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.

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 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.

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.

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.

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.

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.

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.

Oral Nicorandil effectively attenuates the incidence of contrast-induced nephropathy in patients undergoing cardiac catheterization: a randomized, controlled, open-label clinical trial.

PURPOSE: The contrast-induced nephropathy (CIN) rate is increasing globally and can increase the rate of mortality and long-term problems. This study aims to determine the effect of Nicorandil on preventing CIN among patients undergoing cardiac catheterization. METHODS: In a controlled randomized open-labeled clinical trial, all included patients undergoing cardiac catheterization due to coronary problems and possessing at least two risk factors of contrast nephropathy were divided into two groups of intervention and control. The intervention group received oral Nicorandil and normal saline, while the control group was treated with intravenous normal saline. Serum creatinine was measured before and 48 h after the procedure, and patients were assessed regarding CIN. RESULTS: In this study, 172 patients entered each group; 41.86% and 45.34% were male in the control and Nicorandil groups. We showed that the incidence of CIN was meaningfully lower in the Nicorandil group (12, 7%) than in the control group (34, 19.8%, P = 0.001). Additionally, the incidence of CIN was notably lower in the female patients in the Nicorandil (85.7%) than in the control group (14.3%, P = 0.001); however, these numbers were not significantly different among men (64.0% and 36.0%, respectively, P = 0.850). After the injection of the contrast agent, the serum levels of blood urea nitrogen (P = 0.248), creatinine (P = 0.081), and glomerular filtration rate (P = 0.386) showed no significant differences between the control and Nicorandil groups. Multivariate regression analysis showed that Nicorandil significantly lowered the odds of CIN [odds ratio (OR) = 0.299, 95% confidence interval (CI) 0.149-0.602; P = 0.001] after adjustment for baseline creatinine (OR = 1.404, 95% CI 0.431-4.572; P = 0.574). CONCLUSION: Our results indicate that pre-procedural treatment with Nicorandil may be effective against CIN in contrast to agent-exposed patients.

The effect of nicorandil on cardiac function and clinical outcomes in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: a randomised trial.

BACKGROUND: We investigated the effect of nicorandil on infarct size, cardiac function assessed by cardiac magnetic resonance imaging (CMR) and outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). METHODS: In a prospective, randomised, controlled trial, 83 patients with STEMI receiving primary PCI were randomised into the nicorandil (n =  40) or placebo (n  =  43) groups. Nicorandil was administered in the emergency room before primary PCI as an intravenous bolus of 4 mg followed by a continuous infusion of 6 mg/h for 24 h and as 2-mg intracoronary injections prior to balloon dilatation and coronary stenting. Nicorandil was continued orally at 10-20 mg/d for 6 months. Infarct size and cardiac function were measured by CMR at 5 d and 6 months after primary PCI. Furthermore, major adverse cardiac events (MACEs) including all-cause death, nonfatal myocardial infarction (MI), any revascularisation, stroke, and definite/probable stent thrombosis (ST) were compared. RESULTS: There were no significant differences in baseline clinical characteristics between the groups. Infarct size at baseline and 6 months as well as infarct size changes during 6 months as measured by CMR were similar between the groups. Similarly, other CMR parameters were comparable at baseline and 6 months between the groups. MACEs occurred in four patients (4.8%) during 6 months. No significant difference in the risk of MACEs was observed between the groups. CONCLUSIONS: Treatment with nicorandil for 6 months after primary PCI was not associated with any improvement in infarct size, CMR-determined cardiac function, and outcomes in STEMI patients.

Beneficial effect of the mitochondrial ATP­sensitive potassium channel­specific opener nicorandil on the collapsed lung via inhibition of apoptosis in clinical thoracic surgery.

