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The antiarrhythmic and cardiac electrophysiological effects of SZV-2649 that contains a 2,6-diiodophenoxy moiety but lacks the benzofuran ring system present in amiodarone, were studied in mammalian cell line, rat and dog cardiac preparations. SZV-2649 exerted antiarrhythmic effects against coronary artery occlusion/reperfusion induced ventricular arrhythmias in rats and in acetylcholine- and burst stimulation induced atrial fibrillation in dogs. SZV-2649 inhibited hERG and GIRK currents in HEK cells (IC 50 : 342 and 529 nM, respectively). In canine ventricular myocytes, SZV-2649 (10 µM) decreased the densities of I Kr , and I to outward and I NaL and I CaL inward currents. The compound (2.5-10 µM) elicited Class IB type V max reducing and Class III type action potential duration prolonging effects in dog right ventricular muscle preparations. In canine atrial muscle, SZV-2629 (2.5-10 µM) moderately prolonged action potential duration and this effect was greatly augmented in preparations pretreated with 1 µM carbachol. In conclusion, SZV-2649, has antiarrhythmic effects based on its multiple ion channel blocking properties. Since its chemical structure substantially differs from that of amiodarone, it is expected that SZV-2649 would exhibit fewer adverse effects than the currently used most effective multichannel inhibitor drug amiodarone and may be a promising molecule for further development., (© 2024. The Author(s).)

Recent experimental data shows that hesperetin, a citrus flavonoid, affects potassium channels and can prolong the QT c interval in humans. Therefore, in the present study we investigated the effects of hesperetin on various transmembrane ionic currents and on ventricular action potentials. Transmembrane current measurements and action potential recordings were performed by patch-clamp and the conventional microelectrode techniques in dog and rabbit ventricular preparations. At 10 µM concentration hesperetin did not, however, at 30 µM significantly decreased the amplitude of the I K1 , I to , I Kr potassium currents. Hesperetin at 3-30 µM significantly and in a concentration-dependent manner reduced the amplitude of the I Ks current. The drug significantly decreased the amplitudes of the I NaL and I CaL currents at 30 µM. Hesperetin (10 and 30 µM) did not change the action potential duration in normal preparations, however, in preparations where the repolarization reserve had been previously attenuated by 100 nM dofetilide and 1 µg/ml veratrine, caused a moderate but significant prolongation of repolarization. These results suggest that hesperetin at close to relevant concentrations inhibits the I Ks outward potassium current and thereby reduces repolarization reserve. This effect in certain specific situations may prolong the QT interval and consequently may enhance proarrhythmic risk., (© 2024. The Author(s).)

Enhancement of the late Na + current (I NaL ) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of I NaL . In the present study, effects of GS967 on I NaL and action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. The effects of GS967 (1 µM) were compared to those of the class I/B antiarrhythmic compound mexiletine (40 µM). Under conventional voltage clamp conditions, I NaL was significantly suppressed by GS967 and mexiletine, causing 80.4 ± 2.2% and 59.1 ± 1.8% reduction of the densities of I NaL measured at 50 ms of depolarization, and 79.0 ± 3.1% and 63.3 ± 2.7% reduction of the corresponding current integrals, respectively. Both drugs shifted the voltage dependence of the steady-state inactivation curve of I NaL towards negative potentials. GS967 and mexiletine dissected inward I NaL profiles under AP voltage clamp conditions having densities, measured at 50% of AP duration (APD), of -0.37 ± 0.07 and -0.28 ± 0.03 A/F, and current integrals of -56.7 ± 9.1 and -46.6 ± 5.5 mC/F, respectively. Drug effects on peak Na + current (I NaP ) were assessed by recording the maximum velocity of AP upstroke (V + max ) in multicellular preparations. The offset time constant was threefold faster for GS967 than mexiletine (110 ms versus 289 ms), while the onset of the rate-dependent block was slower in the case of GS967. Effects on beat-to-beat variability of APD was studied in isolated myocytes. Beat-to-beat variability was significantly decreased by both GS967 and mexiletine (reduction of 42.1 ± 6.5% and 24.6 ± 12.8%, respectively) while their shortening effect on APD was comparable. It is concluded that the electrophysiological effects of GS967 are similar to those of mexiletine, but with somewhat faster offset kinetics of V + and I max at the same concentration, the current view that GS967 represents a new class of drugs that selectively block I + has to be questioned and it is suggested that GS967 should be classified as a class I/B antiarrhythmic agent.max and I NaL at the same concentration, the current view that GS967 represents a new class of drugs that selectively block I NaL has to be questioned and it is suggested that GS967 should be classified as a class I/B antiarrhythmic agent.

Sudden cardiac death among top athletes is very rare, however, it is 2-4 times more frequent than in the age-matched control population. In the present study, the electrophysiological consequences of long-term exercise training were investigated on Ca 2+ homeostasis and ventricular repolarization, together with the underlying alterations of ion channel expression, in a rat athlete's heart model. 12-week swimming exercise-trained and control Wistar rats were used. Electrophysiological data were obtained by using ECG, patch clamp and fluorescent optical measurements. Protein and mRNA levels were determined by the Western immunoblot and qRT-PCR techniques. Animals in the trained group exhibited significantly lower resting heart rate, higher incidence of extrasystoles and spontaneous Ca 2+ release events. The Ca 2+ content of the sarcoplasmic reticulum (SR) and the Ca 2+ transient amplitude were significantly larger in the trained group. Intensive physical training is associated with elevated SR Ca 2+ content, which could be an important part of physiological cardiac adaptation mechanism to training. However, it may also sensitize the heart for the development of spontaneous Ca 2+ release and extrasystoles. Training-associated remodeling may promote elevated incidence of life threatening arrhythmias in top athletes.

The sodium-calcium exchanger (NCX) is a critical mediator of calcium homeostasis. In the heart, NCX1 predominantly operates in forward mode to extrude Ca(2+); however, reverse-mode NCX1 activity during ischemia/reperfusion (IR) contributes to Ca(2+) loading and electrical and contractile dysfunction. IR injury has also been associated with altered fat metabolism and accumulation of long-chain acyl CoA esters. Here, we show that acyl CoAs are novel, endogenous activators of reverse-mode NCX1 activity, exhibiting chain length and saturation dependence, with longer chain saturated acyl moieties being the most effective NCX1 activators. These results implicate dietary fat composition as a plausible determinant of IR injury. We further show that acyl CoAs may interact directly with the XIP (exchanger inhibitory peptide) sequence, a known region of anionic lipid modulation, to dynamically regulate NCX1 activity and Ca(2+) homeostasis. Additionally, our findings have broad implications for the coupling of Ca(2+) homeostasis to fat metabolism in a variety of tissues.