CLINICAL STUDIES
Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels
Toshiaki Sato, MD, PhDa,1,
Norihito Sasaki, MD, PhDa,
Brian O’Rourke, PhDa and
Eduardo Marbán, MD, PhD, FACCa
a Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland, USA
Manuscript received May 24, 1999;
revised manuscript received September 10, 1999,
accepted October 21, 1999.
Reprint requests and correspondence: Dr. Eduardo Marbán, Institute of Molecular Cardiobiology, Johns Hopkins University, Ross 844/720 Rutland Avenue, Baltimore, Maryland 21205
marban{at}jhmi.edu
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Abstract
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OBJECTIVES
To determine the mechanism of cardioprotection afforded by nicorandil, an orally efficacious antianginal drug, we examined its effects on ATP-dependent potassium (KATP) channels.
BACKGROUND
Nicorandil can mimic ischemic preconditioning, while mitochondrial KATP (mitoKATP) channels rather than sarcolemmal KATP (surfaceKATP) channels have emerged as the likely effectors.
METHODS
Flavoprotein fluorescence and membrane current in intact rabbit ventricular myocytes were measured simultaneously to assay mitoKATP channel and surface KATP channel activities, respectively. In a cell-pelleting model of ischemia, cells permeable to trypan blue were counted as killed by 60 and 120 min of ischemia.
RESULTS
Nicorandil (100 µmol/liter) increased flavoprotein oxidation but not membrane current; a 10-fold higher concentration recruits both mitoKATP and surfaceKATP channels. Pooled dose-response data confirm that nicorandil concentrations as low as 10 µmol/liter turn on mitoKATP channels, while surfaceKATP current requires exposure to millimolar concentrations. Nicorandil blunted the rate of cell death in a pelleting model of ischemia; this cardioprotective effect was prevented by the mitoKATP channel blocker 5-hydroxydecanoate but was unaffected by the surfaceKATP channel blocker HMR1098.
CONCLUSIONS
Nicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mitoKATP channels.
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Abbreviations and Acronyms
| | 5HD | = 5-hydroxydecanoate | | CONT | = control group | | DNP | = 2,4-dinitrophenol | | IK,ATP | = surfaceKATP current | | IPC | = ischemic preconditioning | | KATP | = ATP-dependent potassium | | mitoKATP | = mitochondrial KATP | | NICO | = nicorandil-treated group | | surfaceKATP | = sarcolemmal KATP |
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Nicorandil, a hybrid ATP-dependent potassium (KATP) channel opener and nitrate compound (1), is used clinically for the treatment of angina pectoris (2). The cardioprotective effects of nicorandil in ischemic hearts have received much attention: nicorandil can improve the recovery of postischemic contractile dysfunction and can reduce infarct size in several animal models (3–5) and in humans (6–9). The initial hypothesis to explain these observations invoked sarcolemmal KATP (surfaceKATP) channels: opening of surfaceKATP channels would abbreviate excitability such that calcium overload and energy consumption would be attenuated (10). However, recent studies provide evidence that mitochondrial KATP (mitoKATP) channels rather than surfaceKATP channels are the dominant players (11,12).
The selective mitoKATP channel inhibitor 5hydroxydecanoate (5HD) (13) abolishes the infarct size-limiting effect of nicorandil (5). Furthermore, it has been reported that nicorandil given orally to rats is preferentially distributed into heart mitochondria (14). Therefore, we hypothesized that nicorandil targets mitoKATP channels and the nicorandil-induced cardioprotection is mediated by opening of mitoKATP channels. To test this hypothesis, we simultaneously assayed the activity of surfaceKATP channels and mitoKATP channels by measuring membrane current and flavoprotein fluorescence in rabbit ventricular myocytes (12).
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Methods
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Preparation of rabbit myocytes.
The investigation conforms with The Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). Isolated ventricular myocytes were obtained from New Zealand white rabbits (weighing 1 to 2 kg) by conventional enzymatic dissociation methods (15). Cells were then filtered through nylon mesh and washed several times with Ca2+-free solution. The calcium concentration was gradually brought back to 1 mmol/liter.