With the use of thoracoscopic surgery technology, one­lung ventilation (OLV) is becoming more crucial as a basic requirement for enhanced recovery after surgery; however, it can lead to severe pulmonary injury, which is an issue for anesthesiologists. Therefore, it is important to protect pulmonary function during thoracic surgery anesthesia, particularly to protect the function of the collapsed lung. Our previous study on rabbits reported that nicorandil, a US Food and Drug Administration­approved mitochondrial ATP­sensitive potassium channel­specific opener, can protect against lung injury in the collapsed lung. Therefore, the beneficial effect of nicorandil on OLV­induced pulmonary injury in clinical thoracic surgery was further evaluated in the present study. Nicorandil was infused at 2 mg/h for 2 h from induction to 1 h after OLV in the nicorandil group. Trends in arterial oxygen desaturation (SaO2), arterial partial pressure for oxygen (PaO2) and the lung microstructure were assessed. ELISA was used to assess the levels of TNF­α and malondialdehyde (MDA), and the activity of superoxide dismutase (SOD). A TUNEL assay was performed to evaluate apoptosis. Western blotting was used to analyze the relative expression levels of signaling proteins associated with apoptosis. Western blotting was performed to evaluate the protein expression levels of hypoxia­inducible factor 1α (HIF­1α), PI3K, Akt and NF­κB, and reverse transcription­quantitative PCR was used to detect HIF­1α mRNA expression levels in the lungs of patients infused with nicorandil and nitroglycerin. Nicorandil treatment was associated with higher SaO2 and PaO2 compared with nitroglycerin treatment in OLV. The levels of MDA and TNF­α in the operated lung of the nicorandil group were significantly lower compared with those in the control group. In addition, nicorandil was associated with higher SOD activity compared with nitroglycerin. The nicorandil­treated lung, similar to the sham group, exhibited improved microstructure and less apoptosis in the experimental group. The protein expression levels of PI3K, phosphorylated Akt and HIF­1α were significantly increased, whereas NF­κB was significantly decreased in the nicorandil­treated lung compared with the control group. Overall, nicorandil demonstrated beneficial effects by decreasing apoptosis in the operated lung, which was collapsed and then re­expanded during OLV in thoracic surgery anesthesia. Nicorandil may serve a vital role by decreasing the overloading of calcium in mitochondria, shutting off the mitochondrial membrane permeability transition pore, reducing the release of cytochrome c, simultaneously triggering activation of the PI3K/Akt signaling pathway around the cell membrane, downregulating NF­κB, upregulating HIF­1α, and then reducing Bax/Bcl­2, caspase­3 and apoptosis. The trial registration was ChiCTR­IOR­17014061 (registered on December 20, 2017).

Nicorandil reduces morphine withdrawal symptoms, potentiates morphine antinociception, and ameliorates liver fibrosis in rats.

AIMS: Chronic liver disease (CLD) is a serious medical condition affecting patients globally and pain management poses a unique challenge. ATP-sensitive potassium channels (KATP) are expressed in nociceptive neurons and hepatic cells. We tested the hypothesis whether morphine and nicorandil, KATP channel opener, alone and in combination possess hepatoprotective, antinociceptive effect and alter morphine physical dependence. MAIN METHODS: Intraperitoneal injection (i.p.) of carbon tetrachloride (CCl4) induced liver fibrosis in male Wistar rats. Nicorandil (15 mg/kg/day) was administered per os for two weeks. Morphine (3.8, 5, 10 mg/kg, i.p.) was administered prior to antinociception testing in tail flick and formalin tests. Morphine physical dependence following naloxone injection, fibrotic, oxidative stress markers, and liver histopathology were assessed. KEY FINDINGS: Morphine alone, produced insignificant changes of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), hepatic hydroxyproline (Hyp), malondialdehyde (MDA), and superoxide dismutase (SOD) levels and exerted significant antinociception in the pain models. Nicorandil alone protected against liver damage (decreased serum ALT, AST, HA, hepatic Hyp, MDA, increased SOD levels, improved fibrosis scores). Nicorandil/morphine combination produced remarkable hepatoprotection and persistent analgesia compared to morphine alone as evidenced by reduced (EC50) of morphine. Nicorandil augmented morphine analgesia and markedly decreased withdrawal signs in morphine-dependent rats. SIGNIFICANCE: The data showed for the first time, the hepatoprotection and augmented antinociception mediated by nicorandil/morphine combination in liver fibrosis via antioxidant and antifibrotic mechanisms. Nicorandil ameliorated withdrawal signs in morphine dependence in CLD. Thus, combining nicorandil/morphine provides a novel treatment strategy to ameliorate hepatic injury, potentiate antinociception and overcome morphine-induced physical dependence in liver fibrosis.

