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Cardiology 2018Ischaemic heart disease is a major cause of death and disability worldwide, while angina represents its most common symptom. It is estimated that approximately 9 million... (Review)
Review
Ischaemic heart disease is a major cause of death and disability worldwide, while angina represents its most common symptom. It is estimated that approximately 9 million patients in the USA suffer from angina and its treatment is challenging, thus the strategy to improve the management of chronic stable angina is a priority. Angina might be the result of different pathologies, ranging from the "classical" obstruction of a large coronary artery to alteration of the microcirculation or coronary artery spasm. Current clinical guidelines recommend antianginal therapy to control symptoms, before considering coronary artery revascularization. In the current guidelines, drugs are classified as being first-choice (beta-blockers, calcium channel blockers, and short-acting nitrates) or second-choice (ivabradine, nicorandil, ranolazine, trimetazidine) treatment, with the recommendation to reserve second-line modifications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. However, such a categorical approach is currently questioned. In addition, current guidelines provide few suggestions to guide the choice of drugs more suitable according to the underlying pathology or the patient comorbidities. Several other questions have recently emerged, such as: is there evidence-based data between first- and second-line treatments in terms of prognosis or symptom relief? Actually, it seems that newer antianginal drugs, which are classified as second choice, have more evidence-based clinical data that are more contemporary to support their use than what is available for the first-choice drugs. It follows that actual guidelines are based more on tradition than on evidence and there is a need for new algorithms that are more individualized to patients, their comorbidities, and pathophysiological mechanism of chronic stable angina.
Topics: Adrenergic beta-Antagonists; Angina, Stable; Calcium Channel Blockers; Cardiovascular Agents; Chest Pain; Humans; Ivabradine; Nicorandil; Patient Selection; Practice Guidelines as Topic; Ranolazine; Treatment Outcome; Trimetazidine
PubMed: 29874661
DOI: 10.1159/000487936 -
Cardiovascular Drugs and Therapy Aug 2016Nitrates have been used to treat symptoms of chronic stable angina for over 135 years. These drugs are known to activate nitric oxide (NO)-cyclic... (Review)
Review
Nitrates have been used to treat symptoms of chronic stable angina for over 135 years. These drugs are known to activate nitric oxide (NO)-cyclic guanosine-3',-5'-monophasphate (cGMP) signaling pathways underlying vascular smooth muscle cell relaxation, albeit many questions relating to how nitrates work at the cellular level remain unanswered. Physiologically, the anti-angina effects of nitrates are mostly due to peripheral venous dilatation leading to reduction in preload and therefore left ventricular wall stress, and, to a lesser extent, epicardial coronary artery dilatation and lowering of systemic blood pressure. By counteracting ischemic mechanisms, short-acting nitrates offer rapid relief following an angina attack. Long-acting nitrates, used commonly for angina prophylaxis are recommended second-line, after beta-blockers and calcium channel antagonists. Nicorandil is a balanced vasodilator that acts as both NO donor and arterial K(+) ATP channel opener. Nicorandil might also exhibit cardioprotective properties via mitochondrial ischemic preconditioning. While nitrates and nicorandil are effective pharmacological agents for prevention of angina symptoms, when prescribing these drugs it is important to consider that unwanted and poorly tolerated hemodynamic side-effects such as headache and orthostatic hypotension can often occur owing to systemic vasodilatation. It is also necessary to ensure that a dosing regime is followed that avoids nitrate tolerance, which not only results in loss of drug efficacy, but might also cause endothelial dysfunction and increase long-term cardiovascular risk. Here we provide an update on the pharmacological management of chronic stable angina using nitrates and nicorandil.
Topics: Angina, Stable; Humans; Nicorandil; Nitrates; Nitric Oxide Donors; Vasodilator Agents
PubMed: 27311574
DOI: 10.1007/s10557-016-6668-z -
European Cardiology Aug 2018Nicorandil and long-acting nitrates are vasodilatory drugs used commonly in the management of chronic stable angina pectoris. Both nicorandil and long-acting nitrates... (Review)
Review
Nicorandil and long-acting nitrates are vasodilatory drugs used commonly in the management of chronic stable angina pectoris. Both nicorandil and long-acting nitrates exert anti-angina properties via activation of nitric oxide (NO) signalling pathways, triggering vascular smooth muscle cell relaxation. Nicorandil has additional actions as an arterial K channel agonist, resulting in more "balanced" arterial and venous vasodilatation than nitrates. Ultimately, these drugs prevent angina symptoms through reductions in preload and diastolic wall tension and, to a lesser extent, epicardial coronary artery dilatation and lowering of systemic blood pressure. While there is some evidence to suggest a modest reduction in cardiovascular events among patients with stable angina treated with nicorandil compared to placebo, this prognostic benefit has yet to be proven conclusively. In contrast, there is emerging evidence to suggest that chronic use of long-acting nitrates might cause endothelial dysfunction and increased cardiovascular risk in some patients.
