Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway.

Background: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results: Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion: This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.

Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway.

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial dysfunction, and DCM; however, its effects on ferroptosis and mitophagy remain unexplored. The present study aimed to assess the beneficial effects of nicorandil against endothelial ferroptosis in DCM and the underlying mechanisms. Cardiac microvascular perfusion was assessed using a lectin perfusion assay, while mitophagy was assessed via mt-Keima transfection and transmission electron microscopy. Ferroptosis was examined using mRNA sequencing, fluorescence staining, and western blotting. The mitochondrial localization of Parkin, ACSL4, and AMPK was determined via immunofluorescence staining. Following long-term diabetes, nicorandil treatment improved cardiac function and remodeling by alleviating cardiac microvascular injuries, as evidenced by the improved microvascular perfusion and structural integrity. mRNA-sequencing and biochemical analyses showed that ferroptosis occurred and Pink1/Parkin-dependent mitophagy was suppressed in cardiac microvascular endothelial cells after diabetes. Nicorandil treatment suppressed mitochondria-associated ferroptosis by promoting the Pink1/Parkin-dependent mitophagy. Moreover, nicorandil treatment increased the phosphorylation level of AMPKα1 and promoted its mitochondrial translocation, which further inhibited the mitochondrial translocation of ACSL4 via mitophagy and ultimately suppressed mitochondria-associated ferroptosis. Importantly, overexpression of mitochondria-localized AMPKα1 (mitoAα1) shared similar benefits with nicorandil on mitophagy, ferroptosis and cardiovascular protection against diabetic injury. In conclusion, the present study demonstrated the therapeutic effects of nicorandil against cardiac microvascular ferroptosis in DCM and revealed that the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway mediates mitochondria-associated ferroptosis and the development of cardiac microvascular dysfunction.

Hepatoprotective effect of nicorandil against acetaminophen-induced oxidative stress and hepatotoxicity in mice via modulating NO synthesis.

Acetaminophen (APAP) overdose can produce hepatotoxicity and consequently liver damage. This study investigated the hepatoprotective impacts of nicorandil on hepatic damage induced by APAP. Nicorandil was administered orally (100 mg/kg) for seven days before APAP challenge (500 mg/kg, ip). Pretreatment with nicorandil reduced serum levels of aminotransferases, bilirubin, GGT and LDH, and increased serum level of albumin. Moreover, nicorandil inhibited the increase in liver MDA levels and reversed the decline in GSH content and SOD activity. Besides, it notably alleviated APAP-induced necrosis observed in histopathological findings. Additionally, nicorandil alleviated APAP-induced NO overproduction and iNOS expression; however, the protein expression of eNOS was significantly increased. Moreover, nicorandil markedly reduced hepatic TNF-α and NF-κB levels, in addition to decreasing the protein expression of MPO in hepatic tissues. Furthermore, flow cytometry (annexin V-FITC/PI) displayed a significant decline in late apoptotic and necrotic cells, and an increase in viable cells in nicorandil group. Also, nicorandil caused a significant boost in hepatic antiapoptotic marker bcl-2 level. The presented data proposed that the protective effect of nicorandil might be attributed to its antioxidant, its impact on NO homeostasis, and its anti-inflammatory properties. Therefore, nicorandil may be a promising candidate for protection from liver injury induced by APAP.

Nicorandil, an ATP-sensitive potassium channel activation, attenuates myocardial injury in rats with ischemic cardiomyopathy.

Ischemic cardiomyopathy is a common but underestimated cause of heart failure. This study investigated the myocardial-protective effects of nicorandil on rats with ischemic cardiomyopathy. In the present study, ischemic cardiomyopathy rats model were used to evaluate the effects of nicorandil. Cardiac ultrasonography was employed to examine the changes of heart structure and heart function. Electron microscopy was employed to observe the changes of pathological ultrastructure of the myocardium. Western blot and enzyme-linked immunosorbent assays were employed to detect protein levels and Mitochondrial Ca2+ concentration. The heart color ultrasound and myocardial pathology of the rats in the nicorandil group were improved significantly, the mitochondrial Ca2+ concentration was decreased, the expressions of MFN-1, OPA-1, and Bcl were increased, and the expressions of the mitochondrial mitotic proteins DRP-1, VDAC1, CytC, and Bax were decreased in ICM rats' heart treatment with nicorandil, compared with ICM rats. Nicorandil can reduce myocardial pathological damage in ICM rats, which may be caused by promoting the opening of mitochondrial ATP-sensitive potassium channel and inducing the changes of mitochondrial dynamics to induce the reduction of myocardial cell apoptosis.

