Intracoronary Administration Of Nicorandil Research Articles

Acute Effects of Isosorbide Dinitrate and Nicorandil on the Coronary Slow Flow Phenomenon

Microvascular dysfunction has been proposed as the most likely mechanism of the coronary slow flow phenomenon (CSFP). To determine the effects of isosorbide dinitrate and nicorandil on the CSFP. Changes in thrombolysis in myocardial infarction (TIMI) frame count following the intracoronary administration of isosorbide dinitrate and nicorandil were assessed in 11 patients with the CSFP. After the administration of isosorbide dinitrate, the median TIMI frame count decreased to 32 (range 20-60) [p = 0.003], which was lower than that of the control [43 (29-73)]. The count decreased further to 25 (12-34) [p = 0.041] after the administration of nicorandil. The count after the subsequent administration of contrast medium was increased to 32 (20-49) [p = 0.03]. These angiographic findings indicate that the intracoronary administration of nicorandil is superior to isosorbide dinitrate with regard to improving the CSFP. These findings suggest that microvascular spasm is the main factor in the pathogenesis of the CSFP.

High Index of Microcirculatory Resistance Level After Successful Primary Percutaneous Coronary Intervention Can Be Improved by Intracoronary Administration of Nicorandil

Although microvascular dysfunction following percutaneous coronary intervention (PCI) can be evaluated with the index of microcirculatory resistance (IMR), no method of treatment has been established. We hypothesized that intracoronary administration of nicorandil can improve IMR after successful primary PCI in patients with ST-segment elevation myocardial infarction (STEMI). In 40 patients with first STEMI after successful primary PCI, IMR was measured using PressureWire(TM) Certus (St. Jude Medical, MN, USA). In 20 of the patients (Group N), IMR was measured at baseline and after intracoronary nicorandil (2 mg/10 ml). In the other 20 patients (Control), IMR was measured at baseline, after intracoronary saline (10 ml) and after intracoronary nicorandil (2 mg/10 ml). In Group N, IMR significantly decreased after intracoronary nicorandil (median IMR, 27.7-18.7 U, P<0.0001). In the Control group, IMR did not change after saline administration (median IMR, 24.3-23.8 U, P=0.8193), but was significantly decreased after intracoronary nicorandil (median IMR, 23.8-14.9 U, P<0.0001). Next, all 40 patients were divided into subgroups by tertile of baseline IMR. In those with intermediate to high IMR (baseline IMR > or =21), intracoronary nicorandil significantly decreased IMR, although it did not change IMR in those with low IMR (baseline IMR <21). High IMR levels in patients with STEMI after successful primary PCI can be improved by intracoronary administration of nicorandil.

The Effect of Intracoronary Nicorandil on Coronary Myocardial Bridging

Medical treatments of coronary myocardial bridging (CMB) generally include beta-blockers and calcium channel blockers. Nitrates are avoided because symptoms may worsen. Nicorandil is a hybrid of a nitrate and a potassium channel opener. However, the effect of nicorandil on CMB is unknown. We analyzed nicorandil reactivity at the site with CMB in 51 patients. Maximal and minimal diameters of CMB were measured by quantitative angiography at baseline and at 60 seconds after intracoronary administration of 200 mg nicorandil. The maximal diameter during diastole increased from 2.15 + 0.42 mm to 2.34 + 0.44 mm after administration of nicorandil (P < .001), and the minimal diameter during systole increased from 1.24 + 0.63 mm to 1.67 + 0.64 mm (P < .001). Thus, nicorandil reduced the percentage vessel narrowing from 44.0 + 26.1% to 30.3 + 21.2% (P < .001). In 22 patients, we also evaluated the effect of nitroglycerin. The maximal diameter during diastole increased from 2.25 + 0.47 mm to 2.51 + 0.44 mm after administration of nitroglycerin (P < .019), and the minimal diameter during systole decreased from 1.28 + 0.64 mm to 1.14 + 0.60 mm (P = .276). Thus, nitroglycerin augmented the percentage vessel narrowing from 44.9% + 25.0% to 56.0% + 23.5% (P = .023). These results indicate that intracoronary administration of nicorandil could dilate coronary arteries during diastole as well as systole in patients with CMB during coronary angiography.

