Dennis D M, Raatikainen M J, Martens J R, Belardinelli L
Department of Anesthesiology, University of Florida, Gainesville 32610, USA.
Circulation. 1996 Nov 15;94(10):2551-9. doi: 10.1161/01.cir.94.10.2551.
There has been increasing interest in the development of agents that utilize endogenous adenosine to exert their actions. We tested the hypothesis that substances that either potentiate the activity (allosteric enhancers) or increase the interstitial concentration (inhibitors of metabolism) of endogenous adenosine may cause event (tachycardia)-specific depression of AV nodal conduction.
The frequency-dependent effects of iodotubercidin (ITU, an inhibitor of adenosine kinase), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, an inhibitor of adenosine deaminase), draflazine (a nucleoside transport blocker), and PD81,723 (an allosteric enhancer of the A1 adenosine receptor binding) on the stimulus-to-His bundle (SH) interval, a measure of AV nodal conduction, were determined in guinea pig hearts and compared with those of adenosine and diltiazem. All drugs depressed AV nodal conduction in a frequency-dependent manner. The ratios of SH interval prolongations at fast to slow pacing rates for draflazine, ITU + EHNA, PD81,723, adenosine, and diltiazem were 17.5 +/- 3.4, 11.1 +/- 5.0, 3.5 +/- 0.9, 10.1 +/- 2.8, and 8.3 +/- 3.5, respectively. Coincident with the prolongation of the SH interval at rapid pacing rates, draflazine and ITU + EHNA increased the epicardial fluid adenosine concentrations by 2.2- and 2.6-fold, respectively. In contrast, epicardial transudate levels of adenosine do not change in the presence of PD81,723. The AV nodal effects of draflazine, ITU, EHNA, and PD81,723 were reversed by the A1 adenosine receptor antagonist 8-cyclopentyltheophylline and adenosine deaminase, implicating endogenous adenosine acting at the A1 adenosine receptor.
Adenosine-regulating agents that act in an event- and site-specific manner represent a novel drug design strategy that may potentially be valuable for the long-term treatment of supraventricular arrhythmias and control of ventricular rate during atrial fibrillation or flutter.
利用内源性腺苷发挥作用的药物开发越来越受到关注。我们检验了以下假设：增强内源性腺苷活性（变构增强剂）或增加其间质浓度（代谢抑制剂）的物质可能导致房室结传导的事件（心动过速）特异性抑制。
在豚鼠心脏中测定了碘结核菌素（ITU，一种腺苷激酶抑制剂）、赤藓红-9-（2-羟基-3-壬基）腺嘌呤（EHNA，一种腺苷脱氨酶抑制剂）、draflazine（一种核苷转运阻滞剂）和PD81,723（A1腺苷受体结合的变构增强剂）对刺激至希氏束（SH）间期（一种房室结传导的测量指标）的频率依赖性影响，并与腺苷和地尔硫䓬的影响进行比较。所有药物均以频率依赖性方式抑制房室结传导。draflazine、ITU + EHNA、PD81,723、腺苷和地尔硫䓬在快速起搏率与慢速起搏率时SH间期延长的比值分别为17.5±3.4、11.1±5.0、3.5±0.9、10.1±2.8和8.3±3.5。与快速起搏率时SH间期延长相一致，draflazine和ITU + EHNA使心外膜液腺苷浓度分别增加了2.2倍和2.6倍。相比之下，在存在PD81,723的情况下，心外膜渗出液中的腺苷水平没有变化。draflazine、ITU、EHNA和PD81,723对房室结的作用被A1腺苷受体拮抗剂8-环戊基茶碱和腺苷脱氨酶逆转，提示内源性腺苷作用于A1腺苷受体。
以事件和部位特异性方式起作用的腺苷调节剂代表了一种新的药物设计策略，这可能对室上性心律失常的长期治疗以及房颤或房扑期间心室率的控制具有潜在价值。