Flavoprotein fluorescence and electrophysiologic recording.
After isolation, cells were cultured on laminin-coated coverslips in M199 with 5% fetal bovine serum at 37°C and experiments were performed over the next day. Cells were mounted in a recording chamber and were superfused with external solution containing (in mmol/liter): NaCl, 140; KCl, 5; MgCl2, 1; CaCl2, 1; and HEPES, 10 (pH 7.4 with NaOH) at room temperature (approximately 22°C). Whole-cell current and flavoprotein fluorescence were recorded simultaneously. The internal pipette solution contained (in mmol/liter) the following: potassium glutamate, 120; KCl, 25; MgCl2, 0.5; potassium EGTA, 10; HEPES, 10; and MgATP, 1 (pH 7.2 with KOH). Whole-cell currents were elicited every 6 s from a holding potential of –80 mV by two consecutive steps to –40 (for 100 ms) and 0 mV (for 380 ms). Currents at 0 mV were measured 200 ms into the pulse. Endogenous flavoprotein fluorescence was excited with a xenon arc lamp with a bandpass filter centered at 480 nm, but only during the 100-ms step to –40 mV to minimize photobleaching. Emitted fluorescence was recorded at 530 nm by a photomultiplier tube and digitized. By focusing on individual myocytes with a x40 objective, whole-cell current and fluorescence were monitored simultaneously from one cell at a time. The redox signal was averaged during the excitation window and calibrated with the values after exposure to 2,4-dinitrophenol (DNP), which uncouples respiration from ATP synthesis, collapses the mitochondrial potential and induces maximal oxidation. Therefore, the values of flavoprotein fluorescence were expressed as a percentage of the DNP-induced fluorescence.
Cell pelleting model of ischemia.
The cell pelleting model of ischemia modified from Vander Heide et al. (16) was used to quantify cell injury. In brief, cells were washed with incubation buffer (in mmol/liter): NaCl2, 119; NaHCO3, 25; KH2PO4, 1.2; KCl, 4.8; MgSO4, 1.2; CaCl2, 1; HEPES, 10; glucose, 11; creatine, 24.9; taurine, 58.5; and supplemented with 1% BME amino acids and 1% MEM nonessential amino acids (pH 7.4 with NaOH). An aliquot of each cell suspension (0.5 ml) was placed into a microcentrifuge tube and centrifuged for 15 s into a pellet. Approximately 0.25 ml of excess supernatant was removed to leave a thin fluid layer above the pellet, and 0.2 ml of mineral oil was layered on the top of the pellet to prevent gaseous diffusion. After 60 and 120 min of pelleting, 5 µl of cell pellet was sampled through the oil layer and mixed with 75 µl of 85 mosm/liter hypotonic staining solution (in mmol/liter): NaHCO3, 11.9; KH2PO4, 0.4; KCl, 2.7; MgSO4, 0.8; CaCl2, 1 with 0.5% glutaraldehyde and 0.5% trypan blue. Microscopic examination was performed 2 to 5 min after mixing to determine the permeability of the cells to trypan blue. Cells permeable to trypan blue were counted as killed and expressed as a percentage of the total cells counted (>200 for each sample). Four groups of experiments were performed. In the control group (CONT), cells were pelleted and sampled at 60 and 120 min. For the nicorandil-treated group (NICO), nicorandil at a concentration of 100 µmol/liter was added to the solution 15 min before the pelleting. Cells treated with nicorandil in the presence of 500 µmol/liter of 5HD (NICO+5HD) or in the presence of 30 µmol/liter HMR1098 (NICO+HMR1098) were likewise pelleted and sampled. Once applied, drugs were not washed out and thus were present throughout the period of simulated ischemia. Experiments were performed at 37°C. Individual experiments in each group were performed on cells isolated from different hearts.
Chemicals.
