Nicorandil antiallodynic activity in a model of neuropathic pain is associated with the activation of ATP-dependent potassium channels and opioidergic pathways, and reduced production of cytokines and neutrophils recruitment in paw, sciatic nerve, and dorsal root ganglia.

BACKGROUND: Recently, we demonstrated that nicorandil inhibits mechanical allodynia induced by paclitaxel. In the present study, we evaluated the effect induced by nicorandil in a model of neuropathic pain induced by chronic constriction injury (CCI) in mice. We also investigated putative mechanisms underlying such an effect. METHODS: CCI was induced by three ligatures of the left sciatic nerve. Mechanical allodynia was evaluated by measuring the paw withdrawal threshold with an electronic von Frey apparatus. Concentrations of cytokines and myeloperoxidase activity were determined in the paw tissue, sciatic nerve, and dorsal root ganglia (DRG). RESULTS: Oral administration of two doses of nicorandil (150 mg/kg po), but not equimolar doses of nicotinamide or nicotinic acid, attenuated mechanical allodynia induced by CCI. Nicorandil activity was reduced by previous administration of glibenclamide (40 mg/kg) or naltrexone (5 mg/kg or 10 mg/kg). Two doses of nicorandil (150 mg/kg, po) reduced tumor necrosis factor-α, interleukin-1ß and interleukin-6, but not CXCL-1, concentrations in the paw tissue of CCI mice. Two doses of nicorandil (150 mg/kg, po) reduced concentrations of all these mediators in the sciatic nerve and DRG. Two doses of nicorandil (150 mg/kg, po) also reduced the myeloperoxidase activity in the paw tissue, sciatic nerve, and DRG. CONCLUSIONS: Nicorandil exhibits antiallodynic activity in a model of neuropathic pain induced by CCI. Inhibition of cytokines production and reduction of neutrophils recruitment in paw tissue, sciatic nerve, and DRG as well as activation of ATP-dependent potassium channels and opioidergic pathways, underlie nicorandil antiallodynic activity.

ATP-sensitive potassium channel opener, Nicorandil, inhibits NF-κB/AIM2/GSDMD pathway activation to protect against neuroinflammation in ischemic stroke.

The absent in melanoma 2 (AIM2) inflammasome contributes to ischemic brain injury by inducing cell pyroptosis and inflammatory responses. Our research group has previously demonstrated that ATP-sensitive potassium channels (KATP channels) openers can modulate neuronal synaptic plasticity post-ischemic stroke for neuroprotection. However, the specific mechanisms of KATP channels in the inflammatory response following ischemic stroke remain unclear. Here, we assessed cellular damage by observing changes in BV-2 morphology and viability. 2,3,5-Triphenyl tetrazolium chloride (TTC) staining, mNSS scoring, Nissl staining, and TdT-mediated dUTP nick end labeling (TUNEL) staining were used to evaluate behavioral deficits, brain injury severity, and neuronal damage in mice subjected to middle cerebral artery occlusion (MCAO). Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were used to measure cell pyroptosis and nuclear factor-kappaB (NF-κB) activation in vivo and in vitro. We observed that AIM2 protein expression was upregulated and localized within the cytoplasm of BV-2 cells. Notably, low-dose Nicorandil treatment reduced inflammatory cytokine secretion and pyroptosis-related protein expression, including AIM2, cleaved cysteinyl aspartate-specific protease-1 (cleaved caspase-1), and Gasdermin D N-terminal (GSDMD-NT). Further investigations revealed that the KATP channel inhibitor 5-HD upregulated p-NF-κB p65, NF-κB p65, and p-IκBα expression, reversing Nicorandil's neuroprotective effect in vivo. In summary, our results suggest that Nicorandil may serve as a potential therapeutic option for ischemic stroke. Targeting AIM2 and NF-κB represents effective strategies for inhibiting neuroinflammation.

Reno-protective effect of nicorandil and pentoxifylline against potassium dichromate-induced acute renal injury via modulation p38MAPK/Nrf2/HO-1 and Notch1/TLR4/NF-κB signaling pathways.

