Ryu K H, Tanaka N, Dalton N, Mao L, Rockman H A, Milano C A, Ross J
Department of Medicine, University of California San Diego, La Jolla 92093-0613, USA.
J Card Fail. 1997 Mar;3(1):27-39. doi: 10.1016/s1071-9164(97)90006-3.
Recent experiments have documented the importance of beta-adrenergic regulation of the force-frequency relation (FFR) in the normal and failing heart. As in isolated human cardiac muscle, a descending limb of the FFR occurs at high frequencies in the intact rabbit heart, and therefore a new model of atrial pacing-induced heart failure was developed in the rabbit. Responses of the FFR to beta-adrenergic stimulation were then assessed in the conscious state before and after the induction of heart failure.
Rapid atrial pacing for an average of 19.5 days in instrumented rabbits produced severe left ventricular dilation with reduced cardiac output (echocardiography) and depressed myocardial contractility and relaxation rate (left ventricular dP/dt, catheter-tip micromanometer), associated with reductions in beta-adrenergic receptor density and adenylyl cyclase activity. Before heart failure, heart rate was slowed in the conscious animal from 280 +/- 30 (SD) to about 225 beats/min using a sinus node inhibitor (zatebradine), and heart rate was then increased in steps by atrial pacing from 250 to 450 beats/min; the heart rate-versus-left ventricular dP/dtmax (FFR) response showed an ascending response (increasing contractility), with a descending limb at rates greater than 375 beats/min, and dobutamine infusion amplified the ascending limb of the FFR (increased slope) and attenuated the descending limb. In heart failure the basal FFR was severely depressed with a descending limb over 350 beats/min; dobutamine shifted the FFR upward somewhat without change in the slope of the ascending limb, whereas dobutamine prevented the descending limb of the FFR. Similar responses were observed in the relations between heart rate and cardiac output.
A new model of heart failure in the conscious rabbit was developed using rapid atrial pacing and applied to study force-frequency effects. In heart failure, normal beta-adrenergic amplification of the ascending limb of the FFR by dobutamine was absent, but a marked descending limb of the FFR at higher heart rates was prevented by dobutamine. Observed reductions in components of the beta-adrenergic receptor system likely were responsible for impaired beta-adrenergic FFR amplification, but the mechanism(s) for the descending limb and its correction by dobutamine are not yet established. These responses of the FFR may influence importantly the ability of the failing heart to respond to exercise and stress.
最近的实验证明了β-肾上腺素能调节正常和衰竭心脏中力-频率关系（FFR）的重要性。与在分离的人心肌中一样，完整兔心脏在高频时会出现FFR的下降支，因此在兔中建立了一种新的心房起搏诱导心力衰竭模型。然后在诱导心力衰竭前后的清醒状态下评估FFR对β-肾上腺素能刺激的反应。
在植入仪器的兔中平均快速心房起搏19.5天，导致严重的左心室扩张，心输出量降低（超声心动图），心肌收缩性和舒张速率降低（左心室dP/dt，导管尖端微测压计），同时伴有β-肾上腺素能受体密度和腺苷酸环化酶活性降低。在心力衰竭前，使用窦房结抑制剂（扎替雷定）使清醒动物的心率从280±30（标准差）减慢至约225次/分钟，然后通过心房起搏将心率逐步从250次/分钟增加至450次/分钟；心率与左心室dP/dtmax（FFR）反应显示出上升反应（收缩性增加），在心率大于375次/分钟时有一个下降支，多巴酚丁胺输注增强了FFR的上升支（斜率增加）并减弱了下降支。在心力衰竭时，基础FFR严重降低，在心率超过350次/分钟时有一个下降支；多巴酚丁胺使FFR略有上移，上升支斜率无变化，而多巴酚丁胺阻止了FFR的下降支。在心率与心输出量的关系中也观察到了类似的反应。
使用快速心房起搏建立了清醒兔心力衰竭的新模型，并应用于研究力-频率效应。在心力衰竭时，多巴酚丁胺对FFR上升支的正常β-肾上腺素能增强作用消失，但多巴酚丁胺阻止了较高心率时FFR明显的下降支。观察到的β-肾上腺素能受体系统成分的减少可能是β-肾上腺素能FFR增强受损的原因，但下降支及其被多巴酚丁胺纠正的机制尚未明确。FFR的这些反应可能对衰竭心脏对运动和应激的反应能力产生重要影响。
