Author + information
- Received April 27, 2000
- Revision received September 28, 2000
- Accepted November 3, 2000
- Published online March 1, 2001.
- Atsunori Okamura, MD∗,
- Hiromi Rakugi, MD∗,
- Mitsuru Ohishi, MD∗,
- Yoshihiro Yanagitani, MD∗,
- Masumi Shimizu, MD∗,
- Tadahiko Nishii, MD†,
- Yoshiaki Taniyama, MD∗,
- Takashi Asai, MD∗,
- Shin Takiuchi, MD∗,
- Koichi Moriguchi, MD∗,
- Masashi Ohkuro, MD∗,
- Norio Komai, MD∗,
- Kazuo Yamada, MD†,
- Nozomu Inamoto, MD∗,
- Atsuhiro Otsuka, MD†,
- Jitsuo Higaki, MD∗,* ( and )
- Toshio Ogihara, MD∗
- ↵*Reprint requests and correspondence: Dr. Jitsuo Higaki, Department of Geriatric Medicine, Osaka University Medical School, Yamadaoka 2-2 B6, Suita 565-0871, Japan
We examined whether patients with ischemic heart disease (IHD) should be treated with nicorandil, an adenosine triphosphate-sensitive potassium channel opener, in addition to the regular use of nitrates.
It has been reported that nicorandil possibly has additive effects on nitroglycerin (NTG) treatment for angina, but the mechanism is not clear.
We directly measured anterograde coronary blood flow (CBF) with a Doppler guide wire to examine the effects of intravenous administration of NTG (0.3 mg) and nicorandil (6 mg) during continuous administration of NTG at a sufficient dose (25 μg/min) in subjects with normal and stenotic coronary arteries.
Additional systemic administration of NTG decreased anterograde CBF (normal −19.7%; stenotic −21.2%). In contrast, nicorandil increased anterograde CBF in both normal (54.6%) and stenotic (89.6%) coronary arteries, without the coronary steal phenomenon. There was a tendency toward nicorandil-dilated diameters in the patients with stenotic arteries (p = 0.06). There were no effects of additional administration on pulmonary artery wedge pressure. There was no difference in changes in heart rate and mean aortic blood pressure between NTG and nicorandil therapy.
These results suggest that in patients treated with nitrates, additional administration of nicorandil is more useful, in terms of increasing CBF, than additional administration of nitrates. Adjunctive use of nicorandil with nitrates may provide the further benefit of myocardial protection and may improve the prognosis of patients with IHD.
Nitrates are frequently administered to patients with ischemic heart disease (IHD). It is proposed that nitrates exert their benefits by decreasing myocardial oxygen consumption with cardiac unloading and by increasing regional myocardial blood flow. Regional myocardial blood flow is regulated by anterograde flow through the coronary arteries, including stenotic lesions, and by retrograde flow through collateral arteries. Anterograde coronary blood flow (CBF) is determined mainly by diastolic blood pressure, coronary stenosis severity and microvascular resistance, which is important for oxygen supply to the myocardium. However, the effects of nitrates on anterograde CBF are still controversial.
Fallen et al. (1)showed, by using scintigraphy, that topical nitroglycerin (NTG) in a skin patch increased regional blood flow in patients with IHD, without a reduction in blood pressure. However, 7 of 10 patients in this study had collateral arteries. Therefore, the result of Fallen’s study may only mean that retrograde blood flow through the collateral arteries increased. Other studies measuring great vein blood flow showed that intravenous or sublingual administration of NTG decreased regional blood flow, with a reduction in blood pressure (2,3). There is no study of direct measurement of anterograde CBF to evaluate the effects of NTG. The limitation of nitrates in improving the prognosis of patients with IHD, as shown in the Nifedipine Angina Myocardial Infarction Study (NAMIS) (4)and the fourth International Study of Infarct Survival (ISIS-4) (5), may be partly due to a failure to improve CBF.
Nicorandil, N-(2-hydroxyethyl)-nicotinamide (a nitrate), is an antianginal drug that causes coronary vasodilation of both epicardial and resistance vessels, with little reduction in blood pressure (6–8). These effects are correlated with activation of the adenosine triphosphate (ATP)-sensitive potassium channel and increased production of cyclic guanylate monophosphate (9,10). There are several reports comparing the effects of nicorandil and NTG on hemodynamic variables, including CBF and the microvascular response (11–13). It has also been reported that nicorandil is more effective in relieving ischemia in patients with unstable angina, as compared with NTG (14), and nicorandil reduced the number of unstable angina attacks unresponsive to nitrates (15). Suryapranata et al. (16)reported that intracoronary injection of nicorandil after isosorbide dinitrate also dilated stenotic diameters. However, intracoronary injection is quite different from oral or intravenous administration, which is the normal use of nicorandil. Systemic administration might cause coronary steal and a reduction in preload, which will affect CBF. Therefore, we hypothesized that systemic administration of nicorandil in addition to NTG would be more effective in increasing anterograde CBF, as compared with NTG alone, without causing the coronary steal phenomenon in patients with IHD (17).
