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 attenuates cognitive impairment after traumatic brain injury via inhibiting oxidative stress and inflammation: Involvement of BDNF and NGF.

BACKGROUND AND PURPOSE: Cognitive impairment is a prevalent adverse consequence of traumatic brain injury (TBI). The neuroprotective effects of nicorandil (N-(2-hydroxyethyl)-nicotinamide nitrate) has been previously documented, yet its protective effects against cognitive dysfunction post-TBI remain unclear. Hence, the present study was aimed to evaluate whether nicorandil attenuates cognitive dysfunction in TBI rats and the underlying mechanism behind this process. METHODS: The TBI model was established with a controlled cortical impact (CCI). The effects of nicorandil on cognitive dysfunction of rats with TBI were examined through Novel object recognition (NOR) test, Y-maze test, and Morris water maze (MWM) task. After behavioral tests, hippocampal tissue was collected for Quantitative real-time PCR, Western blot analysis, and Enzyme-linked immunosorbent assay (ELISA) assay. RESULTS: We observed that nicorandil administration effectively ameliorates learning and memory impairment in TBI rats. Alongside, nicorandil treatment attenuated oxidative stress in the hippocampus of TBI rats, characterized by the decreased reactive oxygen species generation, malondialdehyde, and protein carbonyls levels, and concurrent promotion of antioxidant-related factors (including superoxide dismutase, glutathione peroxidase, and catalase) activities. Additionally, nicorandil treatment attenuated the inflammatory response in the hippocampus of TBI rat, as evidenced by the upregulated levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α), as well as the downregulated level of IL-10. Mechanistically, nicorandil treatment significantly enhanced the mRNA and protein levels of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of TBI rats. CONCLUSION: These findings suggest that nicorandil mitigates cognitive impairment after TBI by suppressing oxidative stress and inflammation, potentially through enhancing BDNF and NGF levels.

Efficacy of nicorandil and ranolazine in prevention of contrast-induced nephropathy in patients with mild-to-moderate renal dysfunction: a randomized controlled trial.

INTRODUCTION: Contrast-induced nephropathy (CIN) is a common complication after percutaneous coronary intervention (PCI). There is conflicting evidence regarding efficacy of nicorandil in CIN prevention. With respect to ranolazine, there is physiological possibility as well as data in animal study regarding its protective effect against CIN; there is, however, no human data till date. AIM AND OBJECTIVES: To assess the efficacy of nicorandil and ranolazine in preventing CIN. The secondary endpoint was to measure difference in postprocedure acute kidney injury (AKI) incidence across groups. Also, patients were followed up till 6 months for major adverse events. MATERIAL AND METHODS: This single-center randomized controlled study included 315 patients of coronary artery disease with mild-to-moderate renal dysfunction undergoing elective PCI. Eligible patients were assigned to either nicorandil (n = 105), ranolazine (n = 105) or control group (n = 105) in 1 : 1 : 1 ratio by block randomization. All enrolled patients were given intravenous sodium chloride at rate of 1.0 mL/kg/h (0.5 mL/kg/h for patients with left ventricular ejection fraction <45%) from 6 h before procedure till 12 h after procedure. Iso-osmolar contrast agent (iodixanol) was used for all patients. In addition to hydration, patients in nicorandil group received oral nicorandil (10 mg, 3 times/d) and those in ranolazine group received oral ranolazine (1000 mg, 2 times/d) 1 day before procedure and for 2 days after PCI. Patients in control group received only hydration. RESULTS: Total number of CIN was 34 (10.7%), which included 19 (18.1%) in control, 8 (7.6%) in nicorandil and 7 (6.6%) in ranolazine group. There was significant association of CIN reduction across groups ( P  = 0.012). On pairwise comparison also, there was significant benefit across control and ranolazine as well as control and nicorandil ( P  < 0.025). There was numerically higher incidence of AKI in controls; the difference, however, did not reach statistical significance after applying Bonferroni correction ( P  = 0.044). Over 6-month follow-up, adverse events were similar across groups. CONCLUSION: While this study adds to existing literature that supports role for nicorandil in CIN prevention, the efficacy of ranolazine in protecting against CIN has been demonstrated in humans for the first time.

Utility and optimal dose of nicorandil for physiological assessment of the femoropopliteal artery.

