Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia–reperfusion injury

Abstract

Studies have demonstrated that diabetic (db/db) mice have increased susceptibility to myocardial ischemia–reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury. Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/+ mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies showed that the severity of VA inducibility was higher in db/db mice than control (db/ +) mice. Ranolazine suppressed the VA inducibility and severity. Optical mapping studies in Langendorff-perfused hearts showed that ranolazine significantly shortened action potential duration, Cai transient duration, Cai decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. Western blotting studies showed that the expression of pThr17-phospholamban, calsequestrin 2 and voltage-gated sodium channel in the IR zone was significantly downregulated in db/db mice, which was ameliorated with ranolazine pretreatment and might play a role in the anti-arrhythmic actions of ranolazine in db/db mouse hearts with IR injury.

Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia–Reperfusion Injury

“…Furthermore, both hypothermia-induced RYR2 and SERCA2a dysfunction promote the emergence of SDA (Wang et al, 2021). Because rotigaptide has no significant effects on Ca i homeostasis, the modulation of Ca i dynamics, for example, direct or indirect CaMKII inhibition (Mitsuyama et al, 2014;Chou et al, 2020a), may work synergistically with rotigaptide to suppress arrhythmogenic alternans in our model. Further investigation is required to verify this hypothesis.…”

CaMKII Inhibition is a Novel Therapeutic Strategy to Prevent Diabetic Cardiomyopathy

“…Considering the increased susceptibility of diabetics to arrhythmia following ischaemic injury ( Chou et al, 2020 ), it could be of benefit to examine the effects of CaMKII inhibition in the ischaemic diabetic heart. Altering levels of CaMKII activity/expression in ischaemic diabetic myocardium could have unforeseen effects if studies focus only on the diabetic myocardium.…”

Facilitation of Insulin Effects by Ranolazine in Astrocytes in Primary Culture

“…At therapeutic concentrations, Rn inhibits the late inward sodium current (I(NaL)) [ 23 ], reducing tissue damage caused by intracellular sodium and calcium overload, which is associated with myocardial ischemia [ 24 , 25 , 26 ]. I(NaL) amplitude is increased in many pathological situations, such as myocardial ischemia and oxidative stress [ 27 , 28 , 29 ]. In addition to its antianginal effects, Rn acts as an anti-inflammatory agent, reducing asymmetric dimethylarginine and C-reactive protein plasma levels and promoting the endothelial release of vasodilator mediators in patients with ischemic coronary disease [ 30 ].…”