In the present study, we used a Doppler guide wire to directly measure anterograde CBF. We determined the dose response of CBF to systemic administration of NTG and examined the effects of systemic administration of NTG and nicorandil during continuous administration of a sufficient dose of NTG in subjects with normal coronary arteries. Furthermore, we examined these effects in patients with stenotic coronary arteries to clarify whether additional administration of nicorandil to NTG has a beneficial effect on CBF, or a detrimental effect on CBF, due to the coronary steal phenomenon in at-risk areas. We believe that the present study provides useful information on whether patients with IHD should be treated with nicorandil in addition to the regular use of nitrates.
Table 1shows the clinical characteristics of each subject. First, by using the Doppler guide wire, we studied the dose-response effects of NTG to investigate the direct effect of NTG on CBF. The study group consisted of four patients who were being evaluated for atypical chest pain or who were undergoing follow-up percutaneous transluminal coronary angioplasty (PTCA). In the cases of follow-up PTCA, untargeted vessels were studied. All subjects had normal coronary arteries on angiography.
In the study of the effects of NTG and nicorandil during continuous administration of NTG, the group with normal coronary arteries consisted of six patients who were also being evaluated for atypical chest pain or who were undergoing follow-up PTCA. In the cases of follow-up PTCA, untargeted vessels were studied. All subjects had normal coronary arteries on angiography or lesions with <25% lumen narrowing and normal left ventricular function. The group with stenotic coronary arteries consisted of six patients with angiographic evidence of coronary atherosclerosis. All patients had at least one lesion with >50% lumen narrowing of a major coronary artery branch. Patients with acute myocardial infarction, congestive heart failure, total occlusion of a target vessel or angiographically visible collateral vessels were excluded. The Committee for the Protection of Human Subjects in Research at our institute approved the study protocol, and written, informed consent was obtained from each patient.
The protocol design is presented in Figure 1. All antihypertensive agents and medications that affect cardiac function were withheld for >24 h before cardiac catheterization.
In the study of the dose-response effects of systemic administration of NTG, 20 min after diagnostic coronary angiography, heart rate, aortic blood pressure, CBF velocity and coronary angiography were recorded throughout the study. Bolus doses of 0.01, 0.05, 0.1, 0.3, 0.5 and 0.8 mg of NTG were injected intravenously over a 20-s period at 5-min intervals.
In the study of the effects of NTG and nicorandil during continuous administration of NTG, continuous intravenous infusion of NTG (25 μg/min) was begun 2 h before catheterization to achieve maximal vasodilation of the epicardial coronary arteries. Twenty minutes after diagnostic coronary angiography, heart rate, aortic blood pressure, pulmonary artery wedge pressure and CBF velocity were also recorded throughout the procedure. A bolus dose of NTG (0.3 mg) was injected intravenously over a 20-s period, and hemodynamic changes, CBF velocity and coronary angiographic measurements were recorded for 5 min. After a further 15-min interval, during which CBF velocity returned completely to the rest level, a bolus dose of nicorandil (6 mg) (Chugai Pharmaceutical Co., Tokyo, Japan) was injected intravenously over a 20-s period. Hemodynamic changes, CBF velocity and coronary angiographic measurements were also recorded for 5 min. Then, PTCA was performed in the group with stenotic coronary arteries.
Measurement of CBF velocity and CBF
In patients with normal coronary arteries, the 0.014-in. (0.035-cm) Doppler guide wire (Flowire, Cardiometrics, Inc., Mountain View, California) was placed in the mid portion of the left anterior descending coronary artery (LAD). In patients with coronary artery stenosis, the Doppler guide wire was inserted distal to the stenotic lesion. The tip of the Doppler guide wire was positioned distal to the second diagonal branch of the LAD, distal to the obtuse marginal branch of the left circumflex artery (LCx) or distal to the atrioventricular branch of the right coronary artery. Furthermore, when the stenotic lesion was in the left coronary artery (LCA), we inserted another Doppler catheter into the nonstenotic coronary artery of the LCA to examine the coronary steal phenomenon.
Peak CBF velocity was continuously monitored using a fast Fourier transform–based spectral analyzer (FlowMap, Cardiometrics Inc.). Averaged peak (blood) velocity (APV) signals were obtained, and mean CBF was calculated as follows: CBF (ml/min) = 0.5 × averaged peak CBF velocity (cm/min) × coronary cross-sectional area (CSA) (cm2).
