| As an effective anti-ischemic drug, ranolazine can inhibit late sodium channel to prevent the sodium and calcium overload caused by myocardial ischemia, and effectively improve the heart disfunction and barrier of energy metabolism caused by myocardial ischemia ,without the fluctuations of patients'heart rate and blood pressure ,who have angina and myocardial infarction, having a unique protection of ischemic myocardium. Recently studies show that the use of ranolazine in the treatment of angina may be achieved through the inhibition of myocardial cells late sodium current (INa), and reducing intracellular calcium overload. When cardiac action potential occurs, the sodium ions result in rapid depolarization or peak of the action potential through the cardiac membrane sodium channels into the cell. The open of sodium channel is very short, following a rapid inactivation, and closes in the stage of platform. However, there is a small part of the open of sodium channels is not completely inactivated, and persistent in the whole stage of plateau, when a typical sodium channel close.Delaying the open of the sodium channel allows the slow flow of sodium ions into the cell (in the systolic).Studies show that myocardial cell membrane sodium channel slow and cardiovascular diseases, especially ischemic heart disease and its related diseases are closely linked in the state of the occurrence and development. Undrovinas AI etc. detected that the concentration of ranolazine in the slow sodium channel and the peak current of sodium ions's half-inhibitory (Ic50) is 6.5μM·L-1and 244μM·L-1, by comparing the use of ranolazine in the slow sodium channel with it in the sodium peak current in the of chronic heart failure canine's isolated ventricular muscle. They believed that ranolazine could selectively inhibit slow sodium channel. Based on the experimental preparation, conditions, and different species, the IC50 ranges from 5μM·L-1 to 21μM·L-1.Associated with an imbalance of oxygen supply and demand, the destruction of the environment's homeostasis of cardiac cells'sodium and calcium ion in pathological conditions, sodium outflow's reduction and its inflow's raise will lead to sodium overload in myocardial cells. Result in a large number of intracellular accumulation of sodium ions, through the Na + / Ca + exchange, inducing calcium overload, leading the extension of action potential and inducing the abnormalities of its relaxtion in early after depolarization. The ventricular repolarization and contractile function of the patients with heart failure are often abnormal, these anomalies result in the disorder of the cardiac excitation-contraction coupling's process, destructing the intracellular sodium and calcium homeostasis. Abnormal energy metabolism also plays a crucial role in the heart failure and left ventricular disfunction associating with it. The study found that the slow sodium channel of myocardial cells in dogs with heart failure tripled. Ranolazine can reduce the time of late sodium channel opening, reverse the prolongation of action potential , inhibit early after depolarization, and end the ventricular tachycardia by the effects of antiarrhythmic,Chandle MP etc. detected that short-term use of Ranolazine and dobutamine in dogs with chronic heart failure can increase the stroke volume, cardiac output, ejection fraction and so on. Ranolazine improves left ventricular function, makes mechanical efficiency of left ventricular increasing significantly, without the raise of myocardial oxygen consumption. In summary,Ranolazine is a new anti-ischemic mechanism,It is still under study, In particular, still no for clinical ,Our experimental study will provide a richer and more systematic clinical basis of clinical application.Patch-clamp technique is a received cutting-edge technology of cell electrophysiological studies in the world, which makes a direct study of cell membrane ion channel's current characteristics become reality. The subjects use whole-cell patch-clamp technique to study the effects of ranolazine on ion channels, and analyze the possible mechanism of anti-arrhythmia and improvement of cardiac function.Some studies confirmed that the transient outward potassium current is the most important repolarization currents in human and rat myocardium. The late sodium current mainly occurs in the plateau, therefore, this study made guinea pigs experimental animals for research.This study analyzed the mechanism of antiarrhythmic effects and improvement of cardiac function with the use of ranolazine ,by observing the its influence of cardiac function and arrhythmia in vivo and vitro ischemia - reperfusion of guinea pig model, the its influence on the guinea pig heart papillary muscle action potential (AP) and contractile force, and its influence on right sodium current(INa +) , the late sodium current (INa / L) and delayed rectifier potassium current (Ik +) of guinea pig ventricular myocytes with the combination of the block of calcium current(L-ICa).There is high SOD activity and low content of MDA in serum of vivo myocardial ischemia - reperfusion injury model of the sham group of guinea pig with the use of ranolazine. The SOD activity of Ranolazine group is higher than ischemia-reperfusion model group (P <0.05), while the ranolazine group can significantly reduce serum MDA levels (P <0.05). MDA content in sham-operated group is 2.37±0.71 nmol / ml, while the MDA content in ischemia-reperfusion group was significantly higher (7.21 land 1.65 nmol / ml). After the intervention of ranolazine, MDA contents were decreased to 4.52±0.61nmol / ml in Ranolazine iv group and 3.07±0.56nmol/ml in ranolazine infusion group. There is a contrary of SOD activity, the control group up to 107.66±13.10 nmol / ml, ischemia-reperfusion group a minimum of 74.65±8.05nmol/ml, but ranolazine treatment group were back to 98.91 Soil 6.13 nmol / ml (Reynolds hydrochloride iv group) and 114.11±9.38 nmol / ml (ranolazine infusion group). There was a significant difference of MDA content and SOD activity among ranolazine iv group, ranolazine infusion group and the ischemia-reperfusion group (p <0.05). Ranolazine can improve the body's ability to eliminate free radicals and inhibit lipid peroxidation. Large doses of ranolazine have a significant inhibition