PubMed: 30310466
DOI: 10.15420/ecr.2018.9.2 -
Advances in Therapy Mar 2016Nicorandil is a popular anti-anginal drug in Europe and Japan. Apart from some common adverse drug reactions (ADR), its safety is satisfactory. Several reports have... (Review)
Review
INTRODUCTION
Nicorandil is a popular anti-anginal drug in Europe and Japan. Apart from some common adverse drug reactions (ADR), its safety is satisfactory. Several reports have suggested a link between nicorandil, gastrointestinal (GI) ulceration and fistulas. The review aims to critically appraise, synthesize and present the available evidence of all known GI ADR per anatomical location.
METHODS
The study complied with the PRISMA statement. Literature and pharmacovigilance databases were used to provide rate and/or calculate parameters (median age, median dose, history of symptoms, length of therapy and healing time after withdrawal of the drug). Differences in distribution of quantitative variables were analyzed via Mann-Whitney test. Correlation between quantitative variables was assessed with a Spearman's correlation coefficient. A p value <0.05 was significant.
RESULTS
Oral ulcerations occur in 0.2% of the subjects, anal ulcerations are present between 0.07% and 0.37% of patients. Oral and distal GI involvements are the most common ADR (28-29% and 27-31% of all GI ADR, respectively). The hepatobiliary system, the pancreas and salivary glands are not affected by nicorandil exposure. The time to develop oral ulcerations is 74 weeks among people on <30 mg/day compared to only 7.5 weeks in individuals on higher regimens (p = 0.47). There is a significant correlation between dose and ulcer healing time (Spearman's 0.525, p < 0.001).
CONCLUSIONS
Ulcerative disease is a very commonly reported GI ADR. A delayed ulcerative tendency supports the hypothesis of an ulcerogenic metabolite. Nicorandil seems to act as a cause of the ulcerations, but appears to also work in synergy with other promoting factors. Whether the action of the metabolites relies on a specific mechanism or a simple chemical ulceration is still to be established.
Topics: Aged; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Nicorandil; Oral Ulcer; Peptic Ulcer; Time Factors
PubMed: 26861848
DOI: 10.1007/s12325-016-0294-9 -
ACG Case Reports Journal Mar 2024
PubMed: 38511166
DOI: 10.14309/crj.0000000000001293 -
American Journal of Translational... 2023To compare the efficacy and safety of nicorandil monotherapy and nicorandil-clopidogrel combination therapy on cardiac function in patients with coronary heart disease...
OBJECTIVES
To compare the efficacy and safety of nicorandil monotherapy and nicorandil-clopidogrel combination therapy on cardiac function in patients with coronary heart disease (CHD).
METHODS
The clinical data of 200 patients with CHD were retrospectively analyzed. The patients were divided into two groups according to different treatment methods. Group A (n = 100) received nicorandil-clopidogrel combination therapy (intravenously injected with 25 mg of nicorandil and orally administered 300 mg of clopidogrel for 3 months), and Group B (n = 100) received nicorandil monotherapy (intravenously injected with 25 mg of nicorandil for 3 months). The primary endpoints included cardiac function indices and ST-segment behavior on electrocardiogram (ECG) before and after treatment. The secondary endpoints included adverse reactions, clinical efficacy, platelet aggregation, activated partial thromboplastin time (APTT), high-sensitivity cardiac troponin T (hs-cTnT), and creatine kinase isoenzyme MB (CK-MB) levels after treatment. Multivariate regression analyses were used to assess the contribution of a single drug to the ultimate outcome.
RESULTS
After treatment, both groups exhibited significant decreases in brain natriuretic peptide (BNP) and N-terminal pro-hormone BNP levels compared with before treatment, with the levels significantly lower in Group A than in Group B ( < 0.05). After treatment, left ventricular ejection fraction was significantly increased in both groups compared with before treatment, and that was much higher in Group A than in Group B ( < 0.05). After treatment, the frequency and duration of ST-segment depression were decreased in both groups compared with before treatment, and they were much lower in Group A than in Group B (all < 0.05). The total incidence of adverse reactions in Group A (4.00%) was slightly lower than that in Group B (7.00%), with no significant difference ( > 0.05). Group A (92.00%) had a higher overall response rate than Group B (81.00%) ( < 0.05).
CONCLUSION
Nicorandil-clopidogrel combination therapy exhibited enhanced clinical efficacy in patients with CHD. In addition, the combination therapy regulated hs-cTnT and CK-MB levels, which may suggest a better patient prognosis.
PubMed: 37303660
DOI: No ID Found -
Gut and Liver Nov 2016Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In... (Review)
Review
Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In previous decades, the key revelations that potassium channels and transporters are involved in the production of gastric acid and the regulation of secretion in the stomach have been recognized. Drugs used to treat peptic ulceration are often potassium transporter inhibitors. It has also been reported that potassium channels are involved in ulcerative colitis. Direct toxicity to the intestines from nonsteroidal anti-inflammatory drugs has been associated with altered potassium channel activities. Several reports have indicated that the long-term use of the antianginal drug Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, increases the chances of ulceration and perforation from the oral to anal regions throughout the gastrointestinal (GI) tract. Several of these drug features provide further insights into the role of potassium channels in the occurrence of ulceration in the GI tract. The purpose of this review is to investigate whether potassium channelopathies are involved in the mechanisms responsible for ulceration that occurs throughout the GI tract.
