Effects of ticagrelor pretreatment on electrophysiological properties of stellate ganglion neurons following myocardial infarction

Abstract

Higher sympathetic activity predisposes to malignant ventricular arrhythmias in the context of myocardial infarction (MI). This is, in part, mediated by the electrical activity of the stellate ganglion (SG). The aim of this study is to examine the effects of ticagrelor pretreatment on the electrophysiological properties of SG neurons following MI in rabbits. MI was induced by isoproterenol (ISO) of 150 mg kg‐1 d‐1 (twice at an interval of 24 hours). Ticagrelor pretreatment was administered at low‐ (10 mg kg‐1 d‐1) or high‐dose (20 mg kg‐1 d‐1). Protein and RNA expression were determined by immunohistochemical analysis and real‐time PCR, respectively. The activity of sodium channel current (INa), delayed rectifier potassium current (IKDR), M‐type potassium current (IKM) as well as action potentials (APs) from SG neurons were measured by whole‐cell patch‐clamp. Intracellular calcium concentrations were measured by confocal microscopy. Compared with the control group, the MI group exhibited a greater amplitude of INa, IKDR and IKM, significantly altered activation and inactivation characteristics of INa, no significant alterations in protein or mRNA expression of sodium and M‐type potassium channels, along with higher AP amplitude and frequency and intracellular calcium concentrations. Most of these abnormalities were prevented by pretreatment with low‐ or high‐dose ticagrelor. Our data suggest that ticagrelor exerts cardioprotective effects, potentially through modulating the activity of different ion channels in SG neurons.

Ticagrelor Can Regulate the Ion Channel Characteristics of Superior Cervical Ganglion Neurons after Myocardial Infarction

“…The animals’ use, their groupings, and the MI preparation methods for experimental animals are briefly introduced as follows: 18 male rabbits weighing 300–500 g (Tianjin Yuda Experimental Animal Co., Ltd., Tianjin, China) were randomly and equally divided into a control group, MI group, and P2Y12 receptor antagonist (TIC) group (abbreviated as the TIC group). Rabbit MI was performed via two abdominal subcutaneous injections of 150 mg·kg −1 ·d −1 of isoproterenol (ISO) with an interval of 24 h. The successful establishment of the MI model was verified in our previous study [ 7 ]. Rabbits in the TIC groups were administered 20 mg·kg −1 ·d −1 TIC (on two consecutive days) via gavage, then MI was induced via ISO.…”

“…The patch-clamp protocol and the drawing of the curves (current-voltage (I-V) curves and activation curves) for I K were carried out with reference to our previous study [ 7 , 8 ]. I-V curves were drawn by plotting the peak current density (the x-axis represented the different test membrane potentials; the y-axis represented the maximum current amplitude/neuron membrane capacitance).…”

“…The methods for the SCG neuron acquisition and whole-cell patch-clamp recording were described in our previous reports [ 7 , 8 , 9 , 10 ]. In short, SCG slices were cut, digested in the enzyme solution (50–60 min, 37 °C), and dispersed gently with glass tubes into a single neuron.…”

“…The method for recording the intracellular calcium concentrations of SCG neurons was described in detail in our previous studies [ 7 , 8 ]. The SCG neurons were loaded in incubation solution including 3 μM Fluo 4-AM and Pluronic F-127 (<0.05%) (40 min, 37 °C).…”

“…Previous studies have demonstrated that many components of SCGs are involved in the regulation of cardiac function after MI [ 5 , 6 ]. Our previous results showed that the electrophysiological levels of extracardiac ganglion neurons increased significantly after myocardial ischemia and infarction [ 7 , 8 , 9 , 10 ]. These changes in SCGs were closely related to the occurrence of ventricular arrhythmias after MI.…”