and R. Senior Myocardial contrast echocardiography in ST elevation myocardial infarction: ready for prime time? Eur. Heart J., February 1, 2008; 29(3): 299 - 314. [Abstract] [Full Text] [PDF]

				S. Kasama, T. Toyama, H. Sumino, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi Long-Term Nicorandil Therapy Improves Cardiac Sympathetic Nerve Activity After Reperfusion Therapy in Patients with First Acute Myocardial Infarction J. Nucl. Med., October 1, 2007; 48(10): 1676 - 1682. [Abstract] [Full Text] [PDF]

				M. T. Dirksen, G. J. Laarman, M. L. Simoons, and D. J.G.M. Duncker Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies Cardiovasc Res, June 1, 2007; 74(3): 343 - 355. [Abstract] [Full Text] [PDF]

				C. J. Terkelsen, B. L. Norgaard, J. F. Lassen, S. H. Poulsen, J. C. Gerdes, E. Sloth, L. B.-H. Gotzsche, F. K. Romer, L. Thuesen, T. T. Nielsen, et al. Potential significance of spontaneous and interventional ST-changes in patients transferred for primary percutaneous coronary intervention: observations from the ST-MONitoring in Acute Myocardial Infarction study (The MONAMI study) Eur. Heart J., February 1, 2006; 27(3): 267 - 275. [Abstract] [Full Text] [PDF]

				H. Ishii, S. Ichimiya, M. Kanashiro, T. Amano, T. Matsubara, and T. Murohara Effects of Intravenous Nicorandil Before Reperfusion for Acute Myocardial Infarction in Patients With Stress Hyperglycemia Diabetes Care, February 1, 2006; 29(2): 202 - 206. [Abstract] [Full Text] [PDF]

				H. Ishii, S. Ichimiya, M. Kanashiro, T. Amano, K. Imai, T. Murohara, and T. Matsubara Impact of a Single Intravenous Administration of Nicorandil Before Reperfusion in Patients With ST-Segment-Elevation Myocardial Infarction Circulation, August 30, 2005; 112(9): 1284 - 1288. [Abstract] [Full Text] [PDF]

				G. A. Krombach, C. B. Higgins, M. Chujo, and M. Saeed Gadomer-enhanced MR Imaging in the Detection of Microvascular Obstruction: Alleviation with Nicorandil Therapy Radiology, August 1, 2005; 236(2): 510 - 518. [Abstract] [Full Text] [PDF]

				K. P. Bouki, G. Pavlakis, and E. Papasteriadis Management of Cardiogenic Shock Due to Acute Coronary Syndromes Angiology, March 1, 2005; 56(2): 123 - 130. [Abstract] [PDF]

				R. Bolli, L. Becker, G. Gross, R. Mentzer Jr, D. Balshaw, and D. A. Lathrop Myocardial Protection at a Crossroads: The Need for Translation Into Clinical Therapy Circ. Res., July 23, 2004; 95(2): 125 - 134. [Abstract] [Full Text] [PDF]

				H. Ueda, T. Hayashi, K. Tsumura, K. Yoshimaru, Y. Nakayama, and J. Yoshikawa Intravenous Nicorandil Can Reduce QT Dispersion and Prevent Bradyarrhythmia During Percutaneous Transluminal Coronary Angioplasty of the Right Coronary Artery Journal of Cardiovascular Pharmacology and Therapeutics, July 1, 2004; 9(3): 179 - 184. [Abstract] [PDF]

				S. Schalla, C. B. Higgins, M. Chujo, and M. Saeed Effect of Potassium-Channel Opener Therapy on Reperfused Infarction in Hypertrophied Hearts: Demonstration of Preconditioning by Using Functional and Contrast-Enhanced Magnetic Resonance Imaging Journal of Cardiovascular Pharmacology and Therapeutics, July 1, 2004; 9(3): 193 - 202. [Abstract] [PDF]

				T. Sakuma, J. Sklenar, H. Leong-Poi, N. C. Goodman, D. K. Glover, and S. Kaul Molecular Imaging Identifies Regions with Microthromboemboli During Primary Angioplasty in Acute Coronary Thrombosis J. Nucl. Med., July 1, 2004; 45(7): 1194 - 1200. [Abstract] [Full Text] [PDF]

