Myslivecek J, Trojan S, Tucek S
Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Life Sci. 1996 May 24;58(26):2423-30. doi: 10.1016/0024-3205(96)00246-9.
Chronic treatment with organophosphate inhibitors of cholinesterases is known to bring about down-regulation of muscarinic acetylcholine receptors in the heart while its effect on the functionally antagonistic beta-adrenergic receptors is not known. We describe experiments in which rats were exposed to daily injections of diisopropylflurophosphate (DFP) and the density of muscarinic and beta-adrenergic binding sites in their cardiac atria was measured according to the binding of (3H)quinuclidinyl benzilate ((3H)QNB) and (-)-4-(3-tert-butylamino-2-hydroxy)-propoxy-(5,7-3H) benzimidazol-2-one ((3H)CGP 12177) as subtype non-specific muscarinic and beta-adrenergic ligands, respectively. Biphasic course of changes was discovered with both ligands. With the dosage scheme applied, the density of beta-adrenoceptors was augmented 24 h after the first dose of DFP and decreased to about one half of control values after 5 days of treatment with DFP. The density of muscarinic receptors was augmented after two days of treatment with DFP and decreased to about one half of control values after 5 days of treatment. Comparatively small changes in the heart rate were observed during the treatment, they reflected changes in the muscarinic and beta-adrenergic receptor density. The finding of DFP-induced changes in the binding of (3H)CGP 12177 suggests that the mechanisms responsible for the control of the density of muscarinic and beta-adrenergic receptors in the heart cells are interconnected but potential roles of other factors involved in in vivo experiments deserve further analysis. The transient increase in the density of muscarinic receptors after two days of DFP treatment appears related to published data on transient stimulation by cholinergic agonists of the transcription of mRNAs for muscarinic receptors.
已知用有机磷酸酯类胆碱酯酶抑制剂进行长期治疗会导致心脏中毒蕈碱型乙酰胆碱受体下调，而其对功能上起拮抗作用的β-肾上腺素能受体的影响尚不清楚。我们描述了一些实验，其中给大鼠每日注射二异丙基氟磷酸酯（DFP），并根据（3H）喹核醇基苯甲酸酯（（3H）QNB）和（-）-4-（3-叔丁基氨基-2-羟基）-丙氧基-（5,7-3H）苯并咪唑-2-酮（（3H）CGP 12177）的结合情况，分别作为亚型非特异性毒蕈碱型和β-肾上腺素能配体，来测量其心房中毒蕈碱型和β-肾上腺素能结合位点的密度。两种配体都发现了双相变化过程。按照所应用的给药方案，在首次注射DFP后24小时，β-肾上腺素能受体密度增加，在用DFP治疗5天后降至对照值的约一半。在用DFP治疗两天后，毒蕈碱型受体密度增加，治疗5天后降至对照值的约一半。在治疗期间观察到心率变化相对较小，它们反映了毒蕈碱型和β-肾上腺素能受体密度的变化。DFP诱导（3H）CGP 12177结合变化的这一发现表明，负责控制心脏细胞中毒蕈碱型和β-肾上腺素能受体密度的机制是相互关联的，但体内实验中涉及的其他因素的潜在作用值得进一步分析。DFP治疗两天后毒蕈碱型受体密度的短暂增加似乎与胆碱能激动剂对毒蕈碱型受体mRNA转录的短暂刺激的已发表数据有关。
