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Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia.
Tada, Y, Kume, K, Matsuda, Y, Kurashige, T, Kanaya, Y, Ohsawa, R, Morino, H, Tabu, H, Kaneko, S, Suenaga, T, et al
Journal of human genetics. 2020;(4):363-369
Abstract
Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease characterized by cerebellar ataxia. Many causative genes have been identified to date, the most common etiology being the abnormal expansion of repeat sequences, and the mutation of ion channel genes also play an important role in the development of SCA. Some of them encode calcium and potassium channels. However, due to limited reports about potassium genes in SCA, we screened 192 Japanese individuals with dominantly inherited SCA who had no abnormal repeat expansions of causative genes for potassium channel mutations (KCNC3 for SCA13 and KCND3 for SCA19/SCA22) by target sequencing. As a result, two variants were identified from two patients: c.1973G>A, p.R658Q and c.1018G>A, p.V340M for KCNC3, and no pathogenic variant was identified for KCND3. The newly identified p.V340M exists in the extracellular domain, and p.R658Q exists in the intracellular domain on the C-terminal side, although most of the reported KCNC3 mutations are present at the transmembrane site. Adult-onset and slowly progressive cerebellar ataxia are the main clinical features of SCA13 and SCA19 caused by potassium channel mutations, which was similar in our cases. SCA13 caused by KCNC3 mutations may present with deep sensory loss and cognitive impairment in addition to cerebellar ataxia. In this study, mild deep sensory loss was observed in one case. SCA caused by potassium channel gene mutations is extremely rare, and more cases should be accumulated in the future to elucidate its pathogenesis due to channel dysfunction.
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Obstructive Sleep Apnea and Circulating Potassium Channel Levels.
Jiang, N, Zhou, A, Prasad, B, Zhou, L, Doumit, J, Shi, G, Imran, H, Kaseer, B, Millman, R, Dudley, SC
Journal of the American Heart Association. 2016;(8)
Abstract
BACKGROUND Cardiac arrhythmias and sudden cardiac death are more frequent in patients with obstructive sleep apnea (OSA). OSA is associated with QT prolongation, and QT prolongation is an independent risk factor for sudden cardiac death. Because QT prolongation can be mediated by potassium channel loss of function, we tested whether OSA or continuous positive airway pressure therapy altered mRNA expression of circulating white blood cell potassium channels. METHODS AND RESULTS In total, 28 patients with OSA newly diagnosed by polysomnogram and 6 participants without OSA were enrolled. Potassium channel levels in white blood cells at baseline and at a 4-week follow-up visit were compared. There was a significant inverse correlation between the severity of the OSA stratified by apnea-hypopnea index and mRNA expression of the main potassium channels assessed: KCNQ1 (r=-0.486, P=0.007), KCNH2 (r=-0.437, P=0.016), KCNE1 (r=-0.567, P=0.001), KCNJ2 (r=-0.442, P=0.015), and KCNA5 (r=-0.468, P=0.009). In addition, KCNQ1, KCNH2, and KCNE1 inversely correlated with the oxygen desaturation index 4. After 4 weeks of continuous positive airway pressure therapy, circulating KCNQ1 and KCNJ2 were increased 1.4±0.4-fold (P=0.040) and 2.1±1.4-fold (P=0.046) in the moderate OSA group. Compared with patients with mild or moderate OSA, patients with severe OSA had a persistently higher apnea-hypopnea index (mild 2.0±1.8, moderate 1.0±0.9, severe 5.8±5.6; P=0.015), perhaps explaining why the potassium channel changes were not seen in the severe OSA group. CONCLUSIONS The mRNA expression of most potassium channels inversely correlates with the severity of OSA and hypoxemia. Continuous positive airway pressure therapy improves circulating KCNQ1 and KCNJ2 in patients with moderate OSA.
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The effect of an angiotensin-converting enzyme inhibitor and a K+(ATP) channel opener on warm up angina.
