| (3-receptor blockers are very important as class II anti-arrhythmic drugs, which can significantly increase the survival rate of patients with ventricular fibrillation induced by myocardial infarction and can significantly reduce the incidence and mortality of atrial fibrillation in patients with heart failure. In animal experiments, there is no doubt that β-receptor blockers reduce myocardial injury and promote recovery in cardiopulmonary resuscitation while adrenaline injures myocardium. The combinations of adrenaline and (3-blockers have a significant effect, indicating that maintaining a functional balance in myocardial tissue between different receptor subtypes is very important by drugs. β1-receptor andβ2-receptor accounted for 80% and 20%, respectively, in normal heart, which can regulate the cardiac contractility, heart rate, peripheral vascular resistance and participate in the stress response in common. When heart failure or cardiac hypertrophy accurs, cardiac β-receptors are significantly reduced, while theβ2-receptors are relatively stable, and its function is to keep the heart’s response to adrenaline and maintain cardiac decompensation. In theory, the selectiveβ1 blockers can protect the heart. Nebivolol is the third generation vasodilation type β-blockers with high selection of theβ1-receptors, whose affinity withβ1-andβ2-receptors are 300-fold difference. There is a significant difference between nebivolol and non-selective p-blockers in the pharmacodynamic charateristics.Whether nebivolol has anti-arrhythmic effect or arrhythmogenic effect is unknown. Research has shown that traditional and new anti-arrhythmic drugs in therapeutic dose or sub therapentic dose could aggravate arrhythmias even induce a new arrhythmia. Sotalol as a β-blocker belongs to Class III anti-arrhythmic drugs which can selectively block the rapid delayed rectifier potassium channel, prolong Q-T interval and result in torsade de pointes, which is the main cause of sudden death. In this study, barium chloride inducing arrhythmias as a pathological model. We observed the influence of nebivolol on cardiac arrhythmias and vascular tension in model rats.Objective:To observe the influences on cardiac arrhythmias with different doses of nebivolol in rat model; To observe the results of nebivolol in electrocardiogram P-R, QRS, Q-T interval and Tp-e interval and analysis the arrhythmogenic effect; To observe the effects of Nebivolol on endothelial function in rats with arrhythmia. 1 In VivoRats (n=56) were randomly divided into 7 groups:the nebivolol with the high, medium and low dose (1 mg/kg,0.5 mg/kg,0.25 mg/kg) and propranolol with high and low dose (6 mg/kg,3 mg/kg), bisoprolol (16 mg/kg) group and saline control group.The rats were anesthetized with 10% chloral hydrate intraperitoneally (0.3 ml/100g) and then connected to the electrode and limb Ⅱ lead electrocardiogram was recorded. The drug or normal saline were injected through femoral vein with (0.5 ml/100g of weight), and the electrocardiogram (ECG) was recorded both before and after injection. After 3 minutes, the pump was started with constant speed and input barium chloride was input with 20 μl/s continuous via femoral venous. The occurred time of premature ventricular contractions(PVCs), ventricular tachycardia and ventricular fibrillation for each rat was recorded to observe if different doses of nebivolol have the effects of anti-arrhythmic. The R-R interphase, QRS interphase, P-R inteiphase, Q-T interphase and Tp-time were measured to observe if different doses of nebivolol have the effects of pro-arrhythmic. 2 Vascular ring in vitro experimentTwenty four SD rats were randomly divided into control group, model group and drug group.Control group and model group were gavaged with the saline 1 ml/100 g daily, drug group were lavaged with nebivolol 1 mg/1ml/ 100 g daily. After 7 days, the rats were anesthetized with 10% chloral hydrate intraperitoneally (0.3 ml/kg). The rats of model group and drug group were inputed chloride continuously at a speed of 20 μl/s via femoral vein.The rats of the control group were inputed at a speed of 20 μl/s saline via femoral venous continuously. After ventricular tachycardia, opened the chest immediately, removed the pulmonary artery and thoracic aorta quickly and prepare the vascular ring 5 mm long, fixed in the bath tube which contain 5 ml of PSS liquid.Aortic