on arrhythmia induced by ischemia-reperfusion. Ranolazine iv group and ranolazine continuous infusion group both can low LVEDP, especially the latter. LVEDP is an important indicator reflecting the degree of ventricular myocardial contracture and rigid. Diastolic heart failure results from left ventricular impairment in diastolic filling period ,reduction of stroke volume and the raise of left ventricular end-diastolic pressure leaded by the increasing myocardial stiffness. Therefore, Ranolazine can improves diastolic function and be applied to diastolic heart failure. Ranolazine can protect vivo ischemia-reperfusion's injury , reduce reperfusion arrhythmias, and improve cardiac function, especially cardiac diastolic function.Ranolazine increases LVDP, + dp / dtmax, -dp/dtmax, and reduces myocardial reperfusion at the end of the Ca2 + concentration in the protective effect of vitro simulated ischemia - reperfusion injury cardiac function. Both are dose-dependent. LVDP, dp / dtmax reflects the left ventricular systolic function, -dp/dtmax reflects left ventricular diastolic function. These shows that ranolazine can be against with the reduction of cardiac function induced by isolated myocardial ischemia-reperfusion. At the same time it can reduce the myocardial Ca2 + content of myocardial tissue. That confirmed Ranolazine can inhibit the calcium overload induced by myocardial ischemia - reperfusion. Ranolazine can effectively improve the ischemia and angina and left ventricular decompensation, then increase cardiac contractility and improve diastolic function.APD50 and APD90, compared with the simple perfusion with H2O2 significantly reduced action potential duration (p < 0.05 and p <0.01), after ranolazine (1Μ) + H2O2 perfusion with 3 minutes in the experiments of muscle action potentials and contractile force of guinea pig papillary by using ranolazine. Compared APD50 and APD90 with perfusion with H2O2 alone, there is a significant reduction in action potential duration (p <0.05 and p <0.001) after TTX (2μΜ) + H2O2 perfusion with 3 minutes. H2O2 group contractile force decreased significantly (80.66±6.53)%, (p <0.05), by the comparison between Ranolazine group and the normal group. Amplitude of papillary muscle contraction in ranolazine (10uM) + H2O2 group and TTX (2uM) + H2O2 group compared with the control group has no significant statistical significance (93.00±6.63 and 93.67±6.12)%, (P> 0.05). Intervention of H2O2-induced guinea pig ventricular myocytes by use of ranolazine can reduce the extension of the cell action potentials. Ranolazine reduces guinea pig papillary muscle action potential duration induced by H2O2 and enhance myocardial contractile force. The result is as same as it by using TTX. Further illustrates ranolazine can inhibit the arrhythmias and improve cardiac function. All these guide us to do further study about the mechanism of ranolazine in the level of ion channels. We can observe the ranolazine's effect on cardiac ion channel currents in cells with the application of patch-clamp technique. After adding ranolazine 1μM ? L-1, 10μM ? L-1, and 100μg ? L-1 3 minutes later, comparing with the normal control group, the peak amount of current and medium doses of sodium, respectively (99.50±11.13和96.38±10.35, pA / pF, n = 8) ,has no statistical significance (p> 0.05); the high-dose peak current (79.88±9.88, pA / pF, n = 8) with a significant statistical significance (p <0.05, reversal potential around +10 - +20 mV; compared with normal ventricular myocytes on the opening hours by using H2O2, probability of open increased significantly (p <0.01), closing time significantly lower (p <0.01); however, opening hours, probability of and closing time of the ranolazine group compared with the normal group have no statistical significance (p> 0.05).It shows that ranolazine can inhibit the fast high-dose sodium currents, and the high-dose ranolazine can block the increase of sodium current induced by a hydrogen peroxide(the late sodium current). It has a dose-dependent manner and be as similar as the role of tetrodotoxin. After adding Ranolazine 1μM ? L-1, 10μM ? L-1, and 100μg ? L-1 3 minutes later, the low-dose and medium dose of peak potassium currents, respectively (21.67±3.78 and 18.56±4.78 pA / pF , n = 8) no statistical significance (p> 0.05), and large dose (18.00±2.78 pA / pF, n = 8) has significant statistical significance. Large dose of Ranolazine can inhibit the potassium channels with a dose-dependent manner.It indicates that ranolazine has a role of anti-ventricular arrhythmias and anti-atrial arrhythmia, similar with classⅢantiarrhythmic drug.We found that medium and large doses of ranolazine have inhibition on ventricular myocytes of L-type calcium ion channels. After adding ranolazine 1,10 and 100μg ? L-1 3 minutes later, , the peak sodium current (respectively 3.98±0.75,3.85±0.71和3.53±0.58,pA/pF n=8), group with 200μg ? L -1 was statistically significant (p <0.01). The reduction of guinea pig ventricular myocytes L-Ica's amplitude by Ranolazine is dose-dependent when Reversal potential is at about +50 - +60 mV. Ranolazine can blocked Ca2 + influx of the L-type calcium channels, reduce the concentration of Ca2 + in the cytoplasm, and inhibit cardiac myocyte excitation-contraction coupling. So myocardial contractile force weak as a negative inotropic effect, it can make the power of heart reduce while a corresponding reduction in myocardial oxygen consumption. It played a role in protection of ischemic myocardium, while it also reduce calcium overload. However we need further experiments.In summary, we found that ranolazine has a effect of inhibition in the majority cardiac ion channels of cells, as classⅢantiarrhythmic drugs like amiodarone. Ranolazine also can improve cardiac function, especially left ventricular diastolic function. There will be a very good prospects of it in clinical application . Ranolazine can effectively improve the ischemia and angina, and improveleft ventricular decompensation, particularly those with diastolic dysfunction and arrhythmia. So we expect that ranolazine may become a new category of drug with the effect of anti-arrhythmia and treating heart failure in future. There is a need to conduct more in-depth study.
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