Edwards, RJ, Redwood, SR, Lambiase, PD, Marber, MS
European heart journal. 2005;(6):598-606
Abstract
AIMS: In various models, angiotensin-converting enzyme (ACE) inhibitors and K+(ATP) channel openers can potentiate and mimic ischaemic preconditioning, respectively. Our aim was to determine whether these characteristics are shared by the phenomenon of warm up in angina, often regarded as a surrogate of ischaemic preconditioning. METHODS AND RESULTS Twenty patients with ischaemic heart disease were assigned in a double blind, randomized cross-over design to equivalent pressor doses of nicorandil 20 mg bid, enalapril 10 mg bid, losartan 25 mg bid, or placebo for 3 days. Patients underwent three consecutive exercise tolerance tests on each medication separated by a 1-week interval. Each patient underwent 12 exercise tests in total and 13 patients completed the study. On each medication the second exercise was separated from the first by 15 min of rest and the third exercise was performed 90 min after the second to control for training. The time to 0.1 mV ST depression and rate pressure product at 0.1 mV ST depression increased significantly in all groups during exercise two compared with exercise one. Nicorandil reduced angina but did not attenuate this warm up effect. This benefit of first exercise waned by test three with placebo, losartan, and nicorandil, but not with enalapril. CONCLUSION In contrast to predictions based on ischaemic preconditioning the magnitude of the warm up was apparently unaltered by nicorandil, losartan, or enalapril, however its duration seemed to be extended by enalapril. Thus ischaemic preconditioning and warm up angina are likely to have differing pharmacological profiles suggesting a diverse underlying mechanism.
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A phase II trial comparing five dose levels of BEC2 anti-idiotypic monoclonal antibody vaccine that mimics GD3 ganglioside.
Chapman, PB, Williams, L, Salibi, N, Hwu, WJ, Krown, SE, Livingston, PO
Vaccine. 2004;(21-22):2904-9
Abstract
In previous studies, we showed that immunization with 2.5 mg of BEC2, an anti-idiotypic MAb that mimics GD3 ganglioside, can induce antibodies against GD3 in approximately 25% of patients. In this trial, 50 melanoma patients at high risk for recurrence were randomly assigned to one of the five BEC2 dose levels (2.5 microg-10mg) to determine if lower or higher BEC2 doses are more immunogenic. We also tested whether prolonged booster immunizations can enhance the anti-GD3 antibody response. All patients developed detectable IgG against BEC2 except for one patient at the lowest BEC2 dose level. Six patients developed detectable antibody responses to GD3, all of them at the lower three dose levels of BEC2. We conclude that high doses of BEC2 are not necessary to induce anti-GD3 antibody responses and that lower doses may be more immunogenic than the 2.5 mg dose used in previous BEC2 trials. Prolonged booster immunizations did not induce or maintain antibody responses.
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Prophylactic effect of intravenous nicorandil on perioperative myocardial damage in patients undergoing off-pump coronary artery bypass surgery.
Ito, I, Hayashi, Y, Kawai, Y, Kamibayashi, T, Matsumiya, G, Takahashi, T, Matsuda, H, Mashimo, T
Journal of cardiovascular pharmacology. 2004;(4):501-6
Abstract
Nicorandil, ATP sensitive potassium channel opener, is shown to reduce coronary events for patients with stable angina. The present study was designed to examine the protective potential of nicorandil for patients undergoing off-pump coronary artery bypass grafting. Twenty-four patients undergoing off-pump coronary artery bypass grafting were randomly assigned to two groups, one receiving continuous infusion of nicorandil (1.0 microg.kg(-1).min(-1)) (n = 12) through anesthesia to next day and the other receiving no nicorandil for control (n = 12). For assessing myocardial injury, heart type fatty acid binding protein, troponin T, and creatine kinase MB isoform were determined during the first 15 hours after reperfusion. The concentration of heart type fatty acid binding protein in the nicorandil group was significantly lower than that in the control group. On the other hand, the concentrations of troponin T and creatine kinase MB isoform in the nicorandil group were lower than those in the control group, but the differences did not reach statistical significance. Furthermore, nicorandil did not affect the patients' hemodynamic variables. Our data suggest that the infusion of nicorandil provides small myocardial protection without affecting hemodynamic parameters during perioperative treatment of patients undergoing off-pump coronary artery bypass grafting.
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Pharmacological modulation of the ATP sensitive potassium channels during repeated coronary occlusions: no effect on myocardial ischaemia or function.
