Mitochondrial basis of the anti‐arrhythmic action of lidocaine and modulation by the n‐6 to n‐3 PUFA ratio of cardiac phospholipids

Abstract

The aim of this study was to evaluate the involvement of mitochondria in the mechanism of the anti-arrhythmic lidocaine. Rats were fed with a diet containing either n-6 polyunsaturated fatty acids (PUFAs, SSO group) or an equimolecular mixture of n-3 and n-6 PUFAs (FO group) for 8 weeks. The hearts were perfused according to the working mode using a medium with or without lidocaine 5 μm. They were then subjected to local ischemia (20 min) and reperfusion (30 min). Dietary n-3 PUFAs triggered the expected decrease in the n-6/n-3 PUFA ratio of cardiac phospholipids. Reperfusing the ischemic area favored the incidence of severe arrhythmias. Lidocaine treatment abolished almost completely reperfusion arrhythmias in the FO group, but did not display anti-arrhythmic properties in the SSO group. As it was indicated by measurements of the mitochondrial function, lidocaine seemed to favor mitochondrial calcium retention in the FO group, which might prevent cytosolic calcium spikes and reperfusion arrhythmias. In the SSO group, the resistance to lidocaine was associated with an aggravation of cellular damages. The mitochondrial calcium retention capacities were saturated, and lidocaine was unable to increase them, making the drug inefficient in preventing reperfusion arrhythmias.

Antioxidant and Cardioprotective Effects of EPA on Early Low-Severity Sepsis through UCP3 and SIRT3 Upholding of the Mitochondrial Redox Potential

“…Dietary EPA decreased ω 6 PUFAs in cardiac phospholipids, namely, arachidonic acid, C22:4 ω 6, and C22:5 ω 6, and increased long-chain ω 3 PUFAs (C22:5 and C22:6 ω 3). These modifications are classically observed when a ω 6 PUFA-based diet is enriched with ω 3 PUFAs [17, 18, 39]. The PUFA ( ω 6 + ω 3) level of phospholipids is relatively constant to maintain stability of the membrane fluidity.…”

“…At the end of the cardiac MRI, about 200 mg of the apical heart was freeze clamped in liquid nitrogen and stored at −80°C for later analysis. The mitochondria were extracted as previously described [17]. Atria and the remaining aorta were cut off from the heart.…”

“…Omega-3 ( ω 3) polyunsaturated fatty acids (PUFAs) are known to be cardioprotective in several pathophysiological situations including ischemia/reperfusion [17, 18], hypertrophy [19], and cardiac arrhythmias [20] through preservation of mitochondrial integrity [17, 18]. Eicosapentaenoic acid (C20:5 n -3 or EPA) is the best known of these [21, 22].…”

High-fat, low-carbohydrate diet promotes arrhythmic death and increases myocardial ischemia-reperfusion injury in rats

“…Saturated fatty acids may increase cardiovascular risk and increase susceptibility to ventricular fibrillation and tachycardia after I/R (19,50). There has also been interest in use of n-6 and n-3 polyunsaturated fatty acids to lower the risk of sudden cardiac death and prevention of reperfusion arrhythmias (11,16) although recent clinical prevention and animal studies have not borne this conjecture out (5,17). HFLCD is enriched with all types of fatty acids, which might promote metabolic and electric instability, thereby leading to ventricular arrhythmias during I/R.…”

Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea‐pig

“…With lidocaine, therapeutic plasma levels correspond to 1.4–6.0 μg/mL (i.e., 5–22 μ m ) , and the protein‐unbound lidocaine fraction is 45–50% . In electrophysiological studies on perfused guinea‐pig hearts, procainamide was used at a concentration of 10 μ m , and lidocaine was used at concentrations of 5–10 μ m in rodent models of cardiac arrhythmia .…”