Georget Marie, Mateo Philippe, Vandecasteele Grégoire, Lipskaia Larissa, Defer Nicole, Hanoune Jacques, Hoerter Jacqueline, Lugnier Claire, Fischmeister Rodolphe
Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, Université Paris-Sud, Faculté de Pharmacie, 5, Rue J.-B. Clément, F-92296 Châtenay-Malabry Cedex, France.
FASEB J. 2003 Aug;17(11):1380-91. doi: 10.1096/fj.02-0784com.
Hearts from AC8TG mice develop a higher contractility (LVSP) and larger Ca2+ transients than NTG mice, with (surprisingly) no modification in L-type Ca2+ channel current (ICa,L) (1). In this study, we examined the cardiac response of AC8TG mice to beta-adrenergic and muscarinic agonists and IBMX, a cyclic nucleotide phosphodiesterase (PDE) inhibitor. Stimulation of LVSP and ICa,L by isoprenaline (ISO, 100 nM) was twofold smaller in AC8TG vs. NTG mice. In contrast, IBMX (100 microM) produced a twofold higher stimulation of ICa,L in AC8TG vs. NTG mice. IBMX (10 microM) increased LVSP by 40% in both types of mice, but contraction and relaxation were hastened in AC8TG mice only. Carbachol (10 microM) had no effect on basal contractility in NTG hearts but decreased LVSP by 50% in AC8TG mice. PDE assays demonstrated an increase in cAMP-PDE activity in AC8TG hearts, mainly due to an increase in the hydrolytic activity of PDE4 and PDE1 toward cAMP and a decrease in the activity of PDE1 and PDE2 toward cGMP. We conclude that cardiac expression of AC8 is accompanied by a rearrangement of PDE isoforms, leading to a strong compartmentation of the cAMP signal that shields L-type Ca2+ channels and protects the cardiomyocytes from Ca2+ overload.
与NTG小鼠相比，AC8TG小鼠的心脏具有更高的收缩性（左心室收缩压）和更大的Ca2+瞬变，（令人惊讶的是）L型Ca2+通道电流（ICa,L）没有改变（1）。在本研究中，我们检测了AC8TG小鼠对β-肾上腺素能和毒蕈碱激动剂以及环核苷酸磷酸二酯酶（PDE）抑制剂IBMX的心脏反应。与NTG小鼠相比，异丙肾上腺素（ISO，100 nM）对AC8TG小鼠左心室收缩压和ICa,L的刺激作用小两倍。相反，与NTG小鼠相比，IBMX（100 μM）对AC8TG小鼠ICa,L的刺激作用高两倍。IBMX（10 μM）使两种类型小鼠的左心室收缩压均升高40%，但仅使AC8TG小鼠的收缩和舒张加快。卡巴胆碱（10 μM）对NTG心脏的基础收缩性无影响，但使AC8TG小鼠的左心室收缩压降低50%。PDE分析表明，AC8TG心脏中cAMP-PDE活性增加，主要是由于PDE4和PDE1对cAMP的水解活性增加以及PDE1和PDE2对cGMP的活性降低。我们得出结论，AC8的心脏表达伴随着PDE同工型的重新排列，导致cAMP信号的强烈分隔，从而保护L型Ca2+通道并防止心肌细胞Ca2+过载。