Nicorandil inhibits TLR4/MyD88/NF-κB/NLRP3 signaling pathway to reduce pyroptosis in rats with myocardial infarction.

Pyroptosis is an inflammatory cell death that regulates cardiomyocyte loss after myocardial infarction. Reports indicate that nicorandil has a strong anti-inflammatory effect and protects the myocardium from myocardial infarction. However, its relationship with pyroptosis is largely unreported. Here, we investigated to influence and mechanism of action of nicorandil on cardiomyocyte pyroptosis. Forty Sprague Dawley rats were randomly assigned to sham, MI, MI + nicorandil, and MI + nicorandil + TAK242 groups (10 per group). Myocardial infarction modeling was performed through ligation of the anterior descending branch of the left coronary artery. The function of cardiac was evaluated through echocardiography, detection of myocardial adenine nucleotides, cTnI, LDH, TTC, and HE staining. Moreover, we used qRT-PCR, immunohistochemistry, and Western blotting to examine the expression of pyroptosis-related molecules and the inflammasome pathway of TLR4/MyD88/NF-κB/NLRP3. Myocardial infarction caused the activation of GSDMD, aggravated myocardial injury, and triggered cardiac dysfunction. Myocardial infarction induced pyroptotic cell death, manifested as upregulation in mRNA and protein levels associated with pyroptosis, including caspase-1 cleavage and increased expression of IL-1ß and IL-18. These changes were mitigated by nicorandil. The achieved data implicate that myocardial infarction induces pyroptosis via the TLR4/MyD88/NF-κB/NLRP3 pathway, which can be inhibited by nicorandil pretreatment. Therefore, nicorandil exerts cardioprotective effects by activating KATP channels, and at least in part through inhibition of the TLR4/MyD88/NF-κB/NLRP3 pathway to reduce myocardial infarction-induced pyroptosis. As such, it is a potential therapy for ischemic heart disease.

Exogenous NO Therapy for the Treatment and Prevention of Atherosclerosis.

Amyl nitrite was introduced in 1867 as the first molecule of a new class of agents for the treatment of angina pectoris. In the following 150 years, the nitric oxide pathway has been the subject of a number of pharmacological approaches, particularly since when this elusive mediator was identified as one of the most important modulators of vascular homeostasis beyond vasomotion, including platelet function, inflammation, and atherogenesis. While having potent antianginal and antiischemic properties, however, nitric oxide donors are also not devoid of side effects, including the induction of tolerance, and, as shown in the last decade, of oxidative stress and endothelial dysfunction. In turn, endothelial dysfunction is itself felt to be involved in all stages of atherogenesis, from the development of fatty streaks to plaque rupture and thrombosis. In the present review, we summarize the agents that act on the nitric oxide pathway, with a particular focus on their potentially beneficial antiatherosclerotic and unwanted pro-atherosclerotic effects.

Myocardial Protective Effects of Nicorandil on Rats with Type 2 Diabetic Cardiomyopathy.

BACKGROUND Diabetic cardiomyopathy (DCM) is a common but underestimated cause of heart failure in patients with diabetes. This study investigated the myocardial-protective effects of nicorandil (Nic) on rats with DCM. MATERIAL AND METHODS A total of forty-seven 180-220 g male Wistar rats were randomly divided into 4 groups: a control group (control, n=8), a DCM group (DCM, n=13), a nicorandil-pretreated DCM group (Nic1, n=13), and a nicorandil-treated DCM group (Nic2, n=13). A rat model of type 2 diabetes was induced by high-fat and high-sugar diet and intraperitoneal injection of streptozotocin (STZ). Nicorandil (3 mg/kg/d) was orally administrated to rats in the Nic1 group starting at week 4. Nicorandil (3 mg/kg/d) was orally administrated only after the induction of diabetes in the Nic2 group. The serum lipoids, plasma glucose, insulin levels, heart weight index, serum creatine kinase (CK), lactate dehydrogenase (LDH) levels, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) were analyzed in all groups. RESULTS The DCM group showed increased heart weight index, serum LDH, CK, and MDA content and decreased serum SOD activity, as compared with the control group (P<0.05). The DCM-induced increases in heart weight index, serum LDH, CK, and MDA content and decrease in serum SOD activity were attenuated in both Nic1 and Nic2 groups (P<0.05). However, there was no significant difference between Nic1 and Nic2 groups (P>0.05). CONCLUSIONS Nicorandil has protective effects on cardiac hypertrophy in DCM rats through increased SOD activity and decreased MDA content. Therefore, nicorandil may be a therapeutic method for diabetic patients with DCM.

Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy.

BACKGROUND: Dystrophin-deficient cardiomyopathy is a growing clinical problem without targeted treatments. We investigated whether nicorandil promotes cardioprotection in human dystrophin-deficient induced pluripotent stem cell (iPSC)-derived cardiomyocytes and the muscular dystrophy mdx mouse heart. METHODS AND RESULTS: Dystrophin-deficient iPSC-derived cardiomyocytes had decreased levels of endothelial nitric oxide synthase and neuronal nitric oxide synthase. The dystrophin-deficient cardiomyocytes had increased cell injury and death after 2 hours of stress and recovery. This was associated with increased levels of reactive oxygen species and dissipation of the mitochondrial membrane potential. Nicorandil pretreatment was able to abolish these stress-induced changes through a mechanism that involved the nitric oxide-cyclic guanosine monophosphate pathway and mitochondrial adenosine triphosphate-sensitive potassium channels. The increased reactive oxygen species levels in the dystrophin-deficient cardiomyocytes were associated with diminished expression of select antioxidant genes and increased activity of xanthine oxidase. Furthermore, nicorandil was found to improve the restoration of cardiac function after ischemia and reperfusion in the isolated mdx mouse heart. CONCLUSION: Nicorandil protects against stress-induced cell death in dystrophin-deficient cardiomyocytes and preserves cardiac function in the mdx mouse heart subjected to ischemia and reperfusion injury. This suggests a potential therapeutic role for nicorandil in dystrophin-deficient cardiomyopathy.

Opioid pathways activation mediates the activity of nicorandil in experimental models of nociceptive and inflammatory pain.

We have previously demonstrated that nicorandil inhibits the second phase of the nociceptive response induced by formaldehyde. In the present study, we evaluated the effects induced by nicorandil in other models of nociceptive and inflammatory pain in mice and also whether opioid pathways activation mediates its activity. As we have previously demonstrated, per os (p.o.) administration of nicorandil (50, 100 or 150mg/kg; -1h) inhibited the second phase of the nociceptive response induced by intraplantar (i.pl.) injection of formaldehyde. Nicorandil (50, 100 or 150mg/kg; p.o., -1h) also exhibited activity in models of inflammatory pain induced by i.pl. injection of carrageenan (300µg) and nociceptive pain induced by exposure to noxious heat (50°C). Intraperitoneal (i.p.) administration of the opioid antagonist naltrexone (1, 5 or 10mg/kg, -30min) attenuated or abolished the antinociceptive activity of nicorandil (100mg/kg, p.o.) in the three experimental pain models. In conclusion, we demonstrate that nicorandil exhibits activity in different models of nociceptive and inflammatory pain. The demonstration that the antinociceptive effect induced by nicorandil is markedly attenuated by an opioid antagonist provides solid information about an important mechanism mediating the activity of this antianginal drug. Altogether, our data suggest that the clinical pain relief induced by nicorandil in heart ischemic conditions may result from both vasodilation and intrinsic analgesic activity.

Role of nicotinic acid and nicotinamide in nicorandil-induced ulcerations: from hypothesis to demonstration.

Nicorandil, a nicotinamide ester, was first reported to be involved in the induction of oral ulcers in 1997. Since then, many reports of single or multiple nicorandil-induced ulcerations (NIUs) have been reported. We hypothesised that in the case of high-dosage nicorandil or after an increased dosage of nicorandil, nicotinic acid and nicotinamide (two main metabolites of nicorandil) cannot appropriately merge into the endogenous pool of nicotinamide adenine dinucleotide/phosphate, which leads to abnormal distribution of these metabolites in the body. In recent or maintained trauma, nicotinamide increases blood flow at the edge of the raw area, inducing epithelial proliferation, while nicotinic acid ulcerates this epithelial formation, ultimately flooding the entire scar. We demonstrate, by comparison to a control patient non-exposed to nicorandil, an abnormal amount of nicotinic acid (×38) and nicotinamide (×11) in the ulcerated area in a patient with NIUs. All practitioners, especially geriatricians, dermatologists and surgeons, must be aware of these serious and insidious side effects of nicorandil. It is critical to rapidly reassess the risk-benefit ratio of this drug for any patient, and not only for those with diverticular diseases.