BACKGROUND: Nicorandil is widely used as a vasodilator for the physiological assessment of coronary arteries because of its usefulness and safety; however, there are no data on its use in peripheral arteries. AIMS: To identify the utility of nicorandil and its appropriate dose for the physiological assessment on the femoropopliteal artery. METHODS: We retrospectively enrolled patients from three institutes in which physiological assessment was carried out with various doses of nicorandil before treatment. Twenty-four femoropopliteal artery stenotic lesions from 22 patients were included. The nicorandil doses used were 2, 4, and 6 mg. Twenty-two lesions were also assessed using 30 mg of papaverine. The pressure gradient (PG) and peripheral fractional flow reserve (pFFR) were calculated based on the mean and systolic pressure levels. We examined the correlation of each parameter with the peak systolic velocity ratio (PSVR) based on the duplex ultrasound images using Spearman's rank correlation coefficient. Systemic blood pressure was assessed for safety. RESULTS: The correlations were higher for mean pressure-based parameters than for systolic pressure-based parameters. As the nicorandil dose increased, the correlations among PG, pFFR, and PSVR also increased (mean pressure-based PG: 2 mg, r = 0.360; 4 mg, r = 0.498; 6 mg, r = 0.694, mean pressure-based pFFR: 2 mg, r = -0.479; 4 mg, r = -0.469; 6 mg, r = -0.641). The blood pressure after the administration of 6 mg of nicorandil was low, and the median systemic mean pressure was 65 mmHg. CONCLUSION: A 4 mg dose of nicorandil is effective and safe for the mean pressure-based physiological assessment of lesions in the femoropopliteal artery.

Effect of Perioperative Nicorandil on Myocardial Protection in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass, a Retrospective Study.

Background: The potential myocardial protective effect of nicorandil (NICD) in patients undergoing percutaneous coronary intervention has been established. However, its efficacy in the context of cardiac surgery remains controversial. The present study aimed to evaluate the myocardial protective effect of perioperative NICD use in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods: We retrospectively gathered data from patients undergoing cardiac bypass surgery between 12/2018 and 04/2021 in Fuwai Hospital. Subsequently, the patients were divided into two groups, NICD group and non-nicorandil (non-NICD) group. A 1, 3 propensity score matching (PSM) was conducted. The primary outcome was the incidence of myocardial injury. The secondary outcomes included the mechanical ventilation (MV) duration, intensive care unit (ICU) length of stay (LOS), hospital LOS, duration of chest drainage, the drainage volume, the total cost, the incidence of acute kidney injury (AKI), and the incidence of acute liver injury (ALI). Subsequently, we divided the entire population into two distinct subgroups based on their administration of NICD, and performed a comprehensive subgroup analysis. Results: A total of 2406 patients were ultimately included in the study. After PSM, 250 patients in NICD group and 750 patients in non-NICD group were included in the analysis. Perioperative NICD reduced the incidence of myocardial injury (47.2% versus 38.8%, P=0.025). Our subgroup analysis revealed that preoperative NICD administration not only provided myocardial protection benefits (45.7% vs 35.8%, OR 0.66, 95% CI [0.45-0.97], P=0.041), but also demonstrated statistically significant reduction in ALI, the ICU and hospital LOS, and the duration of chest drainage (all P<0.05). Conclusion: The perioperative NICD administration may confer myocardial protection in patients undergoing cardiac surgery with CPB. Furthermore, the preoperative utilization of NICD has the potential to mitigate the incidence of postoperative ALI, a reduction in the ICU and hospital LOS, and the duration of chest drainage.

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.

Nicorandil and carvedilol mitigates motor deficits in experimental autoimmune encephalomyelitis-induced multiple sclerosis: Role of TLR4/TRAF6/MAPK/NF-κB signalling cascade.

