Molderings G J, Donecker K, Burian M, Simon W A, Schröder D W, Göthert M
Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany.
J Pharmacol Exp Ther. 1998 Apr;285(1):170-7.
Radioligand binding experiments were carried out to identify and characterize nonadrenoceptor [3H]idazoxan binding sites and [3H](1, 2-di-(2-tolyl)guanidine) binding sites in the rat and human stomach. Furthermore, we examined two selected aspects of their potential functional significance. Binding of [3H]idazoxan (Kd = 11.1 nM and 12.4 nM, respectively) and [3H]DTG (Kd = 932 nM and 242 nM, respectively) to cell membranes from rat and human stomach was rapid, reversible, specific and saturable. In rat stomach, binding of the radioligands was inhibited by imidazolines and by nonimidazoline sigma-site ligands, respectively, at different rank orders of affinity, which suggests the existence of I2-imidazoline binding sites as well as sigma2-sites. In two functional models, the direct effects of I2-site ligands and sigma2-site ligands on gastric smooth muscle and glands were investigated. (1) Cirazoline, clonidine and 4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline (BDF 6143) failed to contract the longitudinal muscle of the rat stomach fundus; BDF 6143 also failed to induce relaxation of this preparation when it was precontracted with 30 mM KCl. (2) Clonidine, idazoxan, BDF 6143, 1, 2-di-(2-tolyl)guanidine, agmatine and (R)-3-(3-hydroxyphenyl)-N-propylpiperidine up to 100 microM did not induce acid secretion from rabbit isolated gastric glands. Our data provide evidence that the rat stomach is endowed with sigma2 sites and I2 binding sites in addition to the previously identified non-I1/non-I2 [3H]clonidine binding sites. Our experiments also offer basic evidence of the existence of I2 and sigma binding sites in the human stomach. Neither the I2 and [3H]clonidine binding sites nor the sigma sites in rat stomach are directly related to a postsynaptic effect on gastric smooth muscle or to acid release from isolated gastric glands.
进行放射性配体结合实验以鉴定和表征大鼠和人胃中的非肾上腺素能受体[3H]咪唑克生结合位点和[3H](1,2 - 二-(2 - 甲苯基)胍)结合位点。此外，我们研究了它们潜在功能意义的两个选定方面。[3H]咪唑克生（Kd分别为11.1 nM和12.4 nM）和[3H]DTG（Kd分别为932 nM和242 nM）与大鼠和人胃细胞膜的结合是快速、可逆、特异性和可饱和的。在大鼠胃中，放射性配体的结合分别被咪唑啉和非咪唑啉σ位点配体以不同的亲和力等级抑制，这表明存在I2 - 咪唑啉结合位点以及σ2位点。在两个功能模型中，研究了I2位点配体和σ2位点配体对胃平滑肌和腺体的直接作用。(1) 西拉唑啉、可乐定和4 - 氯 - 2 - (2 - 咪唑啉 - 2 - 基氨基) - 异吲哚啉（BDF 6143）未能使大鼠胃底纵肌收缩；当用30 mM KCl预收缩该制剂时，BDF 6143也未能诱导其舒张。(2) 高达100 microM的可乐定、咪唑克生、BDF 6143、1,2 - 二-(2 - 甲苯基)胍、胍丁胺和(R) - 3 - (3 - 羟基苯基) - N - 丙基哌啶均未诱导兔离体胃腺分泌酸。我们的数据提供了证据，表明除了先前鉴定的非I1/非I2 [3H]可乐定结合位点外，大鼠胃还具有σ2位点和I2结合位点。我们的实验还为人类胃中存在I2和σ结合位点提供了基本证据。大鼠胃中的I2和[3H]可乐定结合位点以及σ位点均与对胃平滑肌的突触后效应或离体胃腺的酸释放无直接关系。
