Nicorandil: A drug with ongoing benefits and different mechanisms in various diseased conditions.

Nicorandil is a well-known antianginal agent, which has been recommended as one of the second-line treatments for chronic stable angina as justified by the European guidelines. It shows an efficacy equivalent to that of classic antianginal agents. Nicorandil has also been applied clinically in various cardiovascular diseases such as variant or unstable angina and reperfusion-induced damage following coronary angioplasty or thrombolysis. Different mechanisms have been involved in the protective effects of nicorandil in various diseases through either opening of adenosine triphosphate-sensitive potassium (KATP) channel or donation of nitric oxide (NO). The predominance or participation of any of these proposed mechanisms depends on the dose of nicorandil used, the location of diseased conditions, and if this mechanism is still functioning or not. The protection afforded by nicorandil has been shown to be mainly attributed to KATP channel opening in experimental models of myocardial and pulmonary fibrosis as well as renal injury or glomerulonephritis, whereas NO donation predominates as a mechanism of protection in hepatic fibrosis and inflammatory bowel diseases. Therefore, in different diseased conditions, it is important to know which mechanism plays the major role in nicorandil-induced curative or protective effects. This can bring new insights into the proper use of selected medication and its recommended dose for targeting certain disease. Copyright:

Introduction

Nicorandil is a safe, well-known antianginal agent that has been approved as a long-term therapy for chronic stable angina in Japan and Europe.[1] The Japanese Coronary Artery Disease (CAD) and the Impact of Nicorandil in Angina studies have revealed a beneficial impact for nicorandil on mortality and morbidity in patients with CAD.[23] The use of nicorandil has been recommended by the European Society of Cardiology as one of the second-line treatments for chronic stable angina.[4] Overall, comparative clinical trials have shown an equivalent efficacy of nicorandil in improving effort angina and ischemic symptoms compared to β blockers and calcium antagonists with minimal hemodynamic disturbance.[5] Moreover, nicorandil intake has not been associated with significant drop in blood pressure (BP) when used with calcium antagonists or β receptor blockers.[6] Importantly, nicorandil acts as an efficient anti-ischemic agent in patients with contraindications to use of beta blockers, such as bradycardia or exacerbated pulmonary disease.[7] According to its pharmacokinetic profile, nicorandil use appears to be safe for patients using anticoagulant therapies or those with renal or hepatic impairments.[8] In addition, its side effects are minimal, including headache as a common side effect in addition to less common side effects such as dizziness, gastrointestinal upset, flushing, and malaise. Nicorandil is contraindicated to be used in the setting of hypotension or concomitantly with other vasodilators.[9]

Nicorandil has been applied clinically in various cardiovascular diseases such as variant angina (coronary vasospasm), unstable angina, and reperfusion-induced damage following coronary angioplasty or thrombolysis.[610] Nicorandil has shown to be effective as a therapy for refractory angina in a clinical study, resulting in great improvements in its frequency or duration, electrocardiographic perturbations, and patients' adverse reactions.[11] Interestingly, a meta-analysis from 17 clinical trials has demonstrated that nicorandil treatment ameliorated left ventricular ejection fraction and microvascular function when used in patients with acute myocardial infarction (AMI) in conjugation with coronary reperfusion therapy.[12] Long-term therapy of nicorandil also showed beneficial effects on left ventricular remodeling and sympathetic nerve activity of myocardium in patients with AMI when used after reperfusion therapy.[13] In addition, nicorandil treatment when used as adjunctive to coronary angioplasty was accompanied by better clinical and functional outcomes in patients with anterior AMI compared to angioplasty alone. This was mainly attributed to a decrease in myocardial injury and improvement in microvascular function and rate of no-reflow.[14] Another study revealed that intravenous nicorandil reduced QT dispersion and ventricular fibrillation in patients after successful coronary angioplasty.[15] On the other hand, several reports demonstrated that nicorandil may cause severe vasodilation and fall in BP when used preoperatively before coronary artery bypass graft, which could be related to several potentiating factors acting during surgery. This necessitates the discontinuation of nicorandil therapy 3 days at least before admission for operation.[6]