Intracoronary Nicorandil Relieves Multiple Coronary Vasospasm With Hemodynamic Collapse

A 49-year-old woman was referred to hospital because of chest discomfort. Coronary angiography revealed subtotal occlusion of the left coronary artery and the right coronary artery, but subsequent hemodynamic collapse occurred. Based on the results of intravascular ultrasound the occlusion was suspected to be caused by coronary vasospasm, which was not relieved by intracoronary injection of isosorbide dinitrate (1 mg), but was alleviated by nicorandil (2 mg), a potassium-channel opener. After discharge from hospital, the patient stopped taking her medication and returned complaining of chest discomfort again. Intravenous verapamil (5 mg) did not improve it, but direct intracoronary administration of nicorandil (2 mg) did bring relief. This case suggests that nicorandil is effective for coronary vasospasm.

Effect of Intra-Coronary Nicorandil Administration Prior to Reperfusion in Acute ST Segment Elevation Myocardial Infarction

Intravenous nicorandil infusion with percutaneous coronary intervention (PCI) has been reported to reduce reperfusion injury events and improve cardiac function in patients with acute myocardial infarction (MI). However, there is limited information on the use of intracoronary nicorandil. In the present study, 73 patients with acute ST segment elevation MI undergoing PCI were randomly assigned to the Nicorandil Group (n=37) or the Control Group (n=36). The composite endpoints were the incidences of ventricular arrhythmia, no-reflow and slow flow. A significant difference in the composite endpoint was observed in the Nicorandil Group when compared with the Control Group (p=0.037). The occurrence of post Thrombolysis In Myocardial Infarction (TIMI) grade 3 was significantly higher in the Nicorandil Group (p=0.019). Major adverse cardiac events during hospitalization and within 30 days of treatment were similar between the 2 groups. Administration of intracoronary nicorandil reduced the occurrence of no-reflow, slow reflow, and reperfusion arrhythmia, and improved the myocardial perfusion grade, TIMI flow during PCI and improved clinical outcomes in patients with acute MI.

Multivessel Coronary Artery Spasm Refractory to Intensive Medical Treatment

This case report describes multivessel coronary artery spasm refractory to oral nifedipine, intravenous isosorbide dinitrate, diltiazem and nicorandil, and intracoronary nitroglycerin. Intracoronary administration of nicorandil only transiently relieved coronary artery spasm. Prednisolone was effective in preventing coronary artery spasm.

Simultaneous Multivessel Coronary Spasm Causing Acute Myocardial Infarction

Spontaneous simultaneous multivessel coronary artery spasm in patients with acute myocardial infarction (AMI) is uncommon. A 79-year-old Japanese man was transferred to this hospital because of severe prolonged chest pain and faintness. Left coronary angiography revealed total occlusion of the left anterior descending and the left circumflex coronary arteries. Moreover, right coronary angiography revealed 99% stenosis of the right coronary artery. After intracoronary administration of nicorandil, left coronary artery and right coronary artery angiography revealed no organic stenosis or thrombus. This is the first report in which simultaneous 3-vessel spasm was documented by emergency angiography in AMI.

Impact of Nicorandil to Prevent Reperfusion Injury in Patients With Acute Myocardial Infarction Sigmart Multicenter Angioplasty Revascularization Trial (SMART)

Nicorandil in conjunction with percutaneous coronary intervention (PCI) has been reported to reduce reperfusion injury events and improve cardiac function in patients with acute myocardial infarction (AMI). This multicenter study was undertaken to determine the effectiveness and optimal administration of nicorandil in AMI patients. Ninety-two patients with first AMI were randomly assigned to 1 of 3 groups: intracoronary administration of nicorandil (Group A), combined intravenous and intracoronary administration of nicorandil (Group B), and no nicorandil administration (Group C). The primary endpoint was a composite of the incidence of reperfusion-induced arrhythmia, chest pain, and no-reflow/slow-reflow. The secondary endpoint was the combined rate of improvement in the Thrombolysis in Myocardial Infarction frame count (cTFC) and ST resolution (STR). A significant difference was observed in the primary endpoint for Group B as compared with Group C (p<0.05). In the meantime, a significant improvement was shown in the secondary endpoint for Group B compared with Group C (p=0.04 and 0.006 for cTFC and STR, respectively). Combined intravenous and intracoronary administration of nicorandil reduces reperfusion injury during PCI and improves the cTFC and STR in AMI, and appears to be preferable to intracoronary administration alone.

