Riou L, Ghezzi C, Mouton O, Mathieu J P, Pasqualini R, Comet M, Fagret D
Laboratoire d'Etudes des Radiopharmaceutiques, ESA CNRS 5077, Faculté de médecine, Université Joseph Fourier, Grenoble, France.
Circulation. 1998 Dec 8;98(23):2591-7. doi: 10.1161/01.cir.98.23.2591.
Bis[N-ethoxy,N-ethyl(dithiocarbamato)]nitrido Tc (V) (TcN-NOET) is a new technetium complex proposed as a tracer of myocardial perfusion. However, its cellular uptake mechanisms are unknown, although membrane localization on rat heart preparations and preferential binding to polymorphonuclear neutrophils (PMNs) have been reported. Because of the central role of calcium in PMN actions, a relationship was hypothesized between this ion flux and TcN-NOET cellular uptake.
The mechanisms of cellular uptake of TcN-NOET were investigated in newborn rat cardiomyocytes by study of the effect of calcium channel modulators on tracer binding. Nifedipine had no effect on tracer uptake at 1 minute. However, verapamil 0.1 micromol/L and diltiazem 0.5 micromol/L induced a 40% decrease in uptake. Conversely, Bay K 8644 0.25 micromol/L increased TcN-NOET uptake by 73%. Alterations in other membrane ion transports failed to modify tracer uptake, indicating the specificity of the relationship between TcN-NOET uptake and calcium channels. Kinetic studies indicated that cellular net accumulation of the tracer was slow (t1/2=28.5 minutes) and retention was prolonged (84% of initial activity retained after 120 minutes of washout). The energy dependence of TcN-NOET uptake was investigated after 60 minutes of metabolic inhibition by iodoacetic acid plus rotenone. The ATP decrease was not associated with reduction in tracer uptake at 1 minute (114.9+/-21.9% of control, P=NS).
The decrease in uptake observed with verapamil and diltiazem, the increase with Bay K 8644, and the lack of effect with nifedipine suggest that TcN-NOET binds to L-type calcium channels in the open configuration, without entering cardiomyocytes. The kinetics of TcN-NOET accumulation and retention are slow, and the mechanism for cellular uptake is not energy-dependent. From a clinical point of view, the effect of concurrent treatment by calcium inhibitors on myocardial binding of TcN-NOET should be taken into account.
双[N-乙氧基，N-乙基（二硫代氨基甲酸盐）]氮基锝（V）（TcN-NOET）是一种新的锝配合物，被提议作为心肌灌注显像剂。然而，尽管已报道在大鼠心脏制剂上有膜定位以及与多形核中性粒细胞（PMN）的优先结合，但它的细胞摄取机制尚不清楚。由于钙在PMN作用中起核心作用，因此推测这种离子通量与TcN-NOET细胞摄取之间存在关联。
通过研究钙通道调节剂对显像剂结合的影响，在新生大鼠心肌细胞中研究了TcN-NOET的细胞摄取机制。硝苯地平在1分钟时对显像剂摄取无影响。然而，0.1微摩尔/升的维拉帕米和0.5微摩尔/升的地尔硫卓使摄取量降低了40%。相反，0.25微摩尔/升的Bay K 8644使TcN-NOET摄取量增加了73%。其他膜离子转运的改变未能改变显像剂摄取，表明TcN-NOET摄取与钙通道之间关系的特异性。动力学研究表明，显像剂的细胞净积累缓慢（t1/2 = 28.5分钟）且滞留时间延长（洗脱120分钟后仍保留84%的初始活性）。在用碘乙酸加鱼藤酮进行60分钟代谢抑制后，研究了TcN-NOET摄取对能量的依赖性。ATP减少与1分钟时显像剂摄取的减少无关（为对照的114.9±21.9%，P =无显著性差异）。
维拉帕米和地尔硫卓使摄取量降低、Bay K 8644使摄取量增加以及硝苯地平无作用，提示TcN-NOET以开放构型与L型钙通道结合，而不进入心肌细胞。TcN-NOET积累和滞留的动力学缓慢，细胞摄取机制不依赖能量。从临床角度来看，应考虑钙抑制剂联合治疗对TcN-NOET心肌结合的影响。
