Published online before print September 19, 2005, doi: 10.1161/01.HYP.0000185191.86908.a7
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(Hypertension. 2005;46:647.)
© 2005 American Heart Association, Inc.
Editorial Commentaries |
Nicorandil
The Drug That Keeps on Giving
From the Cleveland Clinic Foundation, Lerner Research Institute, Department of Cell Biology/NC10, Ohio.
Correspondence to John C. Barbato, Cleveland Clinic Foundation, Lerner Research Institute, Department of Cell Biology/NC10, 9500 Euclid Ave, Cleveland, OH 44195. E-mail barbatj{at}ccf.org
Nicorandil is a nicotinamide nitrate used as an antianginal agent. It has two modes of action. First, by opening adenosine triphosphate–dependent potassium channels, nicorandil increases transmembrane potassium conductance and relaxes peripheral and coronary arterioles. Second, with its nitrate moiety, nicorandil increases intracellular concentrations of cGMP, resulting in peripheral vein and coronary artery dilation. Thus, because of its ability to dilate arteries and veins, nicorandil maximizes coronary flow while concomitantly reducing myocardial work through reductions in afterload. For these reasons, nicorandil has been successful in managing angina and hypertension. However, growing evidence suggests that this drug provides additional benefits that reach beyond its original therapeutic indications.
Recently, the Impact of Nicorandil in Angina (IONA) study demonstrated significant improvement in outcomes in patients with angina when comparing a composite end point of morbidity and mortality attributable to coronary heart disease, nonfatal myocardial infarction, and unplanned hospital admission for chest pain.1 The consensus regarding the success of nicorandil in IONA purports an association between cardiac preservation and mitochondrial adenosine triphosphate–dependent potassium (KATP) channel activation.1 In light of what is already known about KATP channels, this is a germane conclusion, specifically, with regard to the pivotal role KATP channels play in cardiac preconditioning and the beneficial actions that are associated with KATP channel activation.
For more than a decade, the connection between KATP channels and cardiac preconditioning has been known. Numerous studies pertaining to ischemic preconditioning, a phenomenon whereby intermittent bouts of transient ischemia render the heart more resistant to future ischemic insults,2 have demonstrated, in some way, the involvement of KATP channels. More specifically, experiments using nicorandil have demonstrated cardioprotection through preconditioning by selectively activating mitochondrial KATP channels.3 Studies using reversible and irreversible ischemic injury models have demonstrated nicorandil could preserve contractile function and reduce infarct size, respectively.4 Taken collectively, these studies demonstrate that nicorandil provides the same cardioprotective benefits through pharmacological means that can be achieved through small bouts of ischemia. Although the connection between cardioprotection and KATP channel activation is known, the molecular basis in which nicorandil achieves this cardioprotective benefit has yet to be discerned. Until now, the major underlying reasons explaining the benefits associated with KATP channel activation have focused on the conservation of adenylate energy charge, protection of mitochondrial function, preservation of mitochondrial integrity, and protecting myocardial cells from apoptosis.5 Only recently has the notion come under investigation that preconditioning could initiate cardiac angiogenesis.6
Angiogenesis initiated by ischemic preconditioning has been shown to trigger a molecular cascade resulting in increased vascular endothelial growth factor (VEGF), a proangiogenic factor, and B-cell lymphoma (Bcl)-2, an antiapoptotic factor.6 Although it is known that nicorandil increases Bcl-2,7 a connection between KATP channel activators and increased VEGF expression has not been demonstrated. Moreover, the stimulation of capillary and arteriolar growth in the myocardium as a result of nicorandil administration has also been unexplored. In this regard, the work by Xu et al entitled "Nicorandil promotes capillary and arteriolar growth in the failing heart of Dahl salt-sensitive hypertensive rats" demonstrates for the first time that KATP channel activation with nicorandil promotes coronary capillary and arteriolar growth.8 In addition, the Xu study demonstrated that two well-known proangiogenic factors, basic fibroblast growth factor (bFGF) and VEGF,9,10 could be upregulated and associated with nicorandil-mediated vascular growth.8
These findings are interesting for several reasons. First, until now, there were questions regarding whether VEGF actions in angiogenesis were mediated by other angiogenic growth factors. By demonstrating VEGF and bFGF upregulation is associated with nicorandil-mediated vascularization, the Xu study has partially addressed this concern.8 Second, by establishing a connection between nicorandil and proangiogenic factors, this study has demonstrated a potential nonsurgical modality to enhance collateral coronary circulation in patients at high risk for coronary artery disease. Third, pharmacological upregulation of VEGF and bFGF by nicorandil provides an alterative to gene therapy. Finally, knowing that KATP channel activators are associated with angiogenesis, KATP channel blockade may initially provide insight into the molecular basis governing tumor and neoplastic angiogenesis.