Nicorandil protects podocytes via modulation of antioxidative capacity in acute puromycin aminonucleoside-induced nephrosis in rats.

Nephrotic syndrome, characterized by proteinuria and hypoalbuminemia, results from the dysregulation of glomerular podocytes and is a significant cause of end-stage kidney disease. Patients with idiopathic nephrotic syndrome are generally treated with immunosuppressive agents; however, these agents produce various adverse effects. Previously, we reported the renoprotective effects of a stimulator of the mitochondrial ATP-dependent K+ channel (MitKATP), nicorandil, in a remnant kidney model. Nonetheless, the cellular targets of these effects remain unknown. Here, we examined the effect of nicorandil on puromycin aminonucleoside-induced nephrosis (PAN) rats, a well-established model of podocyte injury and human nephrotic syndrome. PAN was induced using a single intraperitoneal injection. Nicorandil was administered orally at 30 mg/kg/day. We found that proteinuria and hypoalbuminemia in PAN rats were significantly ameliorated following nicorandil treatment. Immunostaining and ultrastructural analysis under electron microscopy demonstrated that podocyte injury in PAN rats showed a significant partial attenuation following nicorandil treatment. Nicorandil ameliorated the increase in the oxidative stress markers nitrotyrosine and 8-hydroxy-2-deoxyguanosine in glomeruli. Conversely, nicorandil prevented the decrease in levels of the antioxidant enzyme manganese superoxide dismutase in PAN rats. We found that mitochondrial Ca2+ uniporter levels in glomeruli were higher in PAN rats than in control rats, and this increase was significantly attenuated by nicorandil. We conclude that stimulation of MitKATP by nicorandil reduces proteinuria by attenuating podocyte injury in PAN nephrosis, which restores mitochondrial antioxidative capacity, possibly through mitochondrial Ca2+ uniporter modulation. These data indicate that MitKATP may represent a novel target for podocyte injury and nephrotic syndrome.NEW & NOTEWORTHY Our findings suggest that the mitochondrial Ca2+ uniporter may be an upstream regulator of manganese superoxide dismutase and indicate a biochemical basis for the interaction between the ATP-sensitive K+ channel and Ca2+ signaling. We believe that our study makes a significant contribution to the literature because our results indicate that the ATP-sensitive K+ channel may be a potential therapeutic target for podocyte injury and nephrotic syndrome.

Nicorandil and Bone Marrow-derived Mesenchymal Stem Cells Therapeutic Effect after Ureteral Obstruction in Adult Male Albino Rats.

BACKGROUND: Chronic kidney disease is a global health problem for which renal fibrogenesis is the final treatment target. OBJECTIVE: In our work, we have highlighted two new strategies, nicorandil and Bone marrow-derived mesenchymal stem cells (BM-MSCs), as effective in reversing renal fibrosis induced by partial unilateral ureteral obstruction (PUUO). METHODS: The current study included 96 male albino rats randomly divided into four groups, with 24 rats per group; Group I, the control group; Group II, PUUO, where two-thirds of the left ureter was entrenched in the psoas muscle; Group III, same surgical procedure as in Group II for 7 days, and then the rats received 15 mg/kg/day nicorandil once daily for 21 days; and Group IV, same surgical procedure as in Group II for 7 days, and then rats were given 3 × 106 of labeled MSCs injected intravenous, and left for 21 days. Blood and kidney tissues were collected for biochemical, histological, and molecular analyses. RESULTS: Both the nicorandil and BM-MSCs treatment groups could ameliorate kidney damage evidenced by inhibition of MDA elevation and total antioxidant capacity reduction caused by PUUO. Also, there was a significant reduction observed in TNF, TGF, IL6, collagen I, and α-SMA in addition to improvement in histological examination. However, a significant difference was found between the BM-MSCs and nicorandil-treated groups. CONCLUSION: Our results suggest that BM-MSCs and nicorandil improved renal fibrosis progression through their antiapoptotic, anti-inflammatory, and antifibrotic effects in male albino rats subjected to PUUO, with BM-MSCs being more effective compared to nicorandil.