Multiple sclerosis (MS) is an inflammatory demyelinating neurodegenerative disease that negatively affects neurotransmission. It can be pathologically mimicked by experimental autoimmune encephalomyelitis (EAE) animal model. ATP-sensitive potassium channels (KATP) plays a crucial role in the control of neuronal damage, however their role in MS are still obscure. Additionally, Carvedilol showed a promising neuroprotective activity against several neurological disorders. Therefore, the present study aimed to investigate the potential neuroprotective effect of KATP channel opener (nicorandil) as well as α and ß adrenoceptor antagonist (Carvedilol) against EAE induced neurodegeneration in mice. Mice was treated with nicorandil (6 mg/kg/day; p.o.) and carvedilol (10 mg/kg/day; p.o.) for 14 days. Nicorandil and carvedilol showed improvement in clinical scoring, behaviour and motor coordination as established by histopathological investigation and immunohistochemical detection of MBP. Furthermore, both treatments downregulated the protein expression of TLR4/ MYD88/TRAF6 signalling cascade with downstream inhibition of (pT183/Y185)-JNK/p38 (pT180/Y182)-MAPK axis leading to reduction of neuroinflammatory status, as witnessed by reduction of NF-κB, TNF-α, IL-1ß and IL-6 contents. Moreover, nicorandil and carvedilol attenuated oxidative damage by increasing Nrf2 content and SOD activity together with reduction of MDA content. In addition, an immunomodulating effect via inhibiting the gene expression of CD4, TGF-ß, and IL-17 as well as TGF-ß, IL-17, and IL-23 contents along with anti-apoptotic effect by decreasing Bax protein expression and Caspase-3 content and increasing Bcl-2 protein expression was observed with nicorandil and carvedilol treatments. In conclusion, nicorandil and carvedilol exerted a neuroprotective activity against EAE induced neuronal loss via inhibition of TLR4/MYD88/TRAF6/JNK/p38-MAPK axis besides antioxidant and anti-apoptotic effects.

Nicorandil attenuates cisplatin-induced acute kidney injury in rats via activation of PI3K/AKT/mTOR signaling cascade and inhibition of autophagy.

Cisplatin is a highly effective antitumor agent, but its clinical use is limited due to critical adverse reactions including acute kidney injury (AKI). Nicorandil is an approved antianginal agent decreasing ischemia by potassium channel opening. The aim of this study was to investigate the nephroprotective effects of nicorandil and the possible role of activating PI3K/AKT/mTOR pathway in ameliorating cisplatin-induced AKI. Forty male Wistar rats were randomly allocated in 4 groups (n = 10). Group I: rats received the vehicle and served as control. Group II: rats received a single dose of cisplatin (7 mg/kg, i.p) on the 10th day of the experiment and served as AKI group. Group III: rats received cisplatin as in group II and nicorandil (3 mg/kg/day, p.o) for 14 days. Group IV: rats received cisplatin and nicorandil as in group III as well as wortmannin (15 µg/kg, i.v) for 14 days. Nicorandil exhibited obvious nephroprotective effects via the activation of PI3K/AKT/mTOR pathway. Moreover, nicorandil succeed to reduce the expression of the autophagy markers beclin-1 and LC-3II/I. In parallel, nicorandil showed anti-inflammatory and antiapoptotic effects via inhibition of NF-κB inflammatory pathway and depression of Bax/Bcl-2 ratio. Wortmannin, the PI3K inhibitor, was used to demonstrate the proposed pathway. Our study showed the nephroprotective effects of nicorandil in cisplatin-induced AKI in rats via activation of PI3K/AKT/mTOR signaling cascade, inhibition of autophagy, anti-inflammatory, anti-apoptotic, anti-oxidant activities. Thus, nicorandil could represent a promising renoprotective agent in cancer patients treated with cisplatin.

Combination of Nicorandil and Beta-Adrenergic Receptor Blockers in Patients with Coronary Artery Disease: A Real-World Observational Study.

BACKGROUND: The effect of combined nicorandil and beta-adrenergic receptor blockers (BBs) compared with that of BBs alone on long-term clinical outcomes in patients with coronary artery disease (CAD) remains undetermined. METHODS: A multicenter retrospective cohort study was performed. Adult patients who had been hospitalized for CAD and treated for angina with a combination of nicorandil and BBs or BBs alone were included. The effect of different treatments on the cumulative incidence of major adverse cardiovascular event (MACE) and their components within a follow-up duration of 2.5 years were analyzed using Kaplan-Meier survival curves. An inverse probability of treatment weighting (IPTW) method was used to adjust for the possible effect of confounding factors. RESULTS: A total of 137,714 patients were screened, of whom 16,912 individuals (mean age: 61.5 years, men: 67.1%) were successfully enrolled. Among the enrolled participants, 4669 received the combined treatment of nicorandil and BBs, while 12,243 received BBs alone. After IPTW, the results demonstrated that the combined treatment was associated with a significantly reduced incidence of MACE (hazard ratio [HR] 0.79, 95% conidence interval [CI] 0.72-0.87) and stroke (HR 0.48, 95% CI 0.42-0.54) but not of MI (HR 1.03, 95% CI 0.92-1.15) or all-cause mortality (HR 0.93, 95% CI 0.64-1.37). Sensitivity analyses revealed similar results. CONCLUSIONS: A combined antiangina treatment of nicorandil and BBs may be more effective than treatment of BBs alone in reducing the long-term incidence of MACE in patients with CAD.