Influence of skin thickness on the in vitro permeabilities of drugs through Sprague-Dawley rat or Yucatan micropig skin.

The purpose of this study was to clarify the influence of skin thickness on the in vitro permeabilities of 3 model drugs with different physicochemical properties (nicorandil (NR), isosorbide dinitrate (ISDN) and flurbiprofen (FP)) through Sprague-Dawley rat (rat) or Yucatan micropig (YMP) skin. Intact, dermis-split, stratum corneum-stripped or stratum corneum-stripped and dermis-split rat or YMP skin (rat skin thickness: approximately 0.4, 0.9 or 1.2 mm; YMP skin thickness: approximately 0.4, 0.9, 1.8 or 2.8 mm) were set in Franz-type diffusion cells to determine the permeation rate, lag time and resistance ratio of the viable epidermis and dermis against whole skin (R(ved)/R(tot)) of the drugs. The YMP skin permeabilities of the drugs decreased with an increase in the skin thickness, and significant differences were observed in the permeation rates and lag times between intact and dermis-split (0.4 mm) YMP skins. The decreases in the permeabilities of the drugs through the YMP skin were larger than those through the rat skin. The influence of resistances of ISDN and FP through the dermis-split rat or YMP skin was greater at 0.9 mm skin thickness than 0.4 mm skin thickness. The R(ved)/R(tot) values for the YMP skins were relatively large for lipophilic drugs (ISDN and FP), and these ratios increased with an increase in the dermis thickness. These results suggest that in vitro skin permeation studies must be done using dermis-split (0.4 mm) skin with the thinnest dermis for predicting in vivo human percutaneous absorption rate.

Potassium channel openers and improvement of toxic stress: do they have role in the management of inflammatory bowel disease?

Inflammatory bowel disease (IBD) is a progressive condition in gastrointestinal tract, which refers to two idiopathic diseases; ulcerative colitis and Crohn's disease. Although certain etiology of these conditions is not known, it seems that an abnormality in reaction and regulation of the immune system plays an important role in adventure of the disease. According to the investigations, it is likely that oxidative and nitrosative stress have etiologic roles in IBD. Their destructive effects may contribute to the initiation or progression of the disease. Nowadays, the effectiveness of different medicines in the treatment of IBD has been proved, but none of them has shown a desirable result. Potassium channel openers (PCOs) are a class of drugs with various usages in the aspects of cardiovascular diseases and urinary incontinence. Their major mechanism is the opening of ATP-sensitive potassium (K-ATP) channels and contribute to the relaxation of smooth muscles. Nicorandil is a member of PCOs, with a special chemical structure. Recent investigations mention some novel effects and functions for this drug. Nicorandil reveals an anti-apoptosis property not only via a nitric oxide (NO)/cGMP-dependent mechanism, but also through activating mitochondrial K-ATP channels. Nicorandil can also elevate cGMP levels in some tissues, without direct NO generation. Gastroprotective activity via opening of the K channels, free radical scavenging, prostaglandin E2 elevation, decreasing pepsin and acid secretion, and prevention of the detrimental rise in NO has been proposed for nicorandil. According to these protective mechanisms and the role of oxidative/nitrosative stress in the expression of IBD, we herein hypothesize that nicorandil and other PCOs with similar structure can be used in the management of IBD. This approach offers new hope for the successful treatment of IBD. Further investigations on animal models are needed, to place nicorandil and similar drugs alongside IBD therapy.

Formulation of an HPMC gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing in vitro transdermal delivery of nicorandil.