Nicorandil protects against coronary microembolization-induced myocardial injury by suppressing cardiomyocyte pyroptosis via the AMPK/TXNIP/NLRP3 signaling pathway.

BACKGROUND: Coronary microembolization (CME) is a common and intractable complication of coronary revascularization, which leads to perioperative myocardial injury, cardiac dysfunction, and poor prognosis. Nicorandil is widely used for the management of ischemic heart diseases, but the cardioprotective effects of nicorandil beyond anti-angina in CME-induced myocardial injury are worthy of further exploration. Therefore, the present study investigated the effect of nicorandil on CME-induced cardiomyocyte pyroptosis and explored the underlying mechanism. METHODS: A rat model of CME was established via the injection of microspheres into the left ventricle. A cell model of H9c2 cardiomyocytes stimulated by lipopolysaccharide (LPS) and hypoxia mimicked the microenvironment induced by CME. Nicorandil or the adenosine monophosphate-activated protein kinase (AMPK)-specific inhibitor compound C (CC) was administered before CME induction and cell modeling. Cardiac function, histological alterations in the myocardium, myocardial injury biomarkers in serum and cell culture supernatant, cell viability, adenosine triphosphate (ATP) level, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, reactive oxygen species (ROS) activity, mitochondrial membrane potential, and pyroptosis-associated index were assessed after the animal and cell modeling of CME. RESULTS: Nicorandil pretreatment attenuated cardiac dysfunction and myocardial injury following CME. Nicorandil also alleviated oxidative stress and mitochondrial damage. Moreover, nicorandil promoted AMPK activation, reduced the expression of thioredoxin-interacting protein (TXNIP), inhibited the activation of the NOD-like receptor pyrin containing 3 (NLRP3) inflammasome, and mitigated cardiomyocyte pyroptosis. However, co-treatment with CC reversed the cardioprotective effects of nicorandil. CONCLUSION: Nicorandil pretreatment inhibits cardiomyocyte pyroptosis and alleviates CME-induced myocardial injury via the AMPK/TXNIP/NLRP3 signaling pathway.

Effects of Nicorandil Administration on Infarct Size in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: The CHANGE Trial.

Background Nicorandil was reported to improve microvascular dysfunction and reduce reperfusion injury when administered before primary percutaneous coronary intervention. In this multicenter, prospective, randomized, double-blind clinical trial (CHANGE [Effects of Nicorandil Administration on Infarct Size in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention]), we investigated the effects of nicorandil administration on infarct size in patients with ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention. Methods and Results A total of 238 patients with ST-segment-elevation myocardial infarction were randomized to receive intravenous nicorandil (n=120) or placebo (n=118) before reperfusion. Patients in the nicorandil group received a 6-mg intravenous bolus of nicorandil followed by continuous infusion at a rate of 6 mg/h. Patients in the placebo group received the same dose of placebo. The predefined primary end point was infarct size on cardiac magnetic resonance (CMR) imaging performed at 5 to 7 days and 6 months after reperfusion. CMR imaging was performed in 201 patients (84%). Infarct size on CMR imaging at 5 to 7 days after reperfusion was significantly smaller in the nicorandil group compared with the placebo (control) group (26.5±17.1 g versus 32.4±19.3 g; P=0.022), and the effect remained significant on long-term CMR imaging at 6 months after reperfusion (19.5±14.4 g versus 25.7±15.4 g; P=0.008). The incidence of no-reflow/slow-flow phenomenon during primary percutaneous coronary intervention was much lower in the nicorandil group (9.2% [11/120] versus 26.3% [31/118]; P=0.001), and thus, complete ST-segment resolution was more frequently observed in the nicorandil group (90.8% [109/120] versus 78.0% [92/118]; P=0.006). Left ventricular ejection fraction on CMR imaging was significantly higher in the nicorandil group than in the placebo group at both 5 to 7 days (47.0±10.2% versus 43.3±10.0%; P=0.011) and 6 months (50.1±9.7% versus 46.4±8.5%; P=0.009) after reperfusion. Conclusions In the present trial, administration of nicorandil before primary percutaneous coronary intervention led to improved myocardial perfusion grade, increased left ventricular ejection fraction, and reduced myocardial infarct size in patients with ST-segment-elevation myocardial infarction. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03445728.