DNP was obtained from the manufacturer (Sigma Chemical; St. Louis, Missouri), as was sodium 5HD (Research Biochemicals International; Natick, Massachusetts). Nicorandil was a gift (Chugai Pharmaceutical Co., Ltd; Tokyo, Japan), as was HMR1098 (Hoechst Marion Roussel Chemical Research; Frankfurt, Germany).
Data analysis.
Data are presented as mean ± SEM, and the number of cells or experiments is shown as n. Analysis of variance combined with Fisher post-hoc test was used to test for significance among groups. A value of p < 0.05 was considered significant.
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Results
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Figure 1 shows representative results from simultaneous measurements of flavoprotein fluorescence and surfaceKATP current (IK,ATP) in a single ventricular myocyte. Nicorandil at a concentration of 100 µmol/liter reversibly oxidized the flavoproteins but did not activate IK,ATP. A second exposure to nicorandil at a concentration of 1 mmol/liter increased both flavoprotein fluorescence and IK,ATP. As summarized in Figure 2, nicorandil increased flavoprotein fluorescence in a concentration-dependent manner. Nicorandil at concentrations of 10 and 100 µmol/liter reversibly increased flavoprotein oxidation to 14 ± 2% (n = 4) and 31 ± 4% (n = 5) of the DNP value, respectively, without affecting IK,ATP. However, a very high concentration (1 mmol/liter) of nicorandil was required to increase not only flavoprotein oxidation but also IK,ATP. The selective mitoKATP channel blocker 5HD (500 µmol/liter) (13) virtually abolished the nicorandil (100 µmol/liter)-induced flavoprotein oxidation. However, nicorandil (1 mmol/liter)-induced IK,ATP was completely inhibited by 30 µmol/liter HMR1098, a selective surfaceKATP channel blocker (17). These results suggest that nicorandil primarily activates mitoKATP rather than surfaceKATP channels in rabbit ventricular cells.
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Figure 1 Relative potency of nicorandil in opening surfaceKATP and mitoKATP channels. Records of simultaneous flavoprotein fluorescence (A) and membrane currents (B) in a single rabbit ventricular myocyte. The flavoprotein fluorescence was calibrated by exposing the cells to DNP (100 µmol/liter) at the end of experiments. Bar indicates periods when the cells were exposed to nicorandil (NICO), 100 µmol/liter or 1,000 µmol/liter as noted.
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Figure 2 Summarized dose-response data for mitochondrial (A) and surface (B) effects. Nicorandil (100 µmol/liter)-induced flavoprotein oxidation was prevented by 500 µmol/liter 5-hydroxydecanoate (NICO [100]+5HD), whereas nicorandil (1 mmol/liter)-induced IK,ATP was inhibited by 30 µmol/liter HMR1098 (NICO[1,000]+HMR1098).
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In the next series of experiments, we tested the idea that mitoKATP rather than surfaceKATP channels act as the effectors for cardioprotection afforded by nicorandil, using a cell-pelleting model of ischemia. Figure 3 plots the fraction of cells killed by 60 and 120 min of simulated ischemia as a percentage of the total number of viable cells before ischemia. Pelleting for 60 and 120 min killed 35 ± 4% (n = 4) and 48 ± 4% (n = 4) of cells, respectively (CONT). Inclusion of nicorandil (100 µmol/liter) significantly decreased the percentage of cells killed during ischemia to 22 ± 3% (n = 4) after 60 min and 31 ± 3% (n = 4) after 120 min ischemia (NICO, p < 0.01 vs. CONT). The cardioprotective effects of nicorandil were abolished by 500 µmol/liter 5HD (38 ± 4% after 60 min and 49 ± 4% after 120 min ischemia, respectively). In contrast, the selective surfaceKATP channel inhibitor HMR1098 (30 µmol/liter) did not abolish the cardioprotection by nicorandil (NICO+HMR1098, p < 0.01 vs. CONT). These results indicate that nicorandil-induced cardioprotection against ischemic damage is mediated by opening of mitoKATP channels but not surfaceKATP channels.
