Zhang Qihang, Davidov Tomer, Weiss Harvey R, Scholz Peter M
Heart and Brain Circulation Laboratory, Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08903-0019, USA.
Pharmacology. 2009;83(4):223-30. doi: 10.1159/000205822. Epub 2009 Mar 4.
The negative functional effects of cyclic GMP are controlled by the sarcoplasmic reticulum calcium-ATPase (SERCA). The effects of cyclic GMP are blunted in cardiac hypertrophy. We tested the hypothesis that the interaction between cyclic GMP and SERCA would be reduced in hypertrophic cardiac myocytes. Myocytes were isolated from 7 control and 7 renal-hypertensive hypertrophic rabbits. Control and hypertrophic myocytes received 8-bromo-cGMP (8-Br-cGMP; 10(-7), 10(-6), 10(-5) mol/l), the SERCA blocker thapsigargin (10(-8) mol/l) followed by 8-Br-cGMP, or the SERCA blocker, cyclopiazonic acid (CPA; 10(-7) mol/l) followed by 8-Br-cGMP. Percent shortening and maximal rate of shortening and relaxation were recorded using a video edge detector. Changes in cytosolic Ca2+ were assessed in fura 2-loaded myocytes. In controls, 8-Br-cGMP caused a significant 36% decrease in percent shortening from 5.8 +/- 0.4 to 3.7 +/- 0.3%. Thapsigargin and CPA did not affect basal control or hypertrophic myocyte function. When 8-Br-cGMP was given following thapsigargin or CPA, the negative effects of 8-Br-cGMP on control myocyte function were reduced. In hypertrophic myocytes, 8-Br-cGMP caused a smaller but significant 17% decrease in percent shortening from 4.7 +/- 0.2 to 3.9 +/- 0.1%. When 8-Br-cGMP was given following thapsigargin or CPA, no significant changes occurred in hypertrophic cell function. Intracellular Ca2+ transients responded in a similar manner to changes in cell function in control and hypertrophic myocytes. These results show that the effects of cyclic GMP were reduced in hypertrophic myocytes, but this was not related to SERCA. In presence of SERCA inhibitors, the responses to cyclic GMP were blunted in hypertrophic as well as control myocytes.
环磷酸鸟苷（cGMP）的负性功能作用由肌浆网钙 - ATP酶（SERCA）控制。cGMP的作用在心肌肥厚时会减弱。我们检验了这样一个假设：在肥厚的心肌细胞中，cGMP与SERCA之间的相互作用会减弱。从7只对照兔和7只肾性高血压肥厚兔中分离出心肌细胞。对照和肥厚的心肌细胞分别接受8 - 溴 - cGMP（8 - Br - cGMP；10⁻⁷、10⁻⁶、10⁻⁵mol/L）、SERCA阻滞剂毒胡萝卜素（10⁻⁸mol/L）后再给予8 - Br - cGMP，或SERCA阻滞剂环匹阿尼酸（CPA；10⁻⁷mol/L）后再给予8 - Br - cGMP。使用视频边缘检测器记录缩短百分比、最大缩短速率和舒张速率。在负载fura 2的心肌细胞中评估胞质Ca²⁺的变化。在对照组中，8 - Br - cGMP使缩短百分比从5.8±0.4显著降低至3.7±0.3%，降低了36%。毒胡萝卜素和CPA不影响基础对照或肥厚心肌细胞功能。当在毒胡萝卜素或CPA后给予8 - Br - cGMP时，8 - Br - cGMP对对照心肌细胞功能的负面影响降低。在肥厚心肌细胞中，8 - Br - cGMP使缩短百分比从4.7±0.2显著降低至3.9±0.1%，降低了17%，幅度较小但仍有显著差异。当在毒胡萝卜素或CPA后给予8 - Br - cGMP时，肥厚细胞功能无显著变化。在对照和肥厚心肌细胞中，细胞内Ca²⁺瞬变对细胞功能变化的反应方式相似。这些结果表明，肥厚心肌细胞中cGMP的作用减弱，但这与SERCA无关。在存在SERCA抑制剂的情况下，肥厚和对照心肌细胞对cGMP的反应均减弱。