CoO Nanoparticles Combined with MRI: Analysis of No-Reflow in Patients with Acute ST-Segment Elevation Myocardial Infarction after PCI and the Effect of Coronary Nicorandil.

Magnetic resonance imaging (MRI) has become one of the most important medical imaging techniques in the clinic due to its high degree of soft tissue resolution and no radiation damage, and it plays an important role in the early diagnosis and treatment of tumors. This article mainly studies the analysis of no-reflow in patients with acute ST-segment elevation myocardial infarction after PCI and the effect of coronary nicorandil on CoO nanoparticles combined with MRI. In this paper, the synthesized water-soluble nanoparticles are dispersed in a 2% xanthan gum or agarose solution. In an MRI analyzer, the T1 value is tested with the inversion recovery sequence, and the T2 value is tested with the hard pulse CPMG sequence. The gyroscope imaging sequence performs T1-weighted and T2-weighted imaging tests. Calculated densitometry (QCA) was used to measure the stenosis of the coronary lesions, the length of the lesions and the diameter of the lumen before stent implantation. In order to facilitate the collection of urine samples, this article adopts the method of inserting a catheter to drain the patient for sampling. From the baseline state at the time of enrollment to 150 minutes after PCI, polyethylene containing 0.1% butylated hydroxyanisole is used. Urine samples were taken from the test tube every 30 minutes, a total of 6 times were collected, and the collected urine samples were stored in a low-temperature refrigerator at -80℃ for the final inspection. This paper uses calculation software to calculate the risk of death and death/myocardial infarction in the hospital and at 6 months after discharge. The data showed that the postoperatively detected CKMB and cTnI were higher than those before the operation, but the peak value of the nicorandil group was lower than that of the control group, but there was still no statistical difference (P>0.05). The results show that nicorandil can significantly improve the no-reflow phenomenon in AMI patients during PCI.

Nicorandil attenuates ventricular dysfunction and organ injury after cardiopulmonary bypass.

BACKGROUND: Nicorandil, an adenosine triphosphate-sensitive potassium channel agonist and nitric oxide donor, is a coronary vasodilator used to treat ischemia-induced chest pain, but it's potential cardioprotective benefits during open heart surgery have not been thoroughly investigated. The study objective was to assess the impact of nicorandil on postoperative ventricular dysfunction and end-organ injury in an established experimental model of open-heart surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest. We hypothesized that nicorandil would attenuate myocardial ischemia-reperfusion (IR) injury, preserve ventricular function, and reduce end-organ injury. METHODS: Rabbits were cannulated for CPB, followed by 60 min of aortic cross-clamp (ACC) with cold cardioplegic arrest, and 120 min of recovery after ACC removal. Nicorandil (or normal saline vehicle) was given intravenously 5 min before ACC and continued throughout the recovery period. Left ventricular developed pressure (LVDP), systolic contractility (LV + dP/dt), and diastolic relaxation (LV -dP/dt) were continuously recorded, and blood and tissue samples were collected for measurement of oxidant stress (OS), inflammation, apoptosis, and organ injury. RESULTS: Nicorandil significantly attenuated IR-induced LV dysfunction compared to saline control (R-120: LV + dP/dt: 1596 ± 397 vs. 514 ± 269 mmHg/s, p = 0.010; LV -dP/dt: -1524 ± 432 vs. -432 ± 243 mmHg/s, p < 0.001; LVDP: 55 ± 11 vs. 22 ± 5 mmHg, p = 0.046). Furthermore, nicorandil inhibited IR-induced increases in OS, inflammation, apoptosis, and organ injury. CONCLUSIONS: Nicorandil exhibits myocardial protection by attenuation of IR-induced LV dysfunction associated with OS, inflammation, apoptosis, and organ injury. Nicorandil should be explored further as a potential therapeutic strategy for limiting global IR injury during open-heart surgery in humans.