Salinas Cristian, Muzic Raymond F, Berridge Marc, Ernsberger Paul
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106-5056, USA.
J Cardiovasc Pharmacol. 2005 Aug;46(2):222-31. doi: 10.1097/01.fjc.0000171754.51187.a6.
beta-Adrenergic receptor (beta-AR) concentration can be measured in vivo using positron emission tomography (PET) and the high-affinity antagonist [18F]-(S)-fluorocarazolol {[18F]-(S)-FCZ}. However, the influence of endogenous catecholamines on the in vivo binding properties of [18F]-(S)-FCZ should be measured to aid in selection of the model used to estimate receptor concentration based on PET data. Herein we addressed the questions "What is the influence of endogenous catecholamines on the [18F]-(S)-FCZ binding in the heart?" and "In what range are the in vivo concentrations of endogenous beta-AR ligands?" In PET studies, 3 drug regimens were used to manipulate the levels of endogenous catecholamines. The time courses of myocardial concentration of [18F]-(S)-FCZ were compared before and after drug administration. In vitro binding assays and computer simulations were performed to complement the in vivo studies. Despite the large changes of endogenous catecholamines, no significant changes were observed in the [18F]-(S)-FCZ myocardial concentration. In vitro assays showed that (S)-FCZ has an affinity for beta-receptors that is 3900 and 9500 times higher than those of norepinephrine (NE) and epinephrine (EPI), respectively. Computer simulations support the hypothesis that the binding affinities relative to ligand concentrations in vivo are sufficient to explain the apparent lack of effect of endogenous catecholamines on [18F]-(S)-FCZ myocardial concentration. Increased levels of catecholamines in the physiological range do not affect the myocardial concentration of [18F]-(S)-FCZ as measured by PET. This lack of effect suggests that the myocardial concentration of NE at the synaptic sites cannot be higher than 300 nM.
β-肾上腺素能受体（β-AR）浓度可通过正电子发射断层扫描（PET）和高亲和力拮抗剂[18F]-(S)-氟卡拉洛尔{[18F]-(S)-FCZ}在体内进行测量。然而，应测量内源性儿茶酚胺对[18F]-(S)-FCZ体内结合特性的影响，以辅助选择基于PET数据估计受体浓度的模型。在此，我们探讨了“内源性儿茶酚胺对心脏中[18F]-(S)-FCZ结合有何影响？”以及“内源性β-AR配体的体内浓度范围是多少？”这两个问题。在PET研究中，使用了3种药物方案来控制内源性儿茶酚胺的水平。比较了给药前后心肌中[18F]-(S)-FCZ浓度的时间进程。进行了体外结合试验和计算机模拟以补充体内研究。尽管内源性儿茶酚胺发生了很大变化，但[18F]-(S)-FCZ心肌浓度未观察到显著变化。体外试验表明，(S)-FCZ对β受体的亲和力分别比去甲肾上腺素（NE）和肾上腺素（EPI）高3900倍和9500倍。计算机模拟支持这样的假设，即相对于体内配体浓度的结合亲和力足以解释内源性儿茶酚胺对[18F]-(S)-FCZ心肌浓度明显缺乏影响的现象。生理范围内儿茶酚胺水平的升高不会影响PET测量的[18F]-(S)-FCZ心肌浓度。这种缺乏影响表明突触部位NE的心肌浓度不能高于300 nM。
