Zhang Qihang, Goel Nishant, Rodriguez Roberto, Scholz Peter M, Weiss Harvey R
Heart and Brain Circulation Laboratory, Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, 08854-5635, USA.
Eur J Pharmacol. 2006 May 10;537(1-3):45-51. doi: 10.1016/j.ejphar.2006.03.030. Epub 2006 Mar 17.
We tested the hypothesis that the negative functional effects of cyclic GMP were mediated by ryanodine receptors, and that these effects would be reduced in thyroxine (thyroxine, 0.5 mg/kg/day, 16 days)-induced hypertrophic myocytes. Using rabbit ventricular myocytes from control (n=9) and thyroxine (n=9) hearts, percent cell shortening (%) and maximum rate of contraction and relaxation were determined using a video edge detector at baseline and after 10(-6), 10(-5) M 8-bromo-cyclic GMP. Dantrolene 10(-6) M, ryanodine receptor inhibitor, was added alone or after 8-Br-cGMP treatment. Changes in cytosolic Ca(2+) concentration were assessed in fura-2-loaded control and thyroxine myocytes. 8-Br-cGMP caused a significant decrease in percent shortening, from 5.3+/-0.9% to 3.9+/-0.6% at 10(-5 )M in control, and 3.4+/-0.3% to 2.6+/-0.4% in thyroxine myocytes. Dantrolene significantly decreased percent shortening from 4.5+/-0.8% to 3.7+/-0.1% in control and from 3.7+/-0.1% to 2.8+/-0.3% in thyroxine myocytes. In 8-Br-cGMP treated control myocytes, dantrolene did not significantly change myocyte contractility, which suggested that cyclic GMP acted on ryanodine receptors. However, in 8-Br-cGMP treated thyroxine myocytes, dantrolene further reduced myocyte contractility implying that the interaction of cyclic GMP and ryanodine receptors appeared to be interrupted in thyroxine myocytes. Maximum rate of contraction data were consistent with the percent cell shortening data and Ca(2+) transients changed similarly to myocyte contractility. We conclude that effects of cyclic GMP on myocytes contractility were partially mediated though interaction with ryanodine receptors and the subsequent decrease in cytosolic calcium levels. This interaction was reduced in thyroxine hypertrophic myocytes.
环磷酸鸟苷（cGMP）的负性功能作用是由兰尼碱受体介导的，并且在甲状腺素（甲状腺素，0.5mg/kg/天，16天）诱导的肥大心肌细胞中这些作用会减弱。使用来自对照（n = 9）和甲状腺素处理（n = 9）心脏的兔心室肌细胞，在基线以及给予10(-6)、10(-5)M 8-溴环磷酸鸟苷后，使用视频边缘检测器测定细胞缩短百分比（%）以及最大收缩和舒张速率。单独或在8-溴环磷酸鸟苷处理后加入10(-6)M丹曲林（兰尼碱受体抑制剂）。在负载fura-2的对照和甲状腺素处理的心肌细胞中评估胞质Ca(2+)浓度的变化。10(-5)M的8-溴环磷酸鸟苷使对照细胞的缩短百分比显著降低，从5.3±0.9%降至3.9±0.6%，在甲状腺素处理的心肌细胞中从3.4±0.3%降至2.6±0.4%。丹曲林使对照细胞的缩短百分比从4.5±0.8%显著降至3.7±0.1%，在甲状腺素处理的心肌细胞中从3.7±0.1%降至2.8±0.3%。在8-溴环磷酸鸟苷处理的对照心肌细胞中，丹曲林未显著改变心肌收缩力，这表明环磷酸鸟苷作用于兰尼碱受体。然而，在8-溴环磷酸鸟苷处理的甲状腺素心肌细胞中，丹曲林进一步降低了心肌收缩力，这意味着在甲状腺素心肌细胞中环磷酸鸟苷与兰尼碱受体的相互作用似乎被中断。最大收缩速率数据与细胞缩短百分比数据一致，并且Ca(2+)瞬变与心肌收缩力的变化相似。我们得出结论，环磷酸鸟苷对心肌收缩力的影响部分是通过与兰尼碱受体相互作用以及随后胞质钙水平降低介导的。在甲状腺素肥大心肌细胞中这种相互作用减弱。