The objective of the present study was to formulate a hydroxypropyl methylcellulose (HPMC) gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing the transdermal delivery of nicorandil so as to develop and fabricate a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation of nicorandil was determined across rat abdominal skin from a solvent system consisting of ethanol or various proportions of ethanol and water. The ethanol-water (70:30 v/v) solvent system that provided an optimal transdermal permeation was used in formulating an HPMC gel drug reservoir system with selected concentrations (0% w/w, 4% w/w, 6% w/w, 8% w/w or 10% w/w) of limonene as a penetration enhancer for further enhancement of transdermal permeation of nicorandil. The amount of nicorandil permeated in 24 h was found increased with an increase in the concentration of limonene in the drug reservoir system up to a concentration of 6% w/w, but beyond this concentration there was no further increase in the amount of drug permeated. The flux of nicorandil was 370.9 +/- 4.2 microg/cm2 x h from the drug reservoir system with 6% w/w of limonene, which is about 2.6 times the required flux to be obtained across rat abdominal skin for producing the desired plasma concentration for the predetermined period in humans. The results of a Fourier Transform Infrared study indicated that limonene enhanced the percutaneous permeation of nicorandil by partially extracting the stratum corneum lipids. It is concluded that the HPMC gel drug reservoir system prepared with a 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene is useful in designing and fabricating a membrane-moderated TTS of nicorandil.

Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone.

The potential of ATP-sensitive potassium channel openers (KCOs) for the treatment of male erectile dysfunction has recently been suggested based on positive clinical outcomes following intra-cavernosal administration of pinacidil. Agents that increase the levels of cGMP via elevation of nitric oxide (NO) nitroglycerin, for example, are also effective in improving erectile function preclinically and clinically. The aim of the present study was to determine the effects and mechanism of the action of nicorandil on rabbit corpus cavernosum. The in vitro regulation of smooth muscle tone was assessed in isolated cavernosal tissues pre-contracted with phenylephrine. Nicorandil, but not its major metabolite, relaxed phenylephrine-precontracted cavernosum smooth muscle with an EC(50) of 15 microM. The effects of nicorandil were only partially reversed by the K(ATP) channel blocker glyburide (10 microM) or by a soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one (ODQ, 3 microM). However, a combination of ODQ and glyburide completely blocked the relaxant effects of nicorandil. The results of the present study indicate that nicorandil can relax rabbit cavernosal tissue in vitro via a mechanism that involves activation of K(ATP) channels and stimulation of soluble guanylate cyclase.

Inhibitory effects of nicorandil on rat mesangial cell proliferation via the protein kinase G pathway.

We investigated the effects of nicorandil, which is a hybrid between a nitrate and an ATP-sensitive potassium channel (K(ATP)) opener, on cultured rat mesangial cell proliferation. Nicorandil (1 microM to 1 mM inhibited [(3)H]thymidine incorporation into rat mesangial cells in a concentration-dependent manner. Nicorandil (1 microM to 1 mM) also inhibited the number of cells. Nicorandil increased cyclic guanosine 3',5'-cyclic monophosphate accumulation in mesangial cells. A protein kinase G inhibitor, KT5823, partially eliminated the inhibition of mesangial cell proliferation by nicorandil. Methylene blue, a guanylate cyclase inhibitor, blocked the inhibitory effect of nicorandil on mesangial cell proliferation. We also examined the effects of K(ATP) mediators. Cromakalim, a K(ATP) activator, and glibenclamide, a K(ATP) inhibitor, had little effect on the proliferation of mesangial cells. These results suggest that the inhibitory effects of nicorandil on mesangial cell proliferation are mediated via the protein kinase G pathway.

New windows on the mechanism of action of K(ATP) channel openers.

K(ATP) channel openers are a diverse group of drugs with a wide range of potential therapeutic uses. Their molecular targets, the K(ATP) channels, exhibit tissue-specific responses because they possess different types of regulatory sulfonylurea receptor subunits. It is well recognized that complex interactions occur between K(ATP) channel openers and nucleotides, but the cloning of the K(ATP) channel has introduced a new dimension to the study of these events and has furthered our understanding of the molecular basis of the action of K(ATP) channel openers.

Nicorandil. An updated review of its use in ischaemic heart disease with emphasis on its cardioprotective effects.