Intracoronary administration of nicorandil for the treatment of spontaneous microvascular spasm with ST segment elevation.

A 64-year-old man with a history of previous coronary intervention of the left anterior descending artery was admitted to hospital because of recurrent chest pain at rest. Coronary angiography revealed no significant coronary artery stenosis. During preparation for the second shot of the right coronary artery, chest pain occurred unexpectedly, represented by ST segment elevation in leads II, III and aV(F). Immediate right coronary angiography revealed no significant coronary artery stenosis, but markedly delayed contrast medium washout. Intracoronary administration of nicorandil attenuated this phenomenon, and the patient was diagnosed as having angina pectoris caused by microvascular spasm with ST segment elevation.

Isosorbide-2-mononitrate reduces the consequences of myocardial ischaemia, including arrhythmia severity: implications for preconditioning.

The effects of the intracoronary administration of isosorbide-2-mononitrate (ISMN; 3 microg kg(-1) min(-1)), a major metabolite of isosorbide dinitrate, were examined in chloralose-urethane anaesthetized dogs before and during a 25 min, acute occlusion of the left anterior descending coronary artery. The only significant haemodynamic effects of ISMN administration were a slight (-11 +/- 2 mmHg) decrease in arterial blood pressure and a decrease (< 12%) in diastolic coronary vascular resistance. Coronary occlusion in the presence of ISMN led to a markedly reduced incidence and severity of ventricular arrhythmias compared to those in control, saline-infused dogs. There were fewer ectopic beats (62 +/- 35 versus 202 +/- 72; p < 0.05), a lower incidence (25% versus 75%; p < 0.05) and number of episodes (0.7 +/- 0.4 versus 4.3 +/- 2.1; p < 0.05) of ventricular tachycardia and fewer dogs fibrillated during the ischaemic period (17% versus 82%; p < 0.05). More dogs given ISMN survived the combined ischaemia-reperfusion insult (50% versus 0%; p < 0.05). Changes in ST-segment elevation (recorded by epicardial electrodes) and in the degree of inhomogeneity of electrical activation within the ischaemic area were much less pronounced throughout the occlusion period in dogs given ISMN. These results add weight to the hypothesis that the previously reported antiarrhythmic effects of ischaemic preconditioning, and of the intracoronary administration of nicorandil, involve nitric oxide.

Salutary effect of adjunctive intracoronary nicorandil administration on restoration of myocardial blood flow and functional improvement in patients with acute myocardial infarction

Salutary effect of nicorandil, a K + adenosine triphosphate channel opener, on restoration of myocardial blood flow and functional improvement after coronary revascularization was investigated in 20 patients with first anterior acute myocardial infarction. Ten patients received intracoronary administration of nicorandil (2 mg) after coronary revascularization; the other 10 patients received coronary revascularization only and served as control subjects. Myocardial contrast echocardiography and two-dimensional echocardiography were performed to assess microvascular integrity and regional function in the infarcted area. Nicorandil improved peak contrast intensity ratio ( p < 0.001), calculated as the ratio of peak contrast intensity in the infarcted and noninfarcted areas, indicating the restoration of myocardial blood flow to the infarcted myocardium. Regional wall motion improved more significantly in 1 month in patients who received nicorandil ( p < 0.01). Thus our results suggested the usefulness of intracoronary nicorandil administration after coronary revascularization for restoring blood flow and functional improvement in patients with acute myocardial infarction. (Am Heart J 1997;133:616-21.)

Nicorandil improves ischemic changes in epicardial ECG during short-term coronary occlusion by opening ATP-sensitive potassium channels in pigs.

