Effects of a mitochondrial-acting drug on ischemia/reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and inflammatory cytokines in rat: Role of adenosine triphosphate-sensitive potassium channels
Objective Ischemia/reperfusion (IR)-induced myocardial arrhythmias are a common clinical manifestation in patients with myocardial infarction after reperfusion therapy. Mitochondria play a critical role in cardioprotection. Here, we investigated the effects of KH176 as a new mitochondrial-acting dru...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2022-07-01
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| Series: | European Journal of Inflammation |
| Online Access: | https://doi.org/10.1177/1721727X221115041 |
| _version_ | 1811282651499200512 |
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| author | Xin Zhang Geng Li |
| author_facet | Xin Zhang Geng Li |
| author_sort | Xin Zhang |
| collection | DOAJ |
| description | Objective Ischemia/reperfusion (IR)-induced myocardial arrhythmias are a common clinical manifestation in patients with myocardial infarction after reperfusion therapy. Mitochondria play a critical role in cardioprotection. Here, we investigated the effects of KH176 as a new mitochondrial-acting drug on IR-induced ventricular arrhythmias, mitochondrial function, pro-inflammatory cytokines production, and the role of mitochondrial ATP-dependent K (mK-ATP) channels in rats’ hearts. Methods The hearts of Sprague Dawley rats (250 ± 30 g; 36 rats) underwent 35 min of ischemia followed by 120 min of reperfusion. Myocardial in vivo ischemia was induced by ligation of the left anterior descending coronary artery. KH176 at concentrations of 10 and 50 μM was intraperitoneally injected to rats 10 min before reperfusion onset. Ventricular arrhythmias were quantified during reperfusion, and cardiac mitochondrial function, nitric oxide, and pro-inflammatory cytokines levels were measured by fluorometric, spectrophotometric, and ELISA techniques. Results Administration of KH176 significantly reduced lactate-dehydrogenase release and the number, duration, incidence, and severity of ventricular arrhythmias induced by reperfusion injury. IR-induced elevation of mitochondrial reactive oxygen species production, and cardiac pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, as well as reduction of mitochondrial membrane potential, ATP and nitric oxide levels were significantly restored by KH176 at 50 μM. However, the blockade of mK-ATP channels by 5-hydroxydecanoate considerably inhibited the effects of KH176 on all parameters except nitric oxide. Conclusion KH176 showed strong cardiac antiarrhythmic effects on IR-induced injury through improving mitochondrial function and reducing inflammatory and oxidative responses, and these protective effects are mediated by cardiac mK-ATP channels. |
| first_indexed | 2024-04-13T01:56:18Z |
| format | Article |
| id | doaj.art-aea04d80aa4f4345b5921c8763555d85 |
| institution | Directory Open Access Journal |
| issn | 2058-7392 |
| language | English |
| last_indexed | 2024-04-13T01:56:18Z |
| publishDate | 2022-07-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | European Journal of Inflammation |
| spelling | doaj.art-aea04d80aa4f4345b5921c8763555d852022-12-22T03:07:45ZengSAGE PublishingEuropean Journal of Inflammation2058-73922022-07-012010.1177/1721727X221115041Effects of a mitochondrial-acting drug on ischemia/reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and inflammatory cytokines in rat: Role of adenosine triphosphate-sensitive potassium channelsXin ZhangGeng LiObjective Ischemia/reperfusion (IR)-induced myocardial arrhythmias are a common clinical manifestation in patients with myocardial infarction after reperfusion therapy. Mitochondria play a critical role in cardioprotection. Here, we investigated the effects of KH176 as a new mitochondrial-acting drug on IR-induced ventricular arrhythmias, mitochondrial function, pro-inflammatory cytokines production, and the role of mitochondrial ATP-dependent K (mK-ATP) channels in rats’ hearts. Methods The hearts of Sprague Dawley rats (250 ± 30 g; 36 rats) underwent 35 min of ischemia followed by 120 min of reperfusion. Myocardial in vivo ischemia was induced by ligation of the left anterior descending coronary artery. KH176 at concentrations of 10 and 50 μM was intraperitoneally injected to rats 10 min before reperfusion onset. Ventricular arrhythmias were quantified during reperfusion, and cardiac mitochondrial function, nitric oxide, and pro-inflammatory cytokines levels were measured by fluorometric, spectrophotometric, and ELISA techniques. Results Administration of KH176 significantly reduced lactate-dehydrogenase release and the number, duration, incidence, and severity of ventricular arrhythmias induced by reperfusion injury. IR-induced elevation of mitochondrial reactive oxygen species production, and cardiac pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, as well as reduction of mitochondrial membrane potential, ATP and nitric oxide levels were significantly restored by KH176 at 50 μM. However, the blockade of mK-ATP channels by 5-hydroxydecanoate considerably inhibited the effects of KH176 on all parameters except nitric oxide. Conclusion KH176 showed strong cardiac antiarrhythmic effects on IR-induced injury through improving mitochondrial function and reducing inflammatory and oxidative responses, and these protective effects are mediated by cardiac mK-ATP channels.https://doi.org/10.1177/1721727X221115041 |
| spellingShingle | Xin Zhang Geng Li Effects of a mitochondrial-acting drug on ischemia/reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and inflammatory cytokines in rat: Role of adenosine triphosphate-sensitive potassium channels European Journal of Inflammation |
| title | Effects of a mitochondrial-acting drug on ischemia/reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and inflammatory cytokines in rat: Role of adenosine triphosphate-sensitive potassium channels |
| title_full | Effects of a mitochondrial-acting drug on ischemia/reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and inflammatory cytokines in rat: Role of adenosine triphosphate-sensitive potassium channels |
| title_fullStr | Effects of a mitochondrial-acting drug on ischemia/reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and inflammatory cytokines in rat: Role of adenosine triphosphate-sensitive potassium channels |
| title_full_unstemmed | Effects of a mitochondrial-acting drug on ischemia/reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and inflammatory cytokines in rat: Role of adenosine triphosphate-sensitive potassium channels |
| title_short | Effects of a mitochondrial-acting drug on ischemia/reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and inflammatory cytokines in rat: Role of adenosine triphosphate-sensitive potassium channels |
| title_sort | effects of a mitochondrial acting drug on ischemia reperfusion induced ventricular arrhythmias cardiac mitochondrial function and inflammatory cytokines in rat role of adenosine triphosphate sensitive potassium channels |
| url | https://doi.org/10.1177/1721727X221115041 |
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