Preventive Effects of Nicorandil and Atorvastatin in Contrastinduced Nephropathy in Patients with Renal Dysfunction Undergoing Coronary Artery Angiography: A Double Blind, Randomized, Controlled Clinical Trial.

INTRODUCTIONS: Contrast-induced nephropathy (CIN) is an important issue in patients with cardiovascular disorders undergoing angiography, especially in patients with kidney failure. The purpose of the present study was to compare the preventive effects of nicorandil and atorvastatin on the incidence of CIN in patients with chronic kidney disease (CKD). METHODS: In this clinical trial study, 270 patients with renal insufficiency nominated for angiographic procedures were randomly divided into three groups (each group, n = 90): hydration group (1000 mL saline), hydration + atorvastatin group (80 mg/d for 3 days), and hydration + nicorandil group (10 mg 3 times/d for 3 days). Serum creatinine (Cr) and blood urea nitrogen (BUN) levels as well as glomerular filtration rate (GFR) were evaluated before and 72 hours after the intervention. RESULTS: At the end of the study, serum Cr and BUN levels in all three groups showed a significant increase compared to the pre-intervention levels, which were significantly higher in the control group than the other two groups. The amount of GFR also significantly decreased following the intervention in all three groups, with the decline being significantly more pronounced in the control group than in other two groups. No significant differences were found in serum concentrations of Cr and BUN as well as GFR levels between nicorandil and atorvastatin groups at the end of the study. CONCLUSION: Nicorandil and atorvastatin administration showed preventive effects on CIN in CKD patients undergoing angiography, but there was no significant difference between the two drugs.  DOI: 10.52547/ijkd.7348.

Refractory cardiac arrest caused by type I Kounis syndrome treated with adrenaline and nicorandil: A case report.

RATIONALE: Kounis syndrome is a rare but life-threatening anaphylactic reaction that can lead to acute coronary syndrome and cardiac arrest, and requires prompt diagnosis. Adrenaline, which is used to treat anaphylaxis, may cause coronary vasoconstriction and worsen ischemia, whereas coronary vasodilators may dilate systemic vessels and exacerbate hypotension. Delayed diagnosis of Kounis syndrome and inadequate therapeutic intervention may thus lead to a poor outcome. PATIENT CONCERNS: A 59-year-old man was treated for sepsis due to a liver abscess. Following administration of daptomycin, the patient developed severe anaphylactic shock leading to refractory cardiac arrest. Because conventional cardiopulmonary resuscitation was ineffective, extracorporeal cardiopulmonary resuscitation was considered as an alternative approach. DIAGNOSES: On bedside monitoring during cardiopulmonary resuscitation, unexpected ST-segment elevation was found on lead II electrocardiogram. Accordingly, the patient was clinically diagnosed with Kounis syndrome. INTERVENTIONS: Nicorandil (6 mg/h), a coronary vasodilator with minimal blood pressure effects, was administered along with high doses of vasopressors, including adrenaline 0.2 µg/kg/min. OUTCOMES: After the initiation of nicorandil administration, the patient achieved return of spontaneous circulation and did not require extracorporeal cardiopulmonary resuscitation. Based on the elevated serum tryptase level, normal creatine kinase-MB range, and lack of stenosis on coronary angiography, the patient was definitively diagnosed with type I (coronary vasospasm) Kounis syndrome. He was subsequently transferred to the referring hospital without neurological sequelae. LESSONS: If anaphylaxis leads to refractory shock and cardiac arrest, ischemic changes on the electrocardiogram should be investigated to identify underlying Kounis syndrome. In addition to adrenaline, coronary dilators are the definitive treatment. Nicorandil may be a useful treatment option because of its minimal effect on blood pressure.

Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways.