Quantitative coronary angiography
Coronary cineangiograms were recorded with a cineangiographic system (Siemens Inc., Tokyo, Japan). We determined changes in the lumen diameter of the target coronary artery, a segment 2 to 3 mm distal to the tip of the Doppler guide wire. Measurements were performed on end-diastolic frames with a Cardiac Analyzer for Macintosh (CAM-1000, Nishimoto Co., Osaka, Japan), which allowed automatic edge detection. The diameter of the coronary catheter served as the angiographic reference. Measurements of diameter were performed three times in a blinded manner, without knowledge of the clinical characteristics of the patients.
All data are given as the mean value ± SEM. For all statistical analyses, we used the StatView computer software application (SAS Institute, Cary, North Carolina). Differences in hemodynamic variables, coronary diameter, CSA, APV and CBF between NTG and nicorandil administration and between the normal and stenotic coronary artery groups were analyzed by two-way repeated measures analysis of variance, with appropriate interactions, followed by the Scheffé multiple comparisons procedure. The paired Student ttest was used to analyze the dose-response effects of NTG on CBF and the effects of NTG or nicorandil on epicardial coronary artery diameter during continuous administration of NTG. Clinical characteristics, such as age and body mass index, were compared by unpaired the Student ttest.
Dose-response effects of NTG on CBF
We measured heart rate, blood pressure, CSA, APV and CBF at 1 min after NTG administration. Nitroglycerin gradually increased heart rate and decreased mean blood pressure in a dose-dependent manner (date not shown). Nitroglycerin also gradually increased CSA, but decreased APV. Consequently, CBF was not changed at doses of 0.01 and 0.05 mg of NTG, but was significantly decreased at doses of 0.1, 0.3, 0.5 and 0.8 mg of NTG (Table 2).
Effects of NTG and nicorandil on epicardial coronary artery diameter
Table 3shows the effects of NTG and nicorandil on epicardial coronary artery diameter. Coronary diameter after NTG or nicorandil was individually measured as the maximal dilation in the period of 5 min after drug administration. During continuous systemic administration of NTG (25 μg/min), there was a tendency (p = 0.06) toward nicorandil-dilated obstructive diameters and post-stenotic diameters, where the tip of the Doppler guide wire was positioned, in the group with stenotic coronary arteries.
Effects of NTG and nicorandil on hemodynamic variables in the normal coronary artery group (Fig. 2)
Heart rate was significantly increased 30 s after administration of NTG (from 66 ± 3 to 77 ± 5 beats/min, p < 0.01) and nicorandil (from 69 ± 5 to 75 ± 5 beats/min, p < 0.05). These increases were sustained for 1 min after both NTG and nicorandil administration.
Mean blood pressure was significantly decreased 30 s after administration of NTG (from 102 ± 3 to 89 ± 4 mm Hg, p < 0.01) and nicorandil (from 97 ± 4 to 89 ± 5 mm Hg, p < 0.05).
After continuous intravenous infusion of NTG, no significant change in CSA occurred (data not shown). Nitroglycerin significantly decreased APV and CBF, which were lowest 2 min after injection of NTG (APV −20.0 ± 5.6%; CBF −19.7 ± 5.4%, p < 0.01). This decrease was sustained for 4 min. However, nicorandil increased APV and CBF, which were highest 30 s after injection of nicorandil (APV 53.5 ± 20.4%; CBF 54.6 ± 21.8%; p < 0.01). These increases were sustained for 2 min (Fig. 2). It is noteworthy that the time course of changes in APV and CBF was markedly different between NTG and nicorandil.
Effects of NTG and nicorandil on hemodynamic variables in the stenotic coronary artery group (Fig. 3)
Heart rate was significantly increased 30 s after administration of NTG (from 64 ± 4 to 74 ± 6 beats/min, p < 0.05) and nicorandil (from 64 ± 4 to 71 ± 3 beats/min, p < 0.01). These increases were sustained for 3 min after administration of both NTG and nicorandil.
Mean aortic blood pressure was significantly decreased 30 s after the administration of NTG (from 105 ± 7 to 98 ± 6 mm Hg, p < 0.05) and nicorandil (from 101 ± 6 to 85 ± 5 mm Hg, p < 0.01). These decreases were sustained for 4 and 3 min, respectively.
There were no changes in the time course of pulmonary artery wedge pressure.
