Scridon Alina, Halaţiu Vasile Bogdan, Balan Alkora Ioana, Cozac Dan Alexandru, Moldovan Valeriu, Bănescu Claudia, Perian Marcel, Şerban Răzvan Constantin
University of Medicine, Pharmacy, Science and Technology "George Emil Palade" of Târgu Mureş, Târgu Mureş, Romania.
Center for Advanced Medical and Pharmaceutical Research, Târgu Mureş, Romania.
Front Pharmacol. 2021 Apr 8;12:596956. doi: 10.3389/fphar.2021.596956. eCollection 2021.
The complex interactions that exist between the pacemaker current, , and the parasympathetic nervous system could significantly influence the course of patients undergoing chronic therapy with the blocker ivabradine. We thus aimed to assess the effects of chronic ivabradine therapy on autonomic modulation and on the cardiovascular response to and parasympathetic stimulation. The right atrial expression of HCN genes, encoding proteins for , was also evaluated. Sympathetic and parasympathetic heart rate variability parameters and right atrial (1-4) RNA levels were analyzed in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day). The heart rate (HR) and systolic blood pressure (SBP) responses to electrical stimulation of the vagus nerve (2-20 Hz) were assessed in 6 additional Control and 10 IVA rats. The spontaneous sinus node discharge rate (SNDR) response to cholinergic receptors stimulation using carbamylcholine (10-10 mol/L) was also assessed in these later rats. Ivabradine significantly increased vagal modulation and shifted the sympatho-vagal balance toward vagal dominance. In Control, vagus nerve stimulation induced progressive decrease in both the SBP ( = 0.0001) and the HR (< 0.0001). Meanwhile, in IVA, vagal stimulation had no effect on the HR ( = 0.16) and induced a significantly lower drop in SBP (< 0.05). IVA also displayed a significantly lower SNDR drop in response to carbamylcholine (< 0.01) and significantly higher right atrial expression ( = 0.02). Chronic ivabradine administration enhanced vagal modulation in healthy rats. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to vagal stimulation. These data bring new insights into the mechanisms of ivabradine-related atrial proarrhythmia and suggest that long-term blockade may protect against excessive bradycardia induced by acute vagal activation.
起搏电流（If）与副交感神经系统之间存在的复杂相互作用可能会显著影响接受If阻滞剂伊伐布雷定长期治疗的患者病程。因此，我们旨在评估伊伐布雷定长期治疗对自主神经调节以及对交感和副交感神经刺激的心血管反应的影响。还评估了编码If蛋白的HCN基因在右心房的表达。在6只对照雄性Wistar大鼠和10只接受伊伐布雷定治疗的雄性Wistar大鼠（IVA组；3周，10mg/kg/天）中分析了交感和副交感神经心率变异性参数以及右心房（1-4）RNA水平。在另外6只对照大鼠和10只IVA大鼠中评估了对迷走神经电刺激（2-20Hz）的心率（HR）和收缩压（SBP）反应。在这些后期的大鼠中还评估了使用氨甲酰胆碱（10-10mol/L）刺激胆碱能受体时的自发窦房结放电率（SNDR）反应。伊伐布雷定显著增加了迷走神经调节，并使交感-迷走神经平衡向迷走神经占优势方向转变。在对照组中，迷走神经刺激导致SBP（P = 0.0001）和HR（P < 0.0001）逐渐降低。同时，在IVA组中，迷走神经刺激对HR无影响（P = 0.16），并导致SBP下降显著更低（P < 0.05）。IVA组对氨甲酰胆碱的SNDR下降也显著更低（P < 0.01），且右心房If表达显著更高（P = 0.02）。长期给予伊伐布雷定可增强健康大鼠的迷走神经调节。此外，伊伐布雷定降低了对直接毒蕈碱受体刺激的HR反应，消除了心脏抑制反应，并减弱了对迷走神经刺激的血流动力学反应。这些数据为伊伐布雷定相关房性心律失常的机制带来了新的见解，并表明长期If阻滞可能预防急性迷走神经激活引起的过度心动过缓。
