Meyer M, Lehnart S, Pieske B, Schlottauer K, Munk S, Holubarsch C, Just H, Hasenfuss G
Medizinische Klinik III Universität Freiburg, FRG.
Basic Res Cardiol. 1996 Jan-Feb;91(1):86-93. doi: 10.1007/BF00788869.
The influence of endothelin 1 on isometrically contracting human atrial muscle strip preparations was investigated under physiological conditions (37 degrees C, 1 Hz, Ca2+ 2.5 mM). Endothelin dose-dependently increased isometric tension from 3 x 10(-10) M to 1 x 10(-7) M. At 1 x 10(-7) M the inotropic effect of endothelin was maximum with isometric tension being increased by 32 +/- 6% (n = 11, p < 0.05). At 1 x 10(-7) M endothelin the positive inotropic effect was preceded by a transient negative inotropic effect with a decline in tension by -5 +/- 1% (n = 11, p < 0.05). Endothelin prolonged time from peak tension to 50% relaxation (RT50) by 29 +/- 5%. With BQ123 a competitive antagonist of the ETA receptor positive inotropic effect and the prolongation of relaxation was significantly reduced and initial negative a inotropic effect was abolished, indicating a ETA receptor mediated effect. Preincubation with phorbolmyristateacetate (10(-5) M) to downregulate proteinkinase C (PKC) eliminated the positive inotropic effect of endothelin. Similarly, N-5,5-dimethylamiloride (10(-5) M) which inhibits Na+/H(+)-exchanger activity, abolished the positive inotropic effect of ET. However, with either PMA or DMA the initial transient negative inotropic effect was still present (-13 +/- 7%, n = 9, p < 0.05 and -3 +/- 1%, n = 6, p < 0.05). Furthermore, both substances did not abolish the prolongation of twitch time parameters observed under endothelin. After preincubation with PMA, endothelin prolonged RT50 by 18 +/- 6% and with DMA by 11 +/- 2%. Using the photoprotein aequorin as an indicator for intracellular calcium concentrations showed that the positive inotropic effect was mainly mediated by an increase of systolic intracellular calcium concentrations. Thus, the present data indicate that the positive inotropic effect of endothelin in human atrial myocardium results from activation of PKC with a subsequent activation of the Na+/H(+)-exchanger. However, the initial negative inotropic effects as well as the prolongation of relaxation seem to result from a different intracellular mechanism of endothelin.
在生理条件（37℃、1Hz、Ca2+ 2.5mM）下，研究了内皮素1对人体心房肌条等长收缩制剂的影响。内皮素在3×10(-10)M至1×10(-7)M剂量范围内呈剂量依赖性增加等长张力。在1×10(-7)M时，内皮素的正性肌力作用最大，等长张力增加32±6%（n = 11，p < 0.05）。在1×10(-7)M内皮素作用下，正性肌力作用之前有短暂的负性肌力作用，张力下降-5±1%（n = 11，p < 0.05）。内皮素使从峰值张力到50%舒张（RT50）的时间延长29±5%。使用ETA受体竞争性拮抗剂BQ123后，正性肌力作用和舒张延长显著降低，初始负性肌力作用消失，表明这是ETA受体介导的效应。用佛波酯肉豆蔻酸酯（10(-5)M）预孵育以下调蛋白激酶C（PKC）可消除内皮素的正性肌力作用。同样，抑制Na+/H(+)交换活性的N-5,5-二甲基amiloride（10(-5)M）也消除了ET的正性肌力作用。然而，使用PMA或DMA时，初始短暂的负性肌力作用仍然存在（-13±7%，n = 9，p < 0.05和-3±1%，n = 6，p < 0.05）。此外，两种物质均未消除在内皮素作用下观察到的收缩时间参数的延长。用PMA预孵育后，内皮素使RT50延长18±6%，用DMA预孵育后延长11±2%。使用光蛋白水母发光蛋白作为细胞内钙浓度的指标表明，正性肌力作用主要由收缩期细胞内钙浓度增加介导。因此，目前的数据表明，内皮素在人心房心肌中的正性肌力作用是由PKC激活并随后激活Na+/H(+)交换器所致。然而，初始负性肌力作用以及舒张延长似乎是由内皮素不同的细胞内机制引起的。