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Figure 3 Summarized data for cardioprotective effects of nicorandil. Cells killed by 60 or 120 min of simulated ischemia were plotted as a percentage of the total viable cells before ischemia. CONT = control group; NICO = nicorandil (100 µmol/liter)-treated group; NICO+5HD = nicorandil and 5HD (500 µmol/liter)-treated group; NICO+HMR1098 = nicorandil and HMR1098 (30 µmol/liter)-treated group. *p < 0.01 vs. CONT.
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Discussion
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Nicorandil targets mitoKATP channels.
Previous studies in our laboratory have demonstrated that the mitoKATP channel opener diazoxide oxidizes flavoproteins without affecting IK,ATP in rabbit ventricular myocytes (12). Using the same experimental design, our present results demonstrate that nicorandil reversibly oxidized the mitochondrial matrix in a concentration-dependent manner, while millimolar concentrations are required to elicit IK,ATP. The oxidative effects of nicorandil actually reflect the opening of mitoKATP channels, because the mitoKATP channel blocker 5HD completely abolished the nicorandil-induced flavoprotein oxidation. These results indicate that nicorandil primarily activates mitoKATP channels in intact rabbit ventricular cells.
MitoKATP channels serve as effectors of cardioprotection.
KATP channel openers may shorten the action potential duration, thereby reducing cellular calcium overload and preserving viability in ischemic myocardium: this was initially proposed as the mechanism for protection of ischemic myocardium. Nevertheless, this hypothesis cannot account for the mechanism of cardioprotection, because abbreviation of action potentials is not necessary for protection (18–20). Alternatively, recent pharmacologic evidence hints that mitoKATP channels are the dominant players. The mitoKATP channel opener diazoxide protects rabbit ventricular myocytes in a cell pelleting model of ischemia (12) and improves functional recovery after ischemia in isolated rat and rabbit hearts (11); this diazoxide-induced protection is prevented by 5HD (11,12). In the present study, the cardioprotective effect of nicorandil was examined in a cellular ischemia model. Previous studies have shown that simulated ischemia preconditions myocytes in this model and that the underlying mechanisms for the protection are similar to those in intact hearts (21,22). Critz et al. (23) reported that nicorandil caused neither surfaceKATP channel opening nor cardioprotection in rabbit myocytes. However, we found that nicorandil protects against cell death to the same degree as does genuine ischemic preconditioning. Although the reason for this discrepancy is unknown, the level of nucleotide diphosphates or intracellular pH during ischemia may affect the nicorandil-induced cardioprotection. To probe the final effector for cardioprotection, we used selective blockers of either mitoKATP or surfaceKATP channels. HMR1098, a potent surfaceKATP channel blocker (17), completely inhibited the nicorandil-induced IK,ATP (Fig. 2B). However, the cardioprotective effects of nicorandil were not blocked by HMR1098. In contrast, the mitoKATP channel blocker 5HD completely abolished the nicorandil-induced cardioprotection. These results indicate that mitoKATP rather than surfaceKATP channels are involved in the cardioprotection afforded by nicorandil. In separate experiments not shown herein, we determined that nitric oxide donors only weakly favor the opening of mitoKATP channels (24). Thus, it seems unlikely that the protective effect of nicorandil is solely conferred by its nitrate moiety.
Lethal injury to the heart can be dramatically blunted by brief periods of prior ischemia (25). Such ischemic preconditioning (IPC) exists in most species, including human (26–28). Diazoxide mimics IPC and reduces infarct size in rabbit hearts (29). However, 5HD abolishes genuine IPC (30,31). These results implicate mitoKATP channels as effectors of IPC. Nicorandil can mimic IPC by reducing infarct size in rabbit hearts, and this cardioprotection is abolished by 5HD (5). Interestingly, Sakai et al. (14) reported subcellular localization of nicorandil in myocardial mitochondria. Therefore, taken together, it is reasonable to consider that nicorandil targets mitoKATP channels and that cardioprotective effects of nicorandil are mediated by opening of mitoKATP channels.
Clinical implications.