By demonstrating that a nonantihypertensive dose of nicorandil preserved hemodynamic function and forestalled pathological cardiac remodeling in hypertensive Dahl salt-sensitive rats, the Xu study supports the notion that nicorandil is cardioprotective.8 Moreover, the authors have demonstrated that KATP channel activators could provide a benefit to heart failure patients by increasing vascular growth.8 To these ends, the Xu study advanced our understanding toward the cardioprotective attributes of nicorandil. However, these findings raise important issues for future studies. Specifically, because nicorandil has two modes of action, it is not clear whether the beneficial actions of nicorandil are indirectly related to increased shear created by this potent vasodilator or by the direct action of nicorandil acting at some point along the molecular cascade associated with preconditioning. This is of particular importance because pathological cardiac remodeling was still inhibited, and angiogenesis still occurred despite the elevated blood pressure in the nicorandil-treated Dahl salt-sensitive rats. Moreover, it would be interesting to see whether other antihypertensive drugs administered concomitantly with nicorandil would improve or exacerbate the reported finding. Equally as important is whether antihypertensive doses of nicorandil would have the same effects on capillary and arteriolar growth in the absence of pressure overload.
As a result of the Xu study, we gained a better understanding of the salutary effects of nicorandil. In doing so, we learned of another potential mechanism whereby KATP channels are cardioprotective and may reduce morbidity and mortality from cardiovascular disease. In addition, we have uncovered yet another pathway that, like multiple diverse signaling pathways, seems to converge on KATP channel activation. With this in mind, we still need to know definitely whether the KATP channel is an initiator, mediator, or end-effector in these various pathways. This is especially important if KATP channel activators are going to be a future therapeutic target for pharmacological preconditioning in patients at risk for heart disease or as a therapy for vascular dysfunction.
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Footnotes |
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The opinions expressed in this editorial commentary are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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2. Murry CE, Richard VJ, Reimer KA, Jennings RB. Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode. Circ Res. 1990; 66: 913–931.
3. Sato T, Sasaki N, O’Rourke B, Marban E. Adenosine primes the opening of mitochondrial ATP-sensitive potassium channels: a key step in ischemic preconditioning? Circulation. 2000; 102: 800–805.
4. Gross GJ, Auchampach JA, Maruyama M, Warltier DC, Pieper GM. Cardioprotective effects of nicorandil. J Cardiovasc Pharmacol. 1992; 20 (suppl 3): S22–S28.
5. Garlid KD, Dos Santos P, Xie ZJ, Costa AD, Paucek P. Mitochondrial potassium transport: the role of the mitochondrial ATP-sensitive K(+) channel in cardiac function and cardioprotection. Biochim Biophys Acta. 2003; 1606: 1–21.[Medline] [Order article via Infotrieve]
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7. Tang XL, Xuan YT, Zhu Y, Shirk G, Bolli R. Nicorandil induces late preconditioning against myocardial infarction in conscious rabbits. Am J Physiol Heart Circ Physiol. 2004; 286: H1273–H1280.
8. Xu J, Nagata K, Obata K, Ichihara S, Izawa H, Noda A, Naggasaki T, Iwase M, Noae T, Murohara T, Yokota M. Nicorandil promotes myocardial capillary and arteriolar growth in the failing heart of Dahl salt-sensitive hypertensive rats. Hypertension. 2005; 46: 719–724.
9. Baffour R, Berman J, Garb JL, Rhee SW, Kaufman J, Friedmann P. Enhanced angiogenesis and growth of collaterals by in vivo administration of recombinant basic fibroblast growth factor in a rabbit model of acute lower limb ischemia: dose-response effect of basic fibroblast growth factor. J Vasc Surg. 1992; 16: 181–191.[CrossRef][Medline] [Order article via Infotrieve]
10. Risau W. Mechanisms of angiogenesis. Nature. 1997; 386: 671–674.[CrossRef][Medline] [Order article via Infotrieve]
Related Article:
Hypertension 2005 46: 719-724.
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