BACKGROUND: Occupational and environmental exposure to chromium compounds such as potassium dichromate (PDC) (K2Cr2O7) has emerged as a potential aetiologic cause for renal disease through apoptotic, and inflammatory reactions. The known potent antioxidants such as nicorandil (NIC) and/or pentoxifylline (PTX) were studied for their possible nephroprotective effect in PDC-treated rats. METHODS: Forty male Wistar rats were divided into five groups; control, PDC group, NIC+PDC, PTX+PDC group, and combination+PDC group. Nephrotoxicity was evaluated histopathologically and biochemically. Invasive blood pressure, renal function parameters urea, creatinine, uric acid and albumin, glomerular filtration rate markers Cys-C, Kim-1 and NGAL, inflammatory markers IL-1ß, IL-6, TNF-α, TGF-ß, COX-II, p38MAPK, NF-κB and TLR4, oxidative stress SOD, GSH, MDA, MPO, HO-1 and Nrf2 and apoptotic mediators Notch1 and PCNA were evaluated. Besides, renal cortical histopathology was assayed as well. RESULTS: PDC led to a considerable increase in indicators for kidney injury, renal function parameters, invasive blood pressure, oxidative stress, and inflammatory markers. They were markedly reduced by coadministration of PDC with either/or NIC and PTX. The NIC and PTX combination regimen showed a more significant improvement than either medication used alone. Our results demonstrated the nephroprotective effect of NIC, PTX, and their combined regimen on PDC-induced kidney injury through suppression of oxidative stress, apoptosis, and inflammatory response. CONCLUSION: Renal recovery from PDC injury was achieved through enhanced MAPK/Nrf2/HO-1 and suppressed Notch1/TLR4/NF-κB signaling pathways. This study highlights the role of NIC and PTX as effective interventions to ameliorate nephrotoxicity in patients undergoing PDC toxicity.

Nicorandil mitigates arsenic trioxide-induced lung injury via modulating vital signalling pathways SIRT1/PGC-1α/TFAM, JAK1/STAT3, and miRNA-132 expression.

BACKGROUND AND PURPOSE: Nicorandil, a selective opener of potassium channels, used to treat angina, has drawn attention for its potential in mitigating lung injury, positioning it as a promising therapeutic approach to treat drug-induced lung toxicity. This study aimed to explore the protective role of nicorandil in arsenic trioxide (ATO)-induced lung injury and to elucidate the underlying mechanistic pathways. EXPERIMENTAL APPROACH: We assessed the effects of nicorandil (15 mg·kg-1, p.o.) in a rat model of pulmonary injury induced by ATO (5 mg·kg-1, i.p.). The assessment included oxidative stress biomarkers, inflammatory cytokine levels, and other biomarkers, including sirtuin-1, sirtuin-3, STAT3, TFAM, and JAK in lung tissue. Histological examination using H&E staining and molecular investigations using western blotting and PCR techniques were conducted. KEY RESULTS: In our model of lung injury, treatment with nicorandil ameliorated pathological changes as seen with H&E staining, reduced tissue levels of toxicity markers, and exerted significant antioxidant and anti-inflammatory actions. On a molecular level, treatment with nicorandil down-regulated JAK, STAT3, PPARγ, Nrf2, VEGF, p53, and micro-RNA 132 while up-regulating Sirt1, 3, TFAM, AMPK, and ERR-α in lung tissue. CONCLUSIONS AND IMPLICATIONS: The results presented here show nicorandil as a significant agent in attenuating lung injury induced by ATO in a rodent model. Nonetheless, further clinical studies are warranted to strengthen these findings.

Assessment of cardiac parameters after the administration of nicorandil before primary percutaneous coronary intervention.

Objective: To assess cardiac troponin I and creatine kinase-myocardial band levels, electrocardiogram changes and major adverse cardiac events after treatment with nicorandil before primary percutaneous coronary intervention. METHODS: The comparative, analytical study was conducted from October to November 2022 at the Pharmacology Department of Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan, in collaboration with the Rawalpindi Institute of Cardiology, Rawalpindi. The sample comprised ST-elevated myocardial infarction patients of either gender aged at least 30 years with an ejection fraction of at least 35% undergoing primary percutaneous coronary intervention. Participants were selected based on the above-mentioned inclusion and informed consent was taken before their enrolment in this research study. The sample was randomised into control group A receiving conventional acute coronary syndrome treatment, and intervention group B receiving nicorandil in addition to the conventional treatment. Cardiac troponin I and creatine kinase-myocardial band levels, electrocardiogram changes, and major adverse cardiac events noted and compared. Data was analysed using SPSS 26. RESULTS: Of the 140 patients, 70(50%) were in each of the 2 groups. In group B, 60(85.7%) patients achieved a completely settled ST segment on electrocardiogram compared to 25(35.7%) in group A (p=0.001). There was a significant inter-group difference with respect to cardiac troponin I value 6 hours after percutaneous coronary intervention and major adverse cardiac events (p<0.05), but creatine kinase-myocardial band level was no significantly different between the groups (p=0.761). Conclusion: Prophylactic use of nicorandil in ST-elevated myocardial infarction patients decreased the incidence of reperfusion injury.