Previous report indicated that nicorandil potentiated morphine antinociception and attenuated hepatic injury in liver fibrotic rats. Herein, the underlying mechanisms of nicorandil/morphine interaction were investigated using pharmacological, biochemical, histopathological, and molecular docking studies. Male Wistar rats were injected intraperitoneally (i.p.) with carbon tetrachloride (CCl4, 40%, 2 ml/kg) twice weekly for 5 weeks to induce hepatic fibrosis. Nicorandil (15 mg/kg/day) was administered per os (p.o.) for 14 days in presence of the blockers; glibenclamide (KATP channel blocker, 5 mg/kg, p.o.), L-NG-nitro-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor, 15 mg/kg, p.o.), methylene blue (MB, guanylyl cyclase inhibitor, 2 mg/kg, i.p.) and naltrexone (opioid antagonist, 20 mg/kg, i.p.). At the end of the 5th week, analgesia was evaluated using tail flick and formalin tests along with biochemical determinations of liver function tests, oxidative stress markers and histopathological examination of liver tissues. Naltrexone and MB inhibited the antinociceptive activity of the combination. Furthermore, combined nicorandil/morphine regimen attenuated the release of endogenous peptides. Docking studies revealed a possible interaction of nicorandil on µ, κ and δ opioid receptors. Nicorandil/morphine combination protected against liver damage as evident by decreased liver enzymes, liver index, hyaluronic acid, lipid peroxidation, fibrotic insults, and increased superoxide dismutase activity. Nicorandil/morphine hepatoprotection and antioxidant activity were inhibited by glibenclamide and L-NAME but not by naltrexone or MB. These findings implicate opioid activation/cGMP versus NO/KATP channels in the augmented antinociception, and hepatoprotection, respectively, of the combined therapy and implicate provoked cross talk by nicorandil and morphine on opioid receptors and cGMP signaling pathway. That said, nicorandil/morphine combination provides a potential multitargeted therapy to alleviate pain and preserve liver function.

Effects of nicorandil on QT prolongation and myocardial damage caused by citalopram in rats.

Citalopram is a selective serotonin re-uptake inhibitor (SSRI) antidepressant; it exhibits the greatest cardiotoxic effect among SSRIs. Citalopram can cause drug-induced long QT syndrome (LQTS) and ventricular arrhythmias. We investigated the protective effect of nicorandil, a selective mitochondrial KATP (mito-KATP) channel opener, on LQTS and myocardial damage caused by citalopram in male rats. In a preliminary study, we determined that the minimum citalopram dose that prolonged the QT interval was 102 mg/kg injected intraperitoneally. For the main study, rats were divided randomly into five experimental groups: untreated control, normal saline + citalopram, nicorandil + citalopram, 5-hydroxydecanoate (5-HD) + citalopram, 5-HD + nicorandil + citalopram. Biochemical and histologic data from blood and heart tissue samples from six untreated control rats were evaluated. Electrocardiographic parameters including QRS duration, QT interval, corrected QT interval (QTc) and heart rate (HR) were assessed, and biochemical parameters including malondialdehyde, reduced glutathione, glutathione peroxidase, superoxide dismutase were measured. We also performed histomorphologic and immunohistochemical examination of heart tissue. Citalopram prolonged QT-QTc intervals significantly and increased significantly the histomorphologic score and proportion of apoptotic cells, but produced no differences in the oxidant and antioxidant parameters. Nicorandil did not prevent citalopram induced QT-QTc interval prolongation and produced no significant changes in oxidant and antioxidant parameters; however, it did reduce histologic damage and apoptosis caused by citalopram.

Intravenous nicorandil for patients with acute decompensated heart failure: a meta-analysis of randomized controlled trials.