Lindhardt, TB, Gadsbøll, N, Kelbaek, H, Saunamäki, K, Madsen, JK, Clemmensen, P, Hesse, B, Haunsø, S
Heart (British Cardiac Society). 2004;(4):425-30
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Abstract
BACKGROUND Repeated episodes of myocardial ischaemia may lead to ischaemic preconditioning. This is believed to be mediated by the ATP sensitive potassium channels. OBJECTIVE To examine the effect of pharmacological modulation of the ATP sensitive potassium channels during repeated coronary occlusions. DESIGN Double blind, double dummy study. METHODS 38 patients with a proximal stenosis of the left anterior descending coronary artery and no visible coronary collateral vessels underwent three identical 90 second balloon occlusions, each followed by five minutes of reperfusion. The patients were randomised to pinacidil 25 mg, glibenclamide 10.5 mg, or matching placebo 90 minutes before the start of the procedure. Myocardial ischaemia was measured by continuous monitoring of ECG ST segment changes. Changes in left ventricular function were recorded with a miniature radionuclide detector, and angina was scored on the Borg scale. RESULTS In all patients the first balloon occlusion led to significant ST segment elevation, a clear decrease in left ventricular ejection fraction, and angina pectoris. This response was not attenuated at the second or third balloon occlusion, either in the placebo group or in the patients pretreated with pinacidil or glibenclamide. CONCLUSIONS Under the given experimental conditions, this randomised and double blind study did not support the view that the human myocardium has an intrinsic protective mechanism that is activated by short lasting episodes of ischaemia.
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Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes. The Finnish Diabetes Prevention Study.
Laukkanen, O, Pihlajamäki, J, Lindström, J, Eriksson, J, Valle, TT, Hämäläinen, H, Ilanne-Parikka, P, Keinänen-Kiukaanniemi, S, Tuomilehto, J, Uusitupa, M, et al
The Journal of clinical endocrinology and metabolism. 2004;(12):6286-90
Abstract
Type 2 diabetes is caused by defective insulin secretion and impaired insulin action. We investigated whether common polymorphisms in the SUR1 and Kir6.2 genes are associated with increased risk of type 2 diabetes in 490 subjects with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study. The 1273AGA allele of the SUR1 gene was associated with a 2-fold risk of type 2 diabetes [odds ratio (OR), 2.00; 95% confidence interval (CI), 1.19-3.36; P = 0.009]. This silent polymorphism was in linkage disequilibrium with three promoter polymorphisms (G-2886A, G-1561A, and A-1273G), and they formed a high-risk haplotype having a 2-fold risk of type 2 diabetes (OR, 1.89; 95% CI, 1.09-3.27; P = 0.023). Subjects with both the high-risk haplotype of the SUR1 gene and the 23K allele of the Kir6.2 gene had a 6-fold risk for the conversion to diabetes compared with those without any of these risk genotypes (OR, 5.68; 95% CI, 1.75-18.32; P = 0.004). We conclude that the polymorphisms of the SUR1 gene predicted the conversion from impaired glucose tolerance to type 2 diabetes and that the effect of these polymorphisms on diabetes risk was additive with the E23K polymorphism of the Kir6.2 gene.
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Inhibition of KATP channel activity augments baroreflex-mediated vasoconstriction in exercising human skeletal muscle.
Keller, DM, Ogoh, S, Greene, S, Olivencia-Yurvati, A, Raven, PB
The Journal of physiology. 2004;(Pt 1):273-82
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Abstract
In the present investigation we examined the role of ATP-sensitive potassium (K(ATP)) channel activity in modulating carotid baroreflex (CBR)-induced vasoconstriction in the vasculature of the leg. The CBR control of mean arterial pressure (MAP) and leg vascular conductance (LVC) was determined in seven subjects (25 +/- 1 years, mean +/- S.E.M.) using the variable-pressure neck collar technique at rest and during one-legged knee extension exercise. The oral ingestion of glyburide (5 mg) did not change mean arterial pressure (MAP) at rest (86 versus 89 mmHg, P > 0.05), but did appear to increase MAP during exercise (87 versus 92 mmHg, P = 0.053). However, the CBR-MAP function curves were similar at rest before and after glyburide ingestion. The CBR-mediated decrease in LVC observed at rest (approximately 39%) was attenuated during exercise in the exercising leg (approximately 15%, P < 0.05). Oral glyburide ingestion partially restored CBR-mediated vasoconstriction in the exercising leg (approximately 40% restoration, P < 0.05) compared to control exercise. These findings indicate that K(ATP) channel activity modulates sympathetic vasoconstriction in humans and may prove to be an important mechanism by which functional sympatholysis operates in humans during exercise.