Despite their favorable cardioprotective property, enthusiasm for KATP channel openers has been tempered by the fear that they may promote the development of ventricular arrhythmias (32). This potential drawback limits the clinical utility of surfaceKATP channel openers. In contrast, the selective mitoKATP channel opener diazoxide protects the myocytes from ischemia (11, 12, 29), suggesting that mitoKATP channels might be useful targets for the ischemic cardioprotection. We found that nicorandil, a clinically available anti-ischemic agent, appears to be a fairly selective mitoKATP channel opener. It has been approved for human use (2) and has cardioprotective effects in humans (6–9). The clinical utility of nicorandil indicates drugs that target mitoKATP channels, without activating surfaceKATP channels, may be safe and effective for the protection of ischemic myocardium.
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Conclusion
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Our results indicated that nicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by the selective activation of mitoKATP channels. It links, for the first time, the basic phenomenon of ischemic preconditioning with the existing pharmacopeia for ischemic syndromes. Our findings support the principle that mitoKATP channels are valuable new targets for anti-ischemic drug development.
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Footnotes
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This study was supported by NIH R37HL36957 (to Dr. Marbán), Banyu Fellowship in Lipid Metabolism and Atherosclerosis (to Dr. Sato), and an unrestricted gift from Chugai Pharmaceutical Co.
1 Dr. Toshiaki Sato’s present address: Department of Physiology, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5503, Japan. 
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83(4):
1113 - 1151.
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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.
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S. Sanada, K. Node, H. Asanuma, H. Ogita, S. Takashima, T. Minamino, M. Asakura, Y. Liao, A. Ogai, J. Kim, et al.
Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis: Role of 70-kDa S6 kinase and extracellular signal-regulated kinase
J. Am. Coll. Cardiol.,
September 4, 2002;
40(5):
991 - 997.
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M. Akao, Y. Teshima, and E. Marban
Antiapoptotic effect of nicorandil mediated by mitochondrial atp-sensitive potassium channels in cultured cardiac myocytes
J. Am. Coll. Cardiol.,
August 21, 2002;
40(4):
803 - 810.
[Abstract]
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A. Szewczyk and L. Wojtczak
Mitochondria as a Pharmacological Target
Pharmacol. Rev.,
March 1, 2002;
54(1):
101 - 127.
[Abstract]
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T.-M. Lee, S.-F. Su, T.-F. Chou, Y.-T. Lee, and C.-H. Tsai
Loss of Preconditioning by Attenuated Activation of Myocardial ATP-Sensitive Potassium Channels in Elderly Patients Undergoing Coronary Angioplasty
Circulation,
January 22, 2002;
105(3):
334 - 340.
[Abstract]
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P. Blanc, A. Aouifi, H. Bouvier, P. Joseph, P. Chiari, M. Ovize, C. Girard, O. Jegaden, Y. Khder, and J. J. Lehot
Safety of oral nicorandil before coronary artery bypass graft surgery{dagger}
Br. J. Anaesth.,
December 1, 2001;
87(6):
848 - 854.
[Abstract]
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R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch
Signal transduction of ischemic preconditioning
Cardiovasc Res,
November 1, 2001;
52(2):
181 - 198.
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Y. Wakamatsu, N. Shiiya, T. Kunihara, S. Watanabe, and K. Yasuda
The adenosine triphosphate-sensitive potassium channel opener nicorandil protects the ischemic rabbit spinal cord
J. Thorac. Cardiovasc. Surg.,
October 1, 2001;
122(4):
728 - 733.
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K. Mubagwa and W. Flameng
Adenosine, adenosine receptors and myocardial protection: An updated overview
Cardiovasc Res,
October 1, 2001;
52(1):
25 - 39.
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C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan
Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities
Pharmacol. Rev.,
December 1, 2000;
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557 - 594.
[Abstract]
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B. O'Rourke
Myocardial KATP Channels in Preconditioning
Circ. Res.,
November 10, 2000;
87(10):
845 - 855.
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D. M. Yellon and A. Dana
The Preconditioning Phenomenon : A Tool for the Scientist or a Clinical Reality?
Circ. Res.,
September 29, 2000;
87(7):
543 - 550.
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