Bavendiek U, Brixius K, Münch G, Zobel C, Müller-Ehmsen J, Schwinger R H
Universität zu Köln, Medizinische Klinik III, Germany.
Basic Res Cardiol. 1998;93 Suppl 1:76-85. doi: 10.1007/s003950050224.
In severe human heart failure, an increase in frequency of stimulations is accompanied by a reduced force of contraction in vivo and in vitro. This contrasts the findings in nonfailing human hearts. To investigate influences of inotropic stimulation on the force-frequency relationship in human myocardium, the effects of the cAMP-independent positive inotropic agents ouabain (Na+/K(+)-ATPase inhibitor) and BDF 9148 (Na(+)-channel modulator) as well as of the beta-adrenoceptor agonist isoprenaline on the force-frequency relationship in electrically driven left ventricular papillary muscle strips from nonfailing and terminally failing human myocardium were studied. In nonfailing myocardium, force of contraction increased following an increase in stimulation frequency, whereas in failing human myocardium force of contraction gradually declined following an increase in stimulation frequency. Moderate stimulation of contractility by isoprenaline reversed the negative force-frequency relationship in failing myocardium and preserved the positive force-frequency relationship in nonfailing myocardium. In the presence of ouabain and BDF 9148 the positive force-frequency relationship was completely restored in failing myocardium. In contrast, in the presence of high concentrations of isoprenaline the former positive force-frequency relationship became negative even in nonfailing myocardium. The negative force-frequency relationship in failing human myocardium is accompanied by alterations in the intracellular Ca(2+)-homeostasis. The latter may be due to an impaired function of the sarcoplasmic reticulum (SR) in failing human myocardium. Therefore, the activity of the SR-Ca(2+)-ATPase (SERCA2) of crude membrane preparations was investigated and was significantly reduced in failing compared to nonfailing human myocardium. It is concluded that the negative force-frequency relationship may be due to alterations in the intracellular Ca(2+)-handling caused by an impaired function of the SERCA2 in failing human myocardium. The beneficial effects of cAMP-increasing agents on the force-frequency relationship in failing human hearts could result from an enhanced phosphorylation status of phospholamban in the presence of beta-adrenoceptor-stimulation. The effect of the [Na+]i-modulating agents BDF 9148 and ouabain demonstrates that the intracellular Na(+)-homeostasis influences intracellular Ca(2+)-handling as well. Differences observed in failing compared to nonfailing myocardium may be due to an altered expression or function of the Na+/Ca(2+)-exchanger, Na(+)-channels or the Na+/K(+)-ATPase in addition to the blunted activity of the SERCA2 in failing myocardium.
在严重的人类心力衰竭中，体内和体外刺激频率增加时，收缩力会降低。这与非衰竭人类心脏的研究结果形成对比。为了研究变力刺激对人类心肌力-频率关系的影响，我们研究了不依赖环磷酸腺苷（cAMP）的正性肌力药物哇巴因（钠钾ATP酶抑制剂）和BDF 9148（钠通道调节剂）以及β-肾上腺素能受体激动剂异丙肾上腺素对来自非衰竭和终末期衰竭人类心肌的电驱动左心室乳头肌条带力-频率关系的影响。在非衰竭心肌中，刺激频率增加时收缩力增强，而在衰竭人类心肌中，刺激频率增加时收缩力逐渐下降。异丙肾上腺素适度刺激收缩力可逆转衰竭心肌中的负性力-频率关系，并维持非衰竭心肌中的正性力-频率关系。在哇巴因和BDF 9148存在的情况下，衰竭心肌中的正性力-频率关系完全恢复。相反，在高浓度异丙肾上腺素存在的情况下，即使在非衰竭心肌中，先前的正性力-频率关系也会变为负性。衰竭人类心肌中的负性力-频率关系伴随着细胞内钙稳态的改变。后者可能是由于衰竭人类心肌中肌浆网（SR）功能受损所致。因此，我们研究了粗膜制剂中SR-钙ATP酶（SERCA2）的活性，发现与非衰竭人类心肌相比，衰竭心肌中的该活性显著降低。得出的结论是，负性力-频率关系可能是由于衰竭人类心肌中SERCA2功能受损导致细胞内钙处理改变所致。增加cAMP的药物对衰竭人类心脏力-频率关系的有益作用可能源于在β-肾上腺素能受体刺激存在的情况下受磷蛋白磷酸化状态增强。[Na⁺]i调节剂BDF 9148和哇巴因的作用表明，细胞内钠稳态也会影响细胞内钙处理。与非衰竭心肌相比，在衰竭心肌中观察到的差异可能是由于钠钙交换体、钠通道或钠钾ATP酶的表达或功能改变，以及衰竭心肌中SERCA2活性减弱所致。
