Ryu K H, Tanaka N, Ross J
Department of Medicine, University of California San Diego, La Jolla 92093-0613, USA.
Basic Res Cardiol. 1996 Mar-Apr;91(2):131-9. doi: 10.1007/BF00799685.
The effects on cardiac function of slowed frequency produced by a sinus node inhibitor (zatebradine, or UL-FS 49) were studied in the conscious rabbit under control conditions (n = 16) and after heart failure was produced by rapid atrial pacing for an average of 18.5 days (n = 8). Echocardiography was used to verify severe left ventricular (LV) dysfunction, and high-fidelity micromanometry and cardiac output measurements (Doppler echo) were performed. Echocardiographic fractional shortening was 40.3 +/- 4.1 % (SD) in controls; in heart failure it was 18.0 +/- 1.6 %, and the LV was enlarged. In controls, as heart rate (HR) was decreased from 279 beats per minute (bpm) by incremental doses of zatebradine (up to 0.75 mg/kg), maximal changes occurred when the heart reached 218 bpm with a maximum decrease of the first derivative of LV pressure (LV dP/dtmax) of 15.9 %; LV enddiastolic pressure (EDP) increased from 4.3 to 8.4 mmHg along with a significant decrease in cardiac index (CI) of 15.2 %, while LV systolic pressure (SP) was stable. In heart failure, LV dP/dtmax and CI were markedly reduced compared to controls and with reduction of HR from 257 to 221 bpm LV dP/dtmax was unchanged, LVEDP increased slightly (NS), LVSP was unchanged and CI fell by 13.5 % at the highest dose. In subgroups (control n = 9, failure n = 6), in order to eliminate the hemodynamic effects of cardiac slowing by zatebradine the sinus rate present before zatebradine was matched by atrial pacing; this procedure eliminated all hemodynamic abnormalities accompanying cardiac slowing in both groups. In conclusion, slowed HR due to a sinus node inhibitor was well tolerated in severe heart failure, and all negative hemodynamic responses in both controls and in heart failure were due entirely to a negative forcefrequency effect, without a direct depressant action of zatebradine on the myocardium.
在清醒兔中，研究了窦房结抑制剂（扎替雷定，或UL-FS 49）产生的频率减慢对心脏功能的影响，实验分为对照条件下（n = 16）和通过快速心房起搏平均18.5天导致心力衰竭后（n = 8）两个阶段。使用超声心动图验证严重的左心室（LV）功能障碍，并进行高保真微测压和心输出量测量（多普勒超声）。对照中超声心动图分数缩短率为40.3±4.1%（标准差）；心力衰竭时为18.0±1.6%，且左心室扩大。在对照中，随着扎替雷定剂量递增（高达0.75 mg/kg）使心率（HR）从每分钟279次搏动（bpm）下降，当心率降至218 bpm时出现最大变化，左心室压力一阶导数（LV dP/dtmax）最大下降15.9%；左心室舒张末期压力（EDP）从4.3 mmHg升至8.4 mmHg，同时心脏指数（CI）显著下降15.2%，而左心室收缩压（SP）保持稳定。在心力衰竭时，与对照相比LV dP/dtmax和CI显著降低，当HR从257降至221 bpm时LV dP/dtmax无变化，左心室舒张末期压力（LVEDP）略有升高（无统计学意义），左心室收缩压（LVSP）无变化，最高剂量时CI下降13.5%。在亚组中（对照n = 9，心力衰竭n = 6），为消除扎替雷定引起的心率减慢的血流动力学效应，通过心房起搏使扎替雷定给药前的窦性心率匹配；该操作消除了两组中伴随心率减慢的所有血流动力学异常。总之，窦房结抑制剂导致的心率减慢在严重心力衰竭中耐受性良好，对照和心力衰竭中的所有负性血流动力学反应完全归因于负性力频率效应，而扎替雷定对心肌无直接抑制作用。