OBJECTIVES: Pilot studies have suggested the potential benefits of intravenous nicorandil for patients with acute decompensated heart failure (ADHF). However, clinical evidence remains limited. The aim of the study was to summarize the efficacy and safety of intravenous nicorandil for the treatment of ADHF. DESIGN: A systematic review and meta-analysis was performed. The search for relevant randomised controlled trials (RCTs) was conducted in PubMed, Embase, Cochrane's Library, Wanfang, and CNKI databases. A random-effects model was employed to combine the results. RESULTS: Eight RCTs contributed to the meta-analysis. Pooled results showed that acute treatment with intravenous nicorandil could significantly improve the symptom of dyspnea at 24 h after treatment, as evidenced by the five-point Likert scale for dyspnea after treatment (mean difference [MD]: -0.26, 95% confidence interval [CI]: -0.40 to -0.13, p < 0.001). Furthermore, nicorandil significantly reduced serum B natriuretic peptide (MD: -30.03 ng/dl, 95% CI: -47.00 to -13.06, p < 0.001), and N-terminal proBNP (MD: -138.69, 95% CI: -248.06 to -29.31, p = 0.01). In addition, nicorandil significantly improved ultrasonic parameters including left ventricular ejection fraction and E/e' at discharge. Moreover, during the follow-up duration of up to 90 days, intravenous nicorandil significantly reduced the incidence of major adverse cardiovascular events (risk ratio [RR]: 0.55, 95% CI: 0.32 to 0.93, p = 0.03). The incidence of treatment-related adverse events was not significantly different between nicorandil and controls (RR: 1.22, 95% CI: 0.69 to 2.15, p = 0.49). CONCLUSIONS: Results of this study suggest that intravenous nicorandil may be an effective and safe treatment for patients with ADHF.

Effect of Nicorandil, Diltiazem, or Isosorbide Mononitrate for Oral Antispastic Therapy After Coronary Artery Bypass Grafting Using Radial Artery Grafts-A Pilot Randomized Controlled Trial (ASRAB-Pilot): Rationale and Study Protocol.

INTRODUCTION: The current evidence for chronic oral antispastic medication use after coronary artery bypass grafting using radial artery grafts (RA-CABG) is controversial. Calcium channel blockers, such as diltiazem, are the most commonly used antispastic medications after RA-CABG; other options include nitrates and nicorandil, but to date no sufficiently powered randomized controlled trials have been conducted to compare their efficacy. METHODS: This is a single-center, open-label, parallel three-arm, pilot randomized controlled trial. Patients without contraindications to any study medications and who successfully underwent RA-CABG surgery will be consecutively screened. Eligible patients will be randomized in a ratio of 1:1:1 (a total of 150 patients, 50 per arm) to receive nicorandil 5 mg orally thrice daily, diltiazem 180 mg orally once daily, or isosorbide mononitrate 50 mg orally once daily for 24 weeks. The primary outcomes are RA graft failure at week 1 and week 24. The secondary outcomes include major adverse cardiovascular event (MACE, a composite of all-cause death, myocardial infarction, stroke, and unplanned revascularization) and angina recurrence. The safety outcomes include hypotension occurrence, withdrawal of renin angiotensin aldosterone system inhibitors, serious adverse events, and other concerned adverse events within 24 weeks. CONCLUSION: This pilot trial will compare the preliminary effects of nicorandil, diltiazem, and isosorbide mononitrate on angiographic and clinical outcomes in patients who have undergone RA-CABG. Recruitment began in June 2020, and the estimated primary completion date is early 2023. Results of this study will provide much needed information for design of large confirmatory trials on the effectiveness of oral antispastic medications after RA-CABG.

Protective Effect of Nicorandil on Contrast-Induced Acute Kidney Injury After Emergency Percutaneous Coronary Intervention.

Objective: To investigate the protective effect of nicorandil on contrast-induced acute kidney injury (CIAKI) in patients with acute ST-segment elevation myocardial infarction (STEMI) after emergency percutaneous coronary intervention (PCI). Methods: This is a single-center, retrospective control study. A total of 156 patients with STEMI were divided into the nicorandil group (n = 55) and the control group (n = 101). The incidence of CIAKI, defined as an increase of >25% or absolute values > 44.2 µmol/L in serum creatinine (Scr) from baseline within 72 h of exposure to a contrast agent after exclusion of other causes, was the primary endpoint. The secondary endpoints were: (1) changes of Scr, estimated glomerular filtration rate (eGFR), uric acid, and ß2-microglobulin at 24/48/72 h and 5 to 7 days after PCI; (2) the peak value difference of creatine kinase isoenzymes (CK-MB) after PCI; (3) adverse events within 6 months after PCI. Results: The overall incidence of CIAKI was 21.8%; the incidence of CIAKI in the nicorandil group was significantly lower (12.7% [7/55]) than in the control group (26.7% [27/101]) (P = .043). Compared with the control group, Scr, uric acid, and ß2-microglobulin levels were lower, and the level of eGFR was higher in nicorandil group (P all < .05). The peak value of CK-MB in the nicorandil group was lower than that in the control group (105.30 [56.61, 232.04] vs 178.00 [77.08, 271.91]U/L, P = .042). There was no significant difference in adverse events between the 2 groups within 6 months after PCI. Moreover, multivariate logistic regression analysis showed that hypertension and diabetes were independent risk factors for CIAKI, while nicorandil treatment was a protective factor. Conclusion: Our data suggest that intravenous nicorandil after emergency PCI has a protective effect on the occurrence of CIAKI in STEMI patients.