The aims of this study were to investigate whether nicorandil (NIC), an ATP-sensitive potassium channel (KATP) opener and nitrate, has antiischemic effects during transient ischemia in pigs, and to investigate whether its effects are due to its KATP-opening action or nitrate action. Myocardial ischemia was induced by ligating the proximal portion of the left anterior descending coronary artery for 1 minute in anesthetized open-chest pigs, and was measured as the magnitude of ST-segment elevation on epicardial electrocardiogram (ECG). Epicardial ST-segment elevation during coronary occlusion was significantly reduced by pretreatment with NIC (3 mg, intracoronary [i.c.]), but not by pretreatment with nitroglycerin (NTG, 0.2 mg, i.c.). Pretreatment with glibenclamide (GLB, a KATP blocker, 6 mg, i.c.) significantly augmented the ST-segment elevation during coronary occlusion. The augmentation of ST-segment elevation by GLB was significantly reduced by subsequent administration of NIC, but not by that of NTG (0.2 mg, i.c.). There were no significant differences between hemodynamic variables immediately before coronary occlusion with and without pretreatment. The intracoronary administration of NIC (3 mg) significantly shortened the endocardial monophasic action potential durations at 50% (MAPD50) and 90% repolarization (MAPD90) by 28.3 +/- 6.9% and 17.0 +/- 4.7%, respectively. These results suggest that the intracoronary administration of NIC has antiischemic effects during transient ischemia via KATP activation in myocardium.

Nicorandil suppressed ventricular arrhythmias in a canine model of myocardial ischaemia

These experiments were designed to explore the possibility that a K + channel opener which also donates nitric oxide to the myocardium (nicorandil) may modify ischaemia-induced ventricular arrhythmias in a large animal model. In mongrel dogs anaesthetised with chloralose-urethane and thoracotomised, a side branch of the left anterior descending artery was catheterised for the local intracoronary infusion of nicorandil (2.5 μg kg −1 min −1 for 20 min prior to coronary artery occulusion and then continuing throughout the 25 min occlusion period). In this dose, nicorandil had no haemodynamic effects, increased coronary blood flow by up to 16% and significantly reduced the severity of ischaemia-induced arrhythmias (e.g. from nearly 500 ventricular premature beats in the controls to 160 ± 60 in the nicorandil group). There was a significant reduction in the number of episodes of ventricular tachycardia during the ischaemic period and a reduced incidence of ventricular fibrillation following reperfusion resulting in a 42% survival from the combined ischaemia-reperfusion insult (cf. 0% in the control; P < 0.05). The marked changes that occurred in ST-segment elevation (mapped with epicardial electrodes) and in the inhomogeneity of electrical activation within the ischaemic area in control dogs was markedly reduced in those dogs administered nicorandil. We conclude that the local intracoronary administration of nicorandil reduces the severity of both ischaemia and the life-threatening arrhythmias that result from an abrupt reduction in coronary blood flow in this canine model. Possible mechanisms include an increase in coronary blood flow, a reduction in the severity of myocardial ischaemia and an ability of the compound to ‘donate’ nitric oxide to the ischaemic area.

Reply Mechanisms of action of various ATP-sensitive potassium channel openers

Dr. Grover’s very kind and complimentary remarks about the recent review [l] on ATP-sensitive potassium channel openers during ischemia and reperfusion are much appreciated. One point, however, causes Dr. Grover considerable concern-this is the citation of (and by implication a presumed agreement with) the comments in the paper by Richer et al. [2]. This paper was critical of the conclusions of a study [3] by Dr. Grover and colleagues in which the authors compared intravenous versus intracoronary administration of nicorandil versus cromakalim. This reply to Dr. Grover is from the author of the review [ 1 ] and the senior co-author of the contentious paper [2]. Dr. Grover states that “Professor Hearse criticised this study based on the lOO-fold lower dose of nicorandil given into the coronary”. Dr. Grover then goes on to justify the choice of this dose on the basis of the fact that the coronary bed supplies a very small mass of tissue and therefore a much lower absolute dose is required than with intravenous administration. We filly accept this and indeed, neither the review El] nor the Richer article [2] took specific issue with this aspect of Dr. Grover’s protocol design. The criticism that was intended related not to the choice of dose between intravenous and intracoronary studies but to the fact that Grover et al. [3] used a dose of nicorandil that was only 3 times higher than that selected for cromakalim. What Professor Hearse actually stated in his concluding synopsis of the Richer paper was that “they argued that, since nicorandil was ten times less potent than cromakalim, any study designed to compare the two drugs and the two routes of administration should have employed a larger dose of nicorandil.” The choice of intravenous versus intracoronary dose was not actually contested by the author of the review. The point at issue (which has been made on a previous occasion [4] by the co-signatory of this letter) is quite straight forward: namely, that because nicorandil is at least 10 times less potent than