Efficacy and Safety of Nicorandil in the Treatment of Stable Angina Pectoris.

Background: Stable angina pectoris (SAP) is an ischemic heart disease caused by coronary artery stenosis, which usually occurs during physical activity or emotional excitement. For this type of angina pectoris, reducing the oxygen demand of the heart and increasing the coronary blood flow are the key goals of treatment. Objective: To analyze nicorandil's application effect and adverse reactions in patients with SAP. Methods: Sixty patients with stable angina pectoris admitted to our hospital from December 2020 to May 2022 were randomly selected and included in this study. They were divided into nicorandil group (n=30) and conventional group (n=30). The clinical efficacy, duration of chest pain, number of heart attacks per week, cardiac function indexes, improvement of exercise tolerance, occurrence of adverse reactions, and Seattle Angina Scale (SAQ) score were observed. Results: The effective rate of nicorandil group was 93.33%, which was much higher than that of conventional group (73.33%, P < .05). The results showed that the nicorandil group was significantly better than the conventional group in clinical efficacy, duration of chest pain, number of attacks per week, cardiac function index, improvement of exercise tolerance, occurrence of adverse reactions and SAQ score (P < .05). Conclusions: Nicorandil can improve the clinical symptoms of SAP patients, significantly reduce the duration and frequency of chest pain attacks, and enhance cardiac function indicators. It can be used as an effective drug choice to reduce the frequency and intensity of angina pectoris attacks and is worthy of wide clinical application.

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.

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.

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.

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.

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 Regulates Ferroptosis and Mitigates Septic Cardiomyopathy via TLR4/SLC7A11 Signaling Pathway.

This study mainly explored the role of nicorandil in regulating ferroptosis and alleviating septic cardiomyopathy through toll-like receptor (TLR) 4/solute carrier family 7 member 11 (SLC7A11) signaling pathway. Twenty-four male SD rats were randomly divided into control, Nic (nicorandil), LPS (lipopolysaccharide), and LPS + Nic groups and given echocardiography. A detection kit was applied to measure the levels of lactic dehydrogenase (LDH), cardiac troponin I (cTnI), and creatine kinase-MB (CK-MB); HE staining and the levels of glutathione (GSH), malondialdehyde (MDA), total iron, and Fe2+ of myocardial tissues were detected. Moreover, the expression of TLR4 and SLC7A11 were measured by qRT-PCR and the proteins regulating ferroptosis (TLR4, SLC7A11, GPX4, ACSL4, DMT1, Fpn, and TfR1) were checked by western blot. Myocardial cells (H9C2) were induced with lipopolysaccharide (LPS) and transfected with si-TLR4 or SLC7A11-OE. Then, the viability, ferroptosis, and TLR4/SLC7A11 signaling pathway of cells were examined. Nicorandil could significantly increase left ventricular (LV) ejection fraction (LVEF) while reduce LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV). Also, it greatly reduced the levels of LDH, cTnI, and CK-MB; alleviated the pathological changes of myocardial injury; notably decreased MDA, total iron, and Fe2+ levels in myocardial tissues; and significantly increased GSH level. Besides, nicorandil obviously raised protein levels of GPX4, Fpn, and SLC7A11, and decreased protein levels of ACSL4, DMT1, TfR1, and TLR4. After knockdown of TLR4 or overexpression of SLC7A11, the inhibition effect of nicorandil on ferroptosis was strengthened in LPS-induced H9C2 cells. Therefore, nicorandil may regulate ferroptosis through TLR4/SLC7A11 signaling, thereby alleviating septic cardiomyopathy.

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.

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.

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.

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.

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.

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.