After continuous intravenous infusion of NTG, no significant change in CSA occurred with an additional NTG injection (data not shown). Nitroglycerin injection decreased APV and CBF. In contrast, nicorandil increased APV and CBF, which were highest 30 s after the injection of nicorandil (APV 89.2 ± 41.1%; CBF 89.6 ± 42.4%, p < 0.05). These increases were sustained for 4 min.
Comparison of the effects of nicorandil on normal coronary arteries and stenotic coronary arteries in the stenotic coronary artery group
The diversion of CBF in the LAD and LCx, as measured with two Doppler guide wires in the stenotic coronary artery group, showed that there was no significant difference in the effect of nicorandil on the percent change in anterograde CBF between the normal side and the stenotic side of the LCA (1 min: 84.2 ± 31.4% vs. 83.4 ± 21.0%; 2 min: 34.6 ± 11.2% vs. 38.4 ± 14.6%).
Additive effects of intravenous nicorandil
This study demonstrated, for the first time, to our knowledge, that during continuous administration of NTG at a sufficient dose, additional intravenous administration of NTG decreased anterograde CBF; however, nicorandil increased anterograde CBF in both normal and stenotic coronary arteries. We reconfirmed, using direct measurement, that high dose NTG worsened anterograde CBF without pretreatment with NTG (2,3). This result is probably due to an excess reduction of preload and afterload, and resultant tachycardia.
Furthermore, we demonstrated that nicorandil did not cause the coronary steal phenomenon in patients with IHD. We inserted two Doppler guide wires into both the LAD and LCx and demonstrated that nicorandil significantly increased anterograde CBF beyond the stenotic lesions. Of interest, nicorandil also increased rather than decreased anterograde CBF by 14% in patient no. 5 (with 97% stenosis) and by 64% in patient no. 6 (with 78% stenosis).
This different reaction between NTG and nicorandil could not be related to the effects on heart rate and blood pressure, because there were no significant differences in heart rate and blood pressure at the same times after administration of NTG and nicorandil. Nitrate tolerance might modify the effect of additional NTG on anterograde CBF. However, a reduction of CBF by NTG was also observed without continuous pretreatment with NTG.
We think that there are two possible mechanisms by which nicorandil is capable of further increasing post-stenotic CBF. The first is that nicorandil might dilate the stenotic segments. It has been reported that intracoronary injection of nicorandil after isosorbide dinitrate also dilated stenotic diameters (16). Therefore, it is reasonable that systemic administration of nicorandil also dilated the epicardial stenotic segments that were already dilated by continuous administration of NTG. In this study, however, we could only detect the tendency of the additive effects of nicorandil on the stenotic lesions. Because the coronary arteries were already dilated during continuous administration of NTG, the additive changes in diameter might be small. The other possible mechanism is that nicorandil might function chiefly in the ischemic area, where the intracellular ATP level is reduced. It has been reported that nicorandil could activate KATPchannels in the ischemic area at a lower dose (2 to 3 μmol/liter), which would not activate KATPchannels in the nonischemic area (18). Therefore, it is possible that nicorandil might cause adequate distribution of CBF in ischemic regions through the dilation of coronary resistance vessels.
Nicorandil is usually administered orally or intravenously to obtain an effect additional to that of NTG in patients with IHD. These administration methods are slightly different from the present method of intravenous bolus administration. However, in the present study, the duration of cardiac catheterization was limited for clinical reasons, especially in patients with coronary artery stenosis, who underwent PTCA after the study.
We have demonstrated an additive effect of nicorandil on CBF during NTG treatment; however, additive anti-ischemic effects of nicorandil in the ischemic patient should be addressed in the future clinical studies.
These results demonstrated the safety of nicorandil without the occurrence of the coronary steal phenomenon, as well as the beneficial effect on anterograde CBF of additional administration of nicorandil to NTG over NTG alone. Ito et al. (19)also reported that intravenous administration of nicorandil preserved myocardial viability in patients with reperfused acute myocardial infarction. Of interest, in their study, as well as in our study, most patients were concomitantly treated with nitrates. Therefore, we speculate that the increased anterograde CBF by additional administration of nicorandil can provide further benefit of myocardial protection in patients with IHD treated with NTG. A further clinical study is needed to examine whether treatment with both NTG and nicorandil can improve the long-term prognosis of patients with IHD.
We gratefully acknowledge the excellent technical assistance of Mr. Hiroki Fujita (Goodman Co., Ltd., Osaka, Japan).
- averaged peak (blood) velocity
- adenosine triphosphate
- coronary blood flow
- cross-sectional area
- ischemic heart disease
- left anterior descending coronary artery
- left coronary artery
- left circumflex coronary artery
- percutaneous transluminal coronary angioplasty
- Received April 27, 2000.
- Revision received September 28, 2000.
- Accepted November 3, 2000.
- American College of Cardiology
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