Coronary microvascular response to intracoronary administration of nicorandil

Nicorandil is an antianginal drug that causes potent coronary vasodilation of both epicardial and resistance vessels. To measure the dose-response kinetics of bolus injections of intracoronary nicorandil and to compare the vasodilatory response to nicorandil with that of intracoronary papaverine in humans, coronary blood flow velocity was measured in 30 patients using a 3Fr intravascular Doppler catheter. Continuous intravenous nitroglycerin 6 to 8 μg/min was infused to achieve maximal vasodilation of the epicardial vessels. Bolus doses of nicorandil dissolved in warmed saline solution were injected into the left (0.1, 0.2, 0.5, 1.0, 1.5, and 2.0 mg) and right (0.1, 0.2, 0.4, 0.8, 1.0, and 1.5 mg) coronary arteries. Intracoronary nicorandil caused a dose-dependent increase in coronary flow velocity and a decrease in coronary vascular resistance. Maximal vasodilatory effects equivalent to those obtained with 12 ± 2 mg of intracoronary papaverine were induced with nicorandil 1.5 mg in the left coronary artery, and effects similar to those of 10 ± 2 mg of papaverine were produced with nicorandil 1.0 mg in the right coronary artery. The time from injection of nicorandil to the onset of maximal hyperemia and duration of hyperemia were significantly shorter after nicorandil than after papaverine in both coronary arteries. Each dose of nicorandil produced no clinical symptoms and fewer changes in systemic hemodynamics and electrocardiographic QT intervals than did papaverine. These results suggest that a bolus administration of intracoronary nicorandil can safely, quickly, and reliably induce maximal coronary hyperemia comparable to that achieved with intracoronary papaverine in humans.

Determination of effective and safe dose for intracoronary administration of nicorandil in dogs

The aim was to evaluate the effective and safe dosage for intracoronary administration of nicorandil (2-nicotinamidoethyl nitrate) in dogs. Five ml of saline with or without nicorandil (0.025, 0.25, 1.0 or 2.5 mg) was constantly infused into the left anterior descending coronary artery (LAD) in 1 min without blood flow reduction in group A (normoxic group, n = 5) and with 50% blood flow reduction of the control value in group B (ischaemic group, n = 5). 10 mongrel dogs of either sex were used, weight 14.6-20.5 kg. The myocardial weight of the perfused area was 33.2(SD 7.9) g. In group A, LAD blood flow increased from 28.4(8.6) to 86.3(25.0) ml.min-1, p less than 0.05, following intracoronary infusion of 0.25 mg nicorandil. Higher doses caused no further increase. In both groups, high doses (1.0 mg or more) suppressed regional myocardial contraction, expressed as % segment shortening, from 20.0(4.7) to 10.0(9.0)%, p less than 0.05, in group A, and from 12.7(8.5) to 6.5(5.6)%, p less than 0.05, in group B. Multiple ventricular premature beats developed in both groups only at the dose of 2.5 mg: 6.8(5.5) beats.min-1 in group A and 4.5(4.2) beats.min-1 in group B. Ventricular fibrillation developed in two dogs in group B. Nicorandil did not affect the local bipolar electrocardiogram of the subendo- and subepicardium in the perfused area in either group. Intracoronary administration of 0.25 mg of nicorandil was effective for coronary vasodilatation without deleterious mechanical or electrical effects. Larger doses of the agent showed adverse effects depending on the dosages.