Cardioprotective and Antianginal Efficacy of Nicorandil: A Comprehensive Review.

ABSTRACT: Angina pectoris remains a significant burden despite advances in medical therapy and coronary revascularization. Many patients (up to 30%) with angina have normal coronary arteries, with coronary microvascular disease and/or coronary artery vasospasm being major drivers of the myocardial demand-supply mismatch. Even among patients revascularized for symptomatic epicardial coronary stenosis, recurrent angina remains highly prevalent. Medical therapy for angina currently centers around 2 disparate goals, viz secondary prevention of hard clinical outcomes and symptom control. Vasodilators, such as nitrates, have been first-line antianginal agents for decades, along with beta-blockers and calcium channel blockers. However, efficacy in symptoms control is heterogenous, depending on underlying mechanism(s) of angina in an individual patient, often necessitating multiple agents. Nicorandil (NCO) is an antianginal agent first discovered in the late 1970s with a uniquely dual mechanism of action. Like a typical nitrate, it mediates medium-large vessel vasodilation through nitric oxide. In addition, NCO has adenosine triphosphate (ATP)-dependent potassium channel agonist activity (K ATP ), mediating microvascular dilatation. Hence, it has proven effective in both coronary artery vasospasm and coronary microvascular disease, typically challenging patient populations. Moreover, emerging evidence suggests that cardiomyocyte protection against ischemia through ischemic preconditioning may be mediated through K ATP agonism. Finally, there is now fairly firm evidence in favor of NCO in terms of hard event reduction among patients with stable coronary artery disease, following myocardial infarction, and perhaps even among patients with congestive heart failure. This review aims to summarize the mechanism of action of NCO, its efficacy as an antianginal, and current evidence behind its impact on hard outcomes. Finally, we review other cardiac and emerging noncardiac indications for NCO use.

Effectiveness of intraoperative nicorandil in patients with a history of ischemic heart disease undergoing high-risk noncardiac surgery: a retrospective cohort study.

PURPOSE: Nicorandil is occasionally administered to prevent myocardial ischemia during the perioperative period in patients with ischemic heart disease (IHD); however, its effectiveness has not been clarified. In this study, we examined the effectiveness of intraoperative nicorandil administration in noncardiac surgery. METHODS: We identified patients with a history of IHD who had undergone high-risk noncardiac surgery between April 2015 and March 2020 from a nationwide in-patient database in Japan. The patients were divided into those who received nicorandil (nicorandil group) and those who did not (control group). The primary outcome was the 30-day in-hospital mortality. The secondary outcome was major adverse cardiovascular events (MACE), defined as the composite outcome of the 30-day in-hospital mortality, acute myocardial infarction, percutaneous coronary intervention, and coronary artery bypass grafting. One-to-one propensity score matching was performed. The outcomes were analyzed using a Cox proportional hazards model. RESULTS: Of 8037 patients, 2886 received nicorandil during surgery. After propensity score matching, 2554 pairs were analyzed. There was no significant difference in the 30-day in-hospital mortality (26 [1.02%] vs. 36 [1.41%]; hazard ratio [HR] 1.36; 95% confidence interval [CI] 0.82-2.26; P = 0.229) or incidence of MACE (42 [1.64%] vs. 55 [2.15%]; HR 1.24; 95% CI 0.86-1.93; P = 0.216) between the control and nicorandil groups. CONCLUSION: The findings of this study suggest that intraoperative nicorandil administration is not associated with the 30-day in-hospital mortality in high-risk noncardiac surgery.

Nicorandil Exerts Anticonvulsant Effects in Pentylenetetrazol-Induced Seizures and Maximal-Electroshock-Induced Seizures by Downregulating Excitability in Hippocampal Pyramidal Neurons.