rings were pre-constricted by phenylephrine (10-6mol/L), when the contractionwasmaximum, Asolution acetylcholine (10-9,10-8,10-7,10-6,10-5,10-4 mol/L) was followed. Relaxation of vascular rings percentage of each group was calculated to observe if the nebivolol could protect the vascular endothelium of the rats with arrhythmia.Results:1 The effects of nebivolol on ventricular premature, ventricular tachycardia, ventricular fibrillation of the model rats.Compared with the normal saline group, different doses of nebivolol could significantly delay the occurred time of ventricular premature and ventricular tachycardia induced by barium chloride (P<0.01). Delayed effect of nebivolol (0.25mg/kg) on PVCs and ventricular tachycardia was significantly stronger than nebivolol (lmg/kg,0.5mg/kg) (P<0.01 or P<0.05). But compared with control group, there was no significant difference in the occurred time of ventricular fibrillation. It was indicated that the nebivolol have an antagonism to arrhythmias induced by barium chloride, and low dose of nebivolol is more significant for antiarrhythmic. Propranolol significantly delayed PVCs, ventricular tachycardia, but the impact to ventricular fibrillation is not obvious. Compared with propranolol (3mg/kg), the anti-arrhythmic effects of propranolol (6mg/kg) have an increasing trend, but no significant difference was observed between the two groups.2 Comparison of anti-arrhythmia effect in nebivolol, propranolol and sotalol.There was a significant difference in the delay time of VT by Nebivolol group (0.25 mg/kg) compared with propranolol (6 mg/kg) and sotalol group. In the delayed PVCs effect, there was no statistically significant difference between nebivolol (0.25 mg/kg) and propranolol, but stronger than sotalol (P <0.01).3 Effect of Nebivolol on ECG parametersCompared with before treatment, nebivolol (1 mg/kg,0.5 mg/kg) significantly prolonged the R-R interval of the rats (P<0.01 or P<0.05); There was no statistically significant difference in its P-R interval, QRS duration, Q-T period and Tp-e. Nebivolol(0.25 mg/kg) did not affect ECG parameters of the rats significantly. Propranolol (3 mg/kg,6 mg/kg) significantly prolonged the R-R interval (P<0.01), significantly prolonged P-R interval (allP<0.01), propranolol (6 mg/kg) prolonged QRS duration (P<0.01), propranolol (3 mg/kg,6mg/kg) had no significant effect on the Q-T interval and Tp-e time.Compared with before treatment, sotalol significantly prolonged R-R, P-R, Q-T interval and Tp-e time (P<0.01 or P<0.05). As class III anti-arrhythmic drug, sotalol can prolong repolarization time significantly so that causes classic torsades de pointes ventricular tachycardia (torsades de pointe Tdp), which is the main cause of sudden death. The results showed that high dose of nebivolol can slow the heart rate, the effects of low dose of nebivolol on heart rate, atrioventricular conduction, repolarization time were mild. Unlike sotalol, low dose of nebivolol did not prolong the Q-T interval and Tp-e time.4 Effect of nebivolol on vascular endothelial function in ratsCompared with the control (NS+NS) rats, under the situation of acetylcholine (10-9,10-8,10-7,10-6,10-5 mol/L), the relaxation percentage of TA and PA in the model (NS+BaCL2)rats was significantly lower (P<0.01 or P<0.05) respectively, indicating vascular rings endothelial dysfunction in rat model with VT. Compared with the model (NS+ BaCL2)rats, under the concentration range of acetylcholine (10-9,10-8,10-7 mol/L) or(10-7 mol/L), the vasodilation percentage of the TA and PA in treated(Nebi+ BaCL2) rats was significantly higher (P<0.05) respectively, and showing that nebivolol has a protective effect on the endothelial injury induced by VT.Summary:1 Nebivolol significantly delays the occurred time of PVCs and ventricular tachycardia induced by barium chloride in rats. Low dose of nebivolol shows stronger anti-arrhythmic effect, and is similar to propranolol and sotalol.2 Nebivolol can not significantratly prolong the electrocardiogram P-R, QRS, Q-T interval and Tp-e of the rats. Unlike sotalol, nebivolol does not prolong ventricular repolarization time.3 Nebivolol has the protective effect on endothelial function for the arrhythmic rats, reducing vascular tone, thus improving blood flow dynamics. This may be related to anti-arrhythmic effect of nebivolol. |
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