Nicorandil is a drug with both nitrate-like and ATP-sensitive potassium-channel (K+ ATP) activating properties. By virtue of this dual mechanism of action, the drug acts as a balanced coronary and peripheral vasodilator and reduces both preload and afterload. The K+ ATP channel has been shown to be involved in the phenomenon of myocardial preconditioning, and studies in animal models of ischaemia-reperfusion-induced myocardial stunning or infarction indicate that nicorandil has cardio-protective effects. Studies in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) have shown that the administration of nicorandil reduces ST-segment elevation during ischaemia. Nicorandil significantly improved the results of exercise tolerance tests versus baseline in patients with stable effort angina pectoris in early noncomparative trials. The drug also improved the results of exercise tolerance tests relative to placebo in early randomised, double-blind, placebo-controlled trials. In randomised, double-blind comparative studies in patients with angina pectoris, nicorandil has demonstrated equivalent efficacy, as measured by exercise tolerance testing, to isosorbide di- and mononitrate, metoprolol, propranolol, atenolol, diltiazem, amlodipine and nifedipine. The effects of nicorandil on various aspects of myocardial recovery from ischaemic damage caused by acute myocardial infarction have been investigated in the short term. Regional left ventricular (LV) wall motion, a marker of myocardial function, was significantly improved in nicorandil recipients relative to control. The main adverse event associated with nicorandil as treatment for angina pectoris is headache. This can be minimised by commencing nicorandil at a low dose in patients prone to headache. There have been infrequent case reports of mouth ulcers in patients receiving nicorandil; causality has not been conclusively established, but product prescribing information indicates that an alternative treatment should be considered if persistent aphthous or severe mouth ulceration occurs. Thus, nicorandil remains a useful background therapy for patients with angina pectoris. The drug has also demonstrated potential cardioprotective effects when used as part of an intervention strategy directly after acute myocardial infarction in high-risk patients. Further large scale longer term studies of nicorandil in this latter indication are awaited with interest.

Nicorandil metabolism in rat myocardial mitochondria.

The in vitro study using rats was carried out to clarify the hypothesis that nicorandil is denitrated and then may produce nitric oxide (NO) in myocardial mitochondria. In the presence of a NADPH-generating system, [14C]nicorandil, which was incubated in mitochondrial and microsomal fractions of the lung, heart, or liver, was converted to its main denitrated metabolite, SG-86 and other metabolites. Apparent Km and Vmax for nicorandil in mitochondrial and microsomal fractions of the heart were considerably similar to those of the lung, but completely different from those of the liver. It seems that glutathione-S-transferases (GSTs) are not primarily involved in the conversion of nicorandil to SG-86, because a known GST inhibitor, indomethacin, did not affect the nicorandil degradation in the mitochondrial fraction. Nitrite, the stable metabolite of NO, was measured by the Griess reaction. In the presence of an NADPH-generating system, nicorandil significantly increased nitrite production in myocardial mitochondria, but SG-86 did not. These data strongly indicate that nicorandil is metabolized to SG-86 in myocardial mitochondria, then releasing NO, and that GSTs are not primarily responsible for the conversion of nicorandil to SG-86.

Myocardial distribution and biotransformation in vitro and in vivo of nicorandil in rats, with special reference to mitochondria.

This study reports subcellular localization of nicorandil in the myocardium and metabolism in mitochondria after oral dosing of 3 mg/kg nicorandil to rats. In the in vitro experiments, nicorandil, which was incubated with tissue homogenates (liver, kidney, heart, and small intestine), was metabolized to its denitrated compound, SG-86, and unknown substances. In the absence of a NADPH-generating system in the heart, the metabolic activity existed only in the mitochondrial fraction, but not in cytosolic and microsomal fractions. In the presence of the system, the activity in the mitochondrial fraction became much higher. To examine subcellular distribution of nicorandil in the myocardium, [14C]nicorandil was orally given to rats. Fifteen minutes after oral dosing of 3 mg/kg [14C]nicorandil, of which myocardial concentration reached a peak, nicorandil and SG-86 were found in mitochondrial fractions as well as in cytosolic and microsomal ones of the heart. Electron-microscopic autoradiograms, 15 min after oral dosing of 3 mg/kg [3H]nicorandil to rats, also showed the existence of the silver grains (showing radioactivity) in mitochondria of the heart. We conclude that nicorandil given orally is distributed in mitochondria of the heart, being partly transformed into SG-86, and that the myocardial mitochondria may be a potential site of action of nicorandil, an opener of KATP channels, which have been demonstrated to be present in this subcellular particle.