Pharmacological Actions of Nicorandil

Nicorandil is an opener for adenosine triphosphate-sensitive potassium (KATP) channel and a donor for nitric oxide (NO). Several mechanisms have been proposed for its cardioprotective effects, including improvement of myocardial blood perfusion; reduction in preload and afterload; protection against ischemic damage; anti-arrhythmic effects; prevention of calcium overload; energy-modulating actions; and anti-inflammatory, antiapoptotic, and antiproliferative effects.[1617] Interestingly, nicorandil improves cardiac function without affecting BP as well as cardiac conduction or contraction. Nicorandil produces its antianginal or anti-ischemic effect by dilatation of coronary arteries and by reduction of myocardial oxygen demand mainly by affecting afterload and to a lesser extent, preload. Nicorandil is considered a balanced vasodilator which affects both arterial and venous blood vessels. The effect of nicorandil on preload may be less than that observed with nitrates due to the significant decrease in systemic vascular resistance which tends to increase venous return.[61618]

Nitric oxide donation

Nicorandil administration increases the level of NO through reaction of its nitrate group with sulfhydryl group in cells of vascular smooth muscle. This, in turn, either activates guanylate cyclase or facilitates the release of NO, leading to increased cGMP levels with a reduction in intracellular calcium and vascular smooth muscle cell relaxation.[18]

KATP channel opening

Concerning its action as an opener of KATP channel, this channel is known to be sensitive for the adenosine triphosphate/adenosine diphosphate ratio, which reflects the condition of the cell and its energy status. Depending on the type of potassium channel and its tissue specificity, opening of these channels shows diverse actions. Such channels have been described at both sarcolemmal and mitochondrial levels in myocardial cells in addition to cells of vascular smooth muscle.[171920] Nicorandil is known to activate the receptors, Kir6.2/sulfonylurea receptor 2A (SUR2A) and Kir6.2/SUR2B, which confirms its specificity for KATP channels of cardiac and smooth muscles. In addition, nicorandil shows no observable effect on insulin secretion, which is consistent with lack of its effect on Kir6.2/SUR1 currents, revealing its good tolerability in diabetic patients.[21]

The sarcolemmal KATP channels of cardiomyocytes give a mean of linking the electrical activity to the metabolic and energy states. Specifically, this type of channel modulates the action potential duration where its opening during ischemic status results in action potential shortening and reduction in myocardial work.[22]

On the other hand, when the sarcolemmal KATP channels in vascular smooth muscle are opened, this produces hyperpolarization with subsequent close of the voltage-sensitive calcium channels and decrease in calcium influx and intracellular calcium, resulting in myosin light chain dephosphorylation and vascular smooth muscle relaxation.[623] This type of sarcolemmal KATP channels is also involved in the basal vascular tone maintenance both in mesenteric and coronary arteries.[24] Thus, nicorandil's NO donation and KATP channel opening contribute to its vasodilatory properties. Notably, the opening of KATP channels mainly dilates peripheral and coronary resistance arterioles using low doses of nicorandil, whereas its NO donating property mainly dilates epicardial coronary arteries and veins using high doses.[252627] The lack of tolerance with nicorandil administration compared to nitrates is likely due to its effect as an opener of KATP channel and not due to its nitrate activity.[17]

