Antiarrhythmic activity of a new spiro-cyclic benzopyran activator of the cardiac mitochondrial ATP dependent potassium channels

Abstract

'Compound A' (4(ı)-(N-(4-acetamidobenzyl))-2,2-dimethyl-2,3-dihydro-5(ı)H-spiro[chromene-4,2(ı)-[1,4]oxazinan]-5(ı)-one) is a new spiro-cyclic benzopyran activator of the mitochondrial ATP-dependent potassium channels (mitoKATP). We researched the effect of compound A on ischemia/reperfusion (I/R)-induced ventricular arrhythmias. We also tested the hypothesis that the application of the activation of mitoKATP in combination with the inhibition of sarcolemmal ATP-dependent potassium channels (sarcKATP) may produce a stronger antiarrhythmic effect. In anesthetized rats, myocardial ischemia was performed by ligating the left main coronary artery followed by reperfusion. At a dose of 10 mg/kg, compound A significantly decreased arrhythmia scores and the total length of arrhythmias, whereas this was found to be ineffective at a dose of 3 mg/kg. Pre-treatment with 5-HD, a selective mitoKATP blocker, abolished the antiarrhythmic effect of compound A. Both diazoxide, a selective mitoKATP opener and HMR 1098, a selective sarcKATP blocker, significantly decreased the total length of arrhythmias. However, the combination of neither diazoxide nor compound A with HMR 1098 showed no additional therapeutic benefit. These results reveal that compound A may have a dose-dependent antiarrythmic effect, which is more pronounced than the antiarrhythmic effect of diazoxide. The antiarrhythmic effect of compound A may possibly depend on mitoKATP activation.

Mitochondrial and Sarcoplasmic Reticulum Interconnection in Cardiac Arrhythmia

“…The development of new therapeutics could break the vicious cycle of Ca 2+ overload, mitochondrial dysfunction, and ROS Gonca et al, 2016 generation to substantially reduce the incidence of sudden cardiac death and disease progression, especially in high-risk patients, such as those with HF. Fortunately, there are a few candidates that may prove useful in doing so.…”

“…Compound A, another mitoK ATP agonist, has also been proven to reduce reperfusion arrhythmias in I/R, with effects even more pronounced than diazoxide, a more commonly used mitoK ATP agonist. Unfortunately, these effects were not more effective when used in combination with a sarcolemmal K ATP blocker (Gonca et al, 2016). Even sevoflurane, a commonly used anesthetic, has been demonstrated to have protective effects dependent on mitoK ATP opening.…”

İskemi Sonrası Verilen Kannabidiol Reperfüzyon ile Uyarılan Aritmilere Karşı Koruyucu Etkilidir

“…Ancak klinikte bu amaçla uygulanan mevcut farmakolojik tedavi yöntemleri tam olarak başarılı değildir (3). Bu nedenle reperfüzyonla uyarılan aritmilere karşı yeni farmakolojik tedavi yöntemleri bulmak için araştırmalar yapılmaktadır (4). Bu çalışmalarda birçok etken maddenin iskemi reperfüzyon aritmilerini azalttığı bulunmuştur (5).…”