Brandts B, Borchard R, Dirkmann D, Wickenbrock I, Sievers B, van Bracht M, Prull M W, Trappe H-J
Department of Cardiology and Angiology, University Hospital Heme, Ruhr-University Bochum, Germany.
Br J Pharmacol. 2003 Aug;139(7):1265-72. doi: 10.1038/sj.bjp.0705361.
(1) Diadenosine polyphosphates have been described to be present in the myocardium and exert purinergic- and nonreceptor-mediated effects. Since the electrophysiological properties of atrial myocardium are effectively regulated by A(1) receptors, we investigated the effect of diadenosine pentaphosphate (Ap(5)A) in rabbit myocardium. (2) Parameters of supraventricular electrophysiology and atrial vulnerability were measured in Langendorff-perfused rabbit hearts. Muscarinic potassium current (I(K(ACh/Ado))) and ATP-sensitive potassium current (I(K(ATP))) were measured by using the whole-cell voltage clamp method. (3) Ap(5)A prolonged the cycle length of spontaneously beating Langendorff perfused hearts from 225+/-14 (control) to 1823+/-400 ms (Ap(5)A 50 micro M; n=6; P<0.05). This effect was paralleled by higher degree of atrio-ventricular block. Atrial effective refractory period (AERP) in control hearts was 84+/-14 ms (n=6). Ap(5)A>/=1 micro M reduced AERP (100 micro M, 58+/-11 ms; n=6). (4) Extrastimuli delivered to hearts perfused with Ap(5)A- or adenosine (>/= micro M)-induced atrial fibrillation, the incidence of which correlated to the concentration added to the perfusate. The selective A(1)-receptor antagonist CPX (20 micro M) inhibited the Ap(5)A- and adenosine-induced decrease of AERP. Atrial fibrillation was no longer observed in the presence of CPX. (5) The described Ap(5)A-induced effects in the multicellular preparation were enhanced by dipyridamole (10 micro M), which is a cellular adenosine uptake inhibitor. Dipyridamole-induced enhancement was inhibited by CPX. (6) Ap(5)A (</=1 mM) did neither induce I(K(Ado)) nor I(K(ATP)). No effect on activated I(K(Ado/ATP)) was observed in myocytes superfused with Ap(5)A. However, effluents from Langendorff hearts perfused with Ap(5)A 100 micro M activated I(K(Ado)) by using A(1) receptors. (7) Ap(5)A did not activate A(1) receptors in rabbit atrial myocytes. The Ap(5)A induced A(1)-receptor-mediated effects on supraventricular electrophysiology and vulnerability suggest that in the multicellular preparation Ap(5)A is hydrolyzed to yield adenosine, which acts via A(1) receptors. An influence on atrial electrophysiology or a facilitation of atrial fibrillation under conditions resulting in increased interstitial Ap(5)A concentrations might be of physiological/pathophysiological relevance.
（1）已有人描述多磷酸二腺苷存在于心肌中，并发挥嘌呤能和非受体介导的作用。由于心房肌的电生理特性受A（1）受体有效调节，我们研究了五磷酸二腺苷（Ap（5）A）对兔心肌的影响。（2）在Langendorff灌注的兔心脏中测量室上性电生理参数和心房易损性。采用全细胞膜片钳法测量毒蕈碱钾电流（I（K（ACh/Ado）））和ATP敏感性钾电流（I（K（ATP）））。（3）Ap（5）A使Langendorff灌注心脏的自发搏动周期长度从225±14（对照）延长至1823±400毫秒（Ap（5）A 50微摩尔；n = 6；P<0.05）。这种作用伴随着更高程度的房室传导阻滞。对照心脏的心房有效不应期（AERP）为84±14毫秒（n = 6）。Ap（5）A≥1微摩尔可缩短AERP（100微摩尔时为58±11毫秒；n = 6）。（4）向灌注有Ap（5）A或腺苷（≥微摩尔）的心脏施加额外刺激可诱发心房颤动，其发生率与灌注液中添加的浓度相关。选择性A（1）受体拮抗剂CPX（20微摩尔）可抑制Ap（5）A和腺苷诱导的AERP降低。在存在CPX的情况下不再观察到心房颤动。（5）双嘧达莫（10微摩尔）增强了多细胞制剂中所述的Ap（5）A诱导的作用，双嘧达莫是一种细胞腺苷摄取抑制剂。双嘧达莫诱导的增强作用被CPX抑制。（6）Ap（5）A（≤1毫摩尔）既不诱导I（K（Ado））也不诱导I（K（ATP））。在灌流有Ap（5）A的心肌细胞中未观察到对激活的I（K（Ado/ATP））有影响。然而，用100微摩尔Ap（5）A灌注的Langendorff心脏流出液通过A（1）受体激活I（K（Ado））。（7）Ap（5）A在兔心房肌细胞中不激活A（1）受体。Ap（5）A诱导的对室上性电生理和易损性的A（1）受体介导作用表明，在多细胞制剂中Ap（5）A被水解产生腺苷，腺苷通过A（1）受体起作用。在导致间质Ap（5）A浓度升高的情况下，对心房电生理的影响或对心房颤动的促进作用可能具有生理/病理生理相关性。