Mitochondrial KATP channel opening and its related cardioprotection

Nicorandil exhibits cardioprotective effects which are mostly attributed to mitochondrial KATP opening. Nonhypotensive dose of nicorandil was reported to be a selective mitochondrial KATP channel opener.[28] Its exact mechanism on mitochondria is still debated where several hypotheses have been proposed. The well-accepted hypothesis includes an increase in potassium uptake in the mitochondrial matrix by mitochondrial KATP channel opening. This may prevent the accumulation of mitochondrial calcium through depolarization of mitochondrial membrane and reduction of the electrochemical gradient for calcium entry via its uniporter.[2930] The prevention of calcium overload protects the heart through either inhibition of mitochondrial permeability transition pore and/or cardiomyocyte hypercontracture.[31] Mitochondrial KATP channel opening could also trigger the generation of low levels of reactive oxygen species (ROS), thereby amplifying the signaling pathway, stimulating the antioxidative action in mitochondria (manganese superoxide dismutase; MnSOD) and inhibiting mitochondrial nicotinamide adenine dinucleotide phosphate oxidase, which is the main source of ROS generation in cardiomyocytes.[32] The activation of this protective signaling pathway also preserves the capacity of oxidative phosphorylation and energy production in addition to maintenance of mitochondrial membrane integrity and inhibition of apoptotic signaling pathway, mitochondrial ultrastructural changes, and DNA fragmentation.[33]

There may be certain interactions between the mechanisms by which nicorandil provides cardioprotection through mitochondrial KATP channel opening. First, NO released from nicorandil can itself activate the mitochondrial KATP channels.[34] Second, protein kinase C (PKC) represents a key-signaling molecule, which by phosphorylation mediates the cardioprotection triggered by both NO and mitochondrial KATP channels.[35] Therefore, the cardioprotection provided by nicorandil may not be related just due to mitochondrial KATP channels opening, but may involve complex interactions between NO, KATP channel, and PKC.[36] Nicorandil can also exert anti-free radical properties that are independent from its KATP channel opening. This could be related to its nicotinamide moiety, which acts as a hydroxyl radical scavenger.[37]

Different Mechanisms Involved in Different Diseased Conditions

Controversy mechanisms have been involved in the protective effects of nicorandil. The predominance or participation of any of proposed mechanisms (KATP channel opening or NO donation) depends on the dose of nicorandil used, the location of diseased conditions, and if this mechanism is still functioning or not [Figure 1].

Figure 1

Predominant mechanism of action of nicorandil in different experimental models

Cardiovascular diseases

Nicorandil exerted its beneficial effect on stunned myocardium of anesthetized dogs by directly activating KATP channels where its afforded cardioprotection was blocked by pretreatment with glibenclamide (a KATP channel blocker).[38] Moreover, KATP channel opening may have important biological actions that prevent cardiac fibrosis. Nicorandil attenuated MI-induced cardiac fibrosis in rats, and its beneficial actions on differentiations of fibroblast were blocked by adding glibenclamide.[39] Glibenclamide is both a blocker for KATP channel and a vasorelaxant through NO generation.[40] This study suggested the predominant role of KATP channels and excluded the role of NO donation by nicorandil when coadministered with glibenclamide.

Nicorandil has been revealed to provide its cardioprotection through mitochondrial KATP channels opening in various experimental models of myocardial injury as ischemia reperfusion (IR) through a phenomenon known as pharmacological preconditioning.[3641] Pharmacological preconditioning with nicorandil was found to attenuate myocardial IR injury in rats through selective mitochondrial KATP channel opening by the lower oral dose of nicorandil (3 not 6 mg/kg/day), which offered more cardioprotection against biochemical changes and ventricular arrhythmias induced by IR.[42] Other experiments on ventricular myocytes showed that the protective effect of nicorandil was abolished using selective blocker of mitochondrial KATP channel (5-hydroxydecanoate), confirming the role of mitochondrial KATP and not its sarcolemmal counterpart as a target for nicorandil's cardioprotective action.[43] Nicorandil also ameliorated the dysfunction of mitochondria and its downstream pathways in experimentally induced heart failure via amelioration of mitochondrial oxidative stress status and its energy production capacity as well as inhibition of mitochondrial ultrastructural changes, apoptotic signaling pathway, and DNA fragmentation.[33] In addition, the cardioprotection afforded by nicorandil against doxorubicin-induced ROS in HL-1 cardiomyocyte cell line was not related to its NO donation, but to its mitochondrial KATP opening.[32]