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Lack of anti-ischemic efficacy of the potassium channel opener bimakalim in patients with stable angina pectoris.
Burian, M, Piske, M, Petkovic, D, Mitrovic, V
Cardiovascular drugs and therapy. 2004;(1):37-46
Abstract
UNLABELLED Aim of the study was to evaluate anti-ischemic, hemodynamic and neurohumoral effects of bimakalim, a novel selective K(+)-channel opener, in patients with stable angina pectoris and reproducible ST-segment depression. METHODS AND RESULTS 86 patients with angiographic signs of CAD were involved in two randomised, placebo-controlled, double-blind trials with single high (0.1, 0.3 or 0.6 mg) and low (0.025 or 0.05 mg) doses of oral bimakalim. The anti-anginal efficacy was evaluated by analysis of ST-segment depression within exercise or RV pacing. A parallel assessment of hemodynamic parameters was done by means of right-heart catheterization. Given in high doses, bimakalim acted as a potent vasodilator and decreased SBP by 15 mm Hg. This was associated with a reflex activation of sympathetic nervous system resulting in an increase in heart rate by 25 /min, a 14% rise of myocardial oxygen consumption and a 63% elevation of noradrenaline plasma level. Low doses of bimakalim had no significant effect on hemodynamics and oxygen consumption. In exercise-induced angina pectoris, administration of bimakalim was neither associated with attenuation of ST-segment depression nor resulted in prolongation of time to 0.1 mV ST-segment depression. CONCLUSION The results of the present study suggest that bimakalim has a dose-dependent vasodilatatory activity but exerts no anti-ischemic benefits in patients with exercise-induced angina pectoris due to coronary artery disease.
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Diazoxide in the treatment of schizophrenia: novel application of potassium channel openers in the treatment of schizophrenia.
Akhondzadeh, S, Mojtahedzadeh, V, Mirsepassi, GR, Moin, M, Amini-Nooshabadi, H, Kamalipour, A
Journal of clinical pharmacy and therapeutics. 2002;(6):453-9
Abstract
OBJECTIVE Schizophrenia is a very common disorder, affecting 1% of the world population. People who develop schizophrenia experience severe suffering and approximately 10% commit suicide. The causes of schizophrenia are still largely unknown. The relative ineffectiveness of dopamine antagonists to treat some symptoms of schizophrenia has promoted many investigators to postulate the involvement of the neuronal system in the pathophysiology of this disease. It has been suggested that the dopamine-coupled adenosine triphosphate (ATP)-sensitive channels may function by hyperpolarizing cells during metabolic stress, a function that may be disrupted in people with schizophrenia. Therefore, application of potassium channel openers/activators may be beneficial in schizophrenia. Diazoxide is a benzothiadiazine derivative related to the thiazide diuretics and a potassium channel opener. The purpose of the present investigation was to assess the efficacy of diazoxide, as an adjuvant agent in the treatment of schizophrenia. METHODS Forty-two patients who met the DSM IV criteria for chronic schizophrenia completed the study. Patients were randomized to haloperidol 20 mg/day plus diazoxide 200 mg/day (21 subjects) or to haloperidol 20 mg/day plus placebo (21 subjects) in this 8-week double-blind study. RESULTS Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of haloperidol and diazoxide showed a significant superiority over haloperidol alone in the treatment of positive and general psychopathology symptoms as well as positive and negative syndrome scale (PANSS) total scores. In addition, in the diazoxide group a rapid onset of action on the positive symptoms was observed in week 2, whereas in the placebo group there was no significant effect at week 2. No significant differences were observed between the two protocols on the negative scores. CONCLUSION The results of this study present a novel application for potassium channel openers/activators in the neuropsychiatric disorders and diazoxide may be an effective adjuvant agent in the management of schizophrenia.