N-(2-hydroxyethyl) nicotinamide nitrate (nicorandil), a nitrate that activates adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, is generally used in the treatment of angina and offers long-term cardioprotective effects. It has been reported that several KATP channel openers can effectively alleviate the symptoms of seizure. The purpose of this study was to investigate the improvement in seizures induced by nicorandil. In this study, seizure tests were used to evaluate the effect of different doses of nicorandil by analysing seizure incidence, including minimal clonic seizure and generalised tonic-clonic seizure. We used a maximal electroshock seizure (MES) model, a metrazol maximal seizure (MMS) model and a chronic pentylenetetrazol (PTZ)-induced seizure model to evaluate the effect of nicorandil in improving seizures. Each mouse in the MES model was given an electric shock, while those in the nicorandil group received 0.5, 1, 2, 3 and 6 mg/kg of nicorandil by intraperitoneal injection, respectively. In the MMS model, the mice in the PTZ group and the nicorandil group were injected subcutaneously with PTZ (90 mg/kg), and the mice in the nicorandil group were injected intraperitoneally with 1, 3 and 5 mg/kg nicorandil, respectively. In the chronic PTZ-induced seizure model, the mice in the PTZ group and the nicorandil group were injected intraperitoneally with PTZ (40 mg/kg), and the mice in the nicorandil group were each given 1 and 3 mg/kg of PTZ at a volume of 200 nL. Brain slices containing the hippocampus were prepared, and cell-attached recording was used to record the spontaneous firing of pyramidal neurons in the hippocampal CA1 region. Nicorandil (i.p.) significantly increased both the maximum electroconvulsive protection rate in the MES model and the seizure latency in the MMS model. Nicorandil infused directly onto the hippocampal CA1 region via an implanted cannula relieved symptoms in chronic PTZ-induced seizures. The excitability of pyramidal neurons in the hippocampal CA1 region of the mice was significantly increased after both the acute and chronic administration of PTZ. To a certain extent, nicorandil reversed the increase in both firing frequency and proportion of burst spikes caused by PTZ (P < 0.05). Our results suggest that nicorandil functions by downregulating the excitability of pyramidal neurons in the hippocampal CA1 region of mice and is a potential candidate for the treatment of seizures.

Exploring the role of ATP-sensitive potassium channel, eNOS, and P-glycoprotein in mediating the hepatoprotective activity of nicorandil in methotrexate-induced liver injury in rats.

BACKGROUND: Methotrexate (MTX) is a commonly used chemotherapeutic agent; however, its clinical use is challenged by various types of injuries, including hepatotoxic side effects. Therefore, finding new protective drugs against MTX-induced toxicities is a critical need. Moreover, the different mechanisms mediating such effects are still not clear. The current study aimed to evaluate the possible ameliorative action of nicorandil (NIC) in MTX-induced hepatotoxicity and examine the roles of the ATP-sensitive potassium channel (KATP), endothelial nitric oxide synthase (eNOS), and P-glycoprotein (P-gp). MATERIALS AND METHODS: Thirty-six male Wistar albino rats were used. NIC (3 mg/kg/day) was given orally for 2 weeks, and hepatotoxicity was induced by a single intraperitoneal injection of MTX (20 mg/kg) on the 11th day of the experiment. We confirmed the role of KATP by co-administering glimepiride (GP) (10 mg/kg/day) 30 min before NIC. The measured serum biomarkers were [alanine transaminase (ALT) and aspartate transaminase (AST)], total antioxidant capacity (TAC), malondialdehyde (MDA), nitric oxide (NOx), tumor necrosis factor-alpha (TNFα), superoxide dismutase (SOD), and P-gp. Histopathology, eNOS, and caspase-3 immunoexpression were evaluated. RESULTS: The MTX group displayed hepatotoxicity in the form of elevations of ALT, AST, MDA, NOx, and caspase-3 immunoexpression. Furthermore, the histopathological examination showed marked liver injury. TAC, SOD, P-gp, and eNOS immunoexpression showed significant inhibition. In the protective group, all parameters improved (P value < 0.05). CONCLUSION: NIC has an ameliorative action against MTX-induced hepatotoxicity, most probably via its antioxidant, anti-inflammatory, and anti-apoptotic functions together with the modulation of the KATP channel, eNOS, and P-glycoprotein.