Importantly, pharmacological preconditioning with nicorandil showed promising results when coadministered with stem cells where it improved the efficacy of bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation after isoproterenol-induced myocardial damage through establishment of a supportive environment for BM-MSC and improvement of its survival and homing by reduction of factors of inflammation, fibrogenesis, and apoptosis that might interfere with the efficiency of cell-based therapy.[44]

Pulmonary diseases

Nicorandil was previously reported to attenuate monocrotaline-induced endothelial damage and pulmonary arterial hypertension in rats, which was mainly attributed to KATP channel opening with an adjunctive effect to its NO-releasing property. This was confirmed by blockade of its beneficial effects using glibenclamide and N omega-nitro-L-arginine methyl ester (L-NAME) (an inhibitor of NO synthase).[45] On the other hand, activation of KATP channel mainly contributes to the beneficial effect of nicorandil against pulmonary fibrosis induced by cyclophosphamide in rats where concomitant administration of glibenclamide completely blocked the effects provided by nicorandil.[46]

Renal diseases

Nicorandil was demonstrated to have beneficial effects in several models of experimental renal diseases. Nicorandil potently reduced renal injury and urinary albumin excretion in diabetic eNOS-deficient mice excluding the role of NO donation in its mediated protection. The protective mechanism was shown to involve the reduction of oxidative stress, likely stimulated via KATP channel opening where it was diminished by the use of glibenclamide.[47] Nicorandil also protected podocytes in kidney from hyperglycemia-induced oxidative stress by activating KATP channels and stimulation of MnSOD expression in the mitochondria.[48] On the other side, nicorandil ameliorated renal injury induced by unilateral ureteral obstruction in rats through an increase in renal NO and a reduction of transforming growth factor-beta where these renoprotective effects were blunted by L-NAME codministration.[49]

Hepatic diseases

Experimentally, nicorandil has been demonstrated to be an adequate therapy against the induction of liver fibrosis by bile duct ligation where its protective effects on biochemical and histological changes were completely reversed by the coadministration of L-NAME, whereas glibenclamide coadministration showed less protection compared to that provided by nicorandil alone. These data suggested that the protection revealed by nicorandil against hepatic fibrosis was related mainly to its action as a donor for NO and to a smaller extent to its KATP channel opening.[50]

Bowel diseases

Nicorandil ameliorated experimentally-induced inflammatory bowel disease (IBD) using a dose with no significant effect on BP and a mechanism, which is partially or completely independent of KATP channels as observed on coadministration of glibenclamide. It seems that upregulation of eNOS, production of NO as well as its antioxidant potential though its nicotinamide moiety could be mainly responsible for its effects in remission of IBD.[37] Nicorandil can also exert an anti-inflammatory effect through inhibition of inflammatory mediators release such as tumor necrosis factor-alpha mainly via donation of NO and to a smaller extent through opening of KATP channel.[51]

Male and female reproductive diseases

Nicorandil showed significant improvement of functional disorders in animals with asymmetric dimethylarginine-induced preeclampsia. Activation of KATP channels seems to play a predominant role in these effects where glibenclamide reduced significantly but not completely the effect of nicorandil.[52] In addition, the capability of nicorandil to relax the uterine muscle, which was mainly achieved through KATP channels, can improve the placental microcirculation.[53]

Moreover, nicorandil may have remarkable effectiveness in the treatment of male impotency. Nicorandil relaxed in an in vitro experiment the corpora cavernosal smooth muscle mainly through its KATP channel opening and to a lesser extent through its NO donation. On the other hand, its vasodilative action on the deep cavernous artery was mediated mainly through guanylate cyclase stimulation.[5455]

Conclusion

Therefore, in various diseased or clinical conditions, it is important to know which mechanism plays the major role in nicorandil-induced curative or protective effects. This can bring new insights into the proper use of the selected medication and its recommended dose for targeting certain disease.

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Conflicts of interest

There are no conflicts of interest.