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

摘要

'Compound A' (4(A +/-)-(N-(4-acetamidobenzyl))-2,2-dimethyl-2,3-dihydro-5(A +/-)H-spiro[chromene-4,2(A +/-)-[1,4]oxazinan]-5(A +/-)-one) is a new spiro-cyclic benzopyran activator of the mitochondrial ATP-dependent potassium channels (mitoK(ATP)). 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 mitoK(ATP) in combination with the inhibition of sarcolemmal ATP-dependent potassium channels (sarcK(ATP)) 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 mitoK(ATP) blocker, abolished the antiarrhythmic effect of compound A. Both diazoxide, a selective mitoK(ATP) opener and HMR 1098, a selective sarcK(ATP) 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 mitoK(ATP) activation.