				K. Greaves, S. R Dixon, I. O. Coker, A. I Mallet, M. Vkiran, M. J Shattock, M. J Fejka, W. W O'Neill, R. Senior, S. Redwood, et al. Influence of isoprostane F2{alpha}-III on reflow after myocardial infarction Eur. Heart J., May 2, 2004; 25(10): 847 - 853. [Abstract] [Full Text] [PDF]

				X.-L. Tang, Y.-T. Xuan, Y. Zhu, G. Shirk, and R. Bolli Nicorandil induces late preconditioning against myocardial infarction in conscious rabbits Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1273 - H1280. [Abstract] [Full Text] [PDF]

				M. Takeuchi, Y. Nohtomi, H. Yoshitani, C. Miyazaki, K. Sakamoto, and J. Yoshikawa Enhanced coronary flow velocity during intra-aortic balloon pumping assessed by transthoracic doppler echocardiography J. Am. Coll. Cardiol., February 4, 2004; 43(3): 368 - 376. [Abstract] [Full Text] [PDF]

				L Galiuto Optimal therapeutic strategies in the setting of post-infarct no reflow: the need for a pathogenetic classification Heart, February 1, 2004; 90(2): 123 - 125. [Full Text] [PDF]

				N Ikeda, T Yasu, N Kubo, S Hashimoto, Y Tsuruya, M Fujii, M Kawakami, and M Saito Nicorandil versus isosorbide dinitrate as adjunctive treatment to direct balloon angioplasty in acute myocardial infarction Heart, February 1, 2004; 90(2): 181 - 185. [Abstract] [Full Text] [PDF]

				S. Kaul and H. Ito Microvasculature in Acute Myocardial Ischemia: Part II: Evolving Concepts in Pathophysiology, Diagnosis, and Treatment Circulation, January 27, 2004; 109(3): 310 - 315. [Full Text] [PDF]

				D. T. Ashby, G. Dangas, E. A. Aymong, I. Iakovou, F. Kuepper, R. Mehran, G. W. Stone, M. B. Leon, and J. W. Moses Effect of percutaneous coronary interventions for in-stent restenosis in degenerated saphenous vein grafts without distal embolic protection J. Am. Coll. Cardiol., March 5, 2003; 41(5): 749 - 752. [Abstract] [Full Text] [PDF]

				A.S Petronio, D Rovai, G Musumeci, R Baglini, C Nardi, U Limbruno, C Palagi, D Volterrani, and M Mariani Effects of abciximab on microvascular integrity and left ventricular functional recovery in patients with acute infarction treated by primary coronary angioplasty Eur. Heart J., January 1, 2003; 24(1): 67 - 76. [Abstract] [Full Text] [PDF]

				K. Iwakura, H. Ito, M. Ikushima, S. Kawano, A. Okamura, K. Asano, T. Kuroda, K. Tanaka, T. Masuyama, M. Hori, et al. Association between hyperglycemia and the no-reflow phenomenon inpatients with acute myocardial infarction J. Am. Coll. Cardiol., January 1, 2003; 41(1): 1 - 7. [Abstract] [Full Text] [PDF]

				J P Greenwood, I Malik, P Jennings, and R N Stevenson Haemodynamic and electrocardiographic consequences of severe nicorandil toxicity Emerg. Med. J., January 1, 2003; 20(1): 98 - 100. [Abstract] [Full Text] [PDF]

				K Shimada, Y Sakanoue, Y Kobayashi, S Ehara, M Hirose, Y Nakamura, D Fukuda, H Yamagishi, M Yoshiyama, K Takeuchi, et al. Assessment of myocardial viability using coronary zero flow pressure after successful angioplasty in patients with acute anterior myocardial infarction Heart, January 1, 2003; 89(1): 71 - 76. [Abstract] [Full Text] [PDF]

				A. Tsuchida, T. Miura, M. Tanno, J. Sakamoto, T. Miki, A. Kuno, T. Matsumoto, Y. Ohnuma, Y. Ichikawa, and K. Shimamoto Infarct size limitation by nicorandil: Roles of mitochondrial KATP channels, sarcolemmal KATP channels, and protein kinase C J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1523 - 1530. [Abstract] [Full Text] [PDF]

				S. Genda, T. Miura, T. Miki, Y. Ichikawa, and K. Shimamoto KATP channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1339 - 1346. [Abstract] [Full Text] [PDF]

C.-K. Wong, J.K. French, M.W. Krucoff, W. Gao, P.E. Aylward, and H.D. White Slowed ST segment recovery despite early infarct