Topics: Animals; Anti-Arrhythmia Agents; Channelopathies; Colon; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Mice; Nicorandil; Peptic Ulcer; Potassium Channels; Ulcer
PubMed: 27784845
DOI: 10.5009/gnl15414 -
Cardiovascular Therapeutics 2021To observe the effect of nicorandil on septic rats and explore the possible mechanism of its myocardial protection, so as to provide theoretical basis for the treatment...
OBJECTIVE
To observe the effect of nicorandil on septic rats and explore the possible mechanism of its myocardial protection, so as to provide theoretical basis for the treatment of septic cardiomyopathy.
METHODS
Sixty male clean SD rats were selected as the research objects and randomly divided into 3 groups by random number method: sham operation group (sham group), cecal ligation and perforation group (CLP group), nicorandil treatment group (nicorandil+CLP group). After the operation, the nicorandil group was pumped with nicorandil diluent 1 ml/h (2 mg/kg/h) with a micropump for 6 hours. The sham group and CLP group were pumped with the same amount of normal saline 1 ml/h for a total of 6 hours. After 24 hours, the survival of the rats in each group was observed. The expression of troponin I (cTnI), tumor necrosis factor (TNF-), and interleukin-1 (IL-1) in the serum was detected. Then, the ventricle was harvested for the observation of the pathological changes of myocardium. Quantitative real-time polymerase chain reaction and immunostaining were used to detect myocardial tissue apoptosis, and Western blot methods were used to detect protein expression changes in nuclear factor-B (NF-B) pathways.
RESULTS
24 hours after operation, the survival rate of the rats in the CLP group was 60%. There was a large amount of necrosis of myocardial cells and inflammatory cell infiltration. The survival rate of rats in the nicorandil+CLP group was 75%. Compared with the CLP group, the necrosis of myocardial cells was reduced, and there was still a small amount of inflammatory cell infiltration. In the CLP group, myocardial inflammation and apoptosis were significant, and NF-B pathway was activated. On the contrary, the NF-B pathway in the nicorandil+CLP group was inhibited, and the expression of inflammatory factors and apoptosis factors was inhibited.
CONCLUSION
Nicorandil can reduce the release of inflammatory factors in septic rats, improve the inflammatory response, reduce myocardial damage, and play a myocardial protective effect. Its mechanism may be related to the inhibition of the activation of NF-B signaling pathway.
Topics: Animals; Anti-Inflammatory Agents; Antisepsis; Apoptosis; Cardiomyopathies; Male; Nicorandil; Rats; Rats, Sprague-Dawley; Sepsis; Tumor Necrosis Factor-alpha
PubMed: 34950238
DOI: 10.1155/2021/5822920 -
Pharmacological Research Feb 2024Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener,...
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.
Topics: Humans; Diabetic Cardiomyopathies; AMP-Activated Protein Kinases; Nicorandil; Endothelial Cells; Ferroptosis; Mitochondria; Signal Transduction; Myocytes, Cardiac; Ubiquitin-Protein Ligases; RNA, Messenger; Diabetes Mellitus
PubMed: 38218357
DOI: 10.1016/j.phrs.2024.107057 -
The Journal of Physiological Sciences :... Nov 2019We previously reviewed our study of the pharmacological properties of cardiac Na/Ca exchange (NCX1) inhibitors among cardioprotective drugs, such as amiodarone,... (Review)
Review
We previously reviewed our study of the pharmacological properties of cardiac Na/Ca exchange (NCX1) inhibitors among cardioprotective drugs, such as amiodarone, bepridil, dronedarone, cibenzoline, azimilide, aprindine, and benzyl-oxyphenyl derivatives (Watanabe et al. in J Pharmacol Sci 102:7-16, 2006). Since then we have continued our studies further and found that some cardioprotective drugs are NCX1 stimulators. Cardiac Na/Ca exchange current (I) was stimulated by nicorandil (a hybrid ATP-sensitive K channel opener), pinacidil (a non-selective ATP-sensitive K channel opener), flecainide (an antiarrhythmic drug), and sodium nitroprusside (SNP) (an NO donor). Sildenafil (a phosphodiesterase-5 inhibitor) further increased the pinacidil-induced augmentation of I. In paper, here I review the NCX stimulants that enhance NCX function among the cardioprotective agents we examined such as nicorandil, pinacidil, SNP, sildenafil and flecainide, in addition to atrial natriuretic (ANP) and dofetilide, which were reported by other investigators.
Topics: Animals; Cardiotonic Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Humans; Nitric Oxide; Signal Transduction; Sodium-Calcium Exchanger
PubMed: 31664641
DOI: 10.1007/s12576-019-00721-5