Pieske B, Trost S, Schütt K, Minami K, Just H, Hasenfuss G
Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Germany.
Basic Res Cardiol. 1998;93 Suppl 1:66-75. doi: 10.1007/s003950050222.
End-stage failing human myocardium is characterized by a negative force-frequency relationship (FFR), possibly as a result of reduced SR Ca2+ uptake capacity. We investigated the effects of the direct adenylate cyclase stimulator, forskolin, on force of contraction and FFR in isolated human myocardium from 7 nonfailing hearts (NF) and end-stage failing hearts (NYHA IV) due to either ischemic (ICM; n = 13) or dilated cardiomyopathy (DCM; n = 16).
Isolated left ventricular muscle strips, isometric contraction, electrical stimulation at a basal stimulation rate of 1 Hz (37 degrees C). Inotropic responses: Cumulative concentration-response curves for forskolin (0.01-10 microM) and for Ca2+ (2.5-15 mM). Force-frequency experiments: stepwise increase in stimulation rate from 0.5 to 3.0 Hz without and in the presence of 0.3, 1.0 or 3.0 microM forskolin.
Forskolin concentration-dependently increased force of contraction to 386 +/- 28% (n = 5) in NF, to 256 +/- 48% (n = 7) in ICM, and to 212 +/- 13% (n = 14) in DCM. The effectiveness of forskolin was significantly reduced in failing myocardium. Ca2+ increased force of contraction to maximally 438 +/- 108% in NF, to 267 +/- 15% in ICM, and to 292 +/- 20% in DCM. Again, the effectiveness of Ca2+ was significantly reduced in failing myocardium. Forskolin activated contractile reserve to similar extents in all types of myocardium (90%, 95%, and 82%, respectively). Force of contraction continuously increased with increasing stimulation rates in nonfailing myocardium (positive FFR), but was blunted or inversed in ICM and DCM. Prestimulation with forskolin (0.3 microM) further enhanced frequency-potentiation in nonfailing, and normalized the slope and optimum stimulation frequency in ICM and DCM. However, at higher concentrations of forskolin, FFR was blunted or inversed in non-failing myocardium, and further impaired in failing myocardium.
Low concentrations of forskolin with only marginal inotropic effects may partially normalize the inverse force-frequency relation in end-stage failing human myocardium. Reduced cAMP levels in conjunction with reduced expression of SR Ca2+ ATPase may be the underlying cause for altered excitation-contraction coupling in diseased human hearts.
终末期衰竭的人心肌的特征是负力-频率关系（FFR），这可能是由于肌浆网Ca2+摄取能力降低所致。我们研究了直接腺苷酸环化酶刺激剂福斯高林对来自7个非衰竭心脏（NF）以及因缺血性心肌病（ICM；n = 13）或扩张型心肌病（DCM；n = 16）导致的终末期衰竭心脏（纽约心脏协会IV级）的离体人心肌收缩力和FFR的影响。
离体左心室肌条，等长收缩，在37℃以1Hz的基础刺激频率进行电刺激。变力反应：福斯高林（0.01 - 10μM）和Ca2+（2.5 - 15mM）的累积浓度-反应曲线。力-频率实验：在无和有0.3、1.0或3.0μM福斯高林存在的情况下，刺激频率从0.5逐步增加到3.0Hz。
福斯高林浓度依赖性地增加收缩力，在NF中增加到386±28%（n = 5），在ICM中增加到256±48%（n = 7），在DCM中增加到212±13%（n = 14）。福斯高林在衰竭心肌中的有效性显著降低。Ca2+使收缩力最大增加到NF中的438±108%，ICM中的267±15%，DCM中的292±20%。同样，Ca2+在衰竭心肌中的有效性也显著降低。福斯高林在所有类型的心肌中激活收缩储备的程度相似（分别为90%、95%和82%）。在非衰竭心肌中，收缩力随刺激频率增加而持续增加（正FFR），但在ICM和DCM中减弱或反转。用福斯高林（0.3μM）预刺激进一步增强了非衰竭心肌中的频率增强作用，并使ICM和DCM中的斜率和最佳刺激频率正常化。然而，在较高浓度的福斯高林作用下，非衰竭心肌中的FFR减弱或反转，而衰竭心肌中的FFR进一步受损。
低浓度的福斯高林仅具有轻微的变力作用，可能部分使终末期衰竭的人心肌中反向的力-频率关系正常化。环磷酸腺苷（cAMP）水平降低以及肌浆网Ca2+ATP酶表达减少可能是患病人类心脏中兴奋-收缩偶联改变的潜在原因。
