Thourani V H, Nakamura M, Ronson R S, Jordan J E, Zhao Z Q, Levy J H, Szlam F, Guyton R A, Vinten-Johansen J
Division of Cardiothoracic Surgery, Department of Surgery, Crawford Long Hospital, Atlanta, Georgia 30365-2225, USA.
Am J Physiol. 1999 Jul;277(1):H228-35. doi: 10.1152/ajpheart.1999.277.1.H228.
We tested the hypothesis that selective adenosine A(3)-receptor stimulation reduces postischemic contractile dysfunction through activation of ATP-sensitive potassium (K(ATP)) channels. Isolated, buffer-perfused rat hearts (n = 8/group) were not drug pretreated (control) or were pretreated with adenosine (20 microM), 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; A(3) agonist, 100 nM), Cl-IB-MECA + 8-(3-noradamantyl)-1,3-dipropylxanthine (KW-3902; A(1) antagonist, 5 microM), Cl-IB-MECA + glibenclamide (Glib; K(ATP)-channel blocker, 0. 3 microM), or Glib alone for 12 min before 30 min of global normothermic ischemia followed by 2 h of reperfusion. After 2 h of reperfusion, left ventricular developed pressure (LVDP, %baseline) in control hearts was depressed to 34 +/- 2%. In hearts pretreated with Cl-IB-MECA, there was a statistically significant increase in LVDP (50 +/- 6%), which was reversed with coadministration of Glib (37 +/- 1%). Control hearts also showed similar decreases in left ventricular peak positive rate of change in pressure (dP/dt). Therefore, the A(3) agonist significantly attenuated postischemic cardiodynamic injury compared with the control, which was reversed by Glib. Cumulative creatine kinase (CK in U/min) activity was most pronounced in the control group (10.4 +/- 0.6) and was significantly decreased by Cl-IB-MECA (7.5 +/- 0.4), which was reversed by coadministration of Glib (9.4 +/- 0.2). Coronary flow was increased during adenosine infusion (160% of baseline) but not during Cl-IB-MECA infusion. Effects of Cl-IB-MECA were not reversed by the specific A(1) antagonist KW-3902. We conclude that cardioprotection afforded by A(3)-receptor stimulation may be mediated in part by K(ATP) channels. Cl-IB-MECA may be an effective pretreatment agent that attenuates postischemic cardiodynamic dysfunction and CK release without the vasodilator liability of other adenosine agonists.
选择性腺苷A(3)受体刺激通过激活ATP敏感性钾（K(ATP)）通道来减轻缺血后收缩功能障碍。将离体的、用缓冲液灌注的大鼠心脏（每组n = 8）不进行药物预处理（对照组），或用腺苷（20微摩尔）、2-氯-N(6)-(3-碘苄基)-腺苷-5'-N-甲基脲苷（Cl-IB-MECA；A(3)激动剂，100纳摩尔）、Cl-IB-MECA + 8-(3-去甲金刚烷基)-1,3-二丙基黄嘌呤（KW-3902；A(1)拮抗剂，5微摩尔）、Cl-IB-MECA + 格列本脲（Glib；K(ATP)通道阻滞剂，0.3微摩尔）或单独使用Glib进行预处理12分钟，然后进行30分钟的整体常温缺血，随后再灌注2小时。再灌注2小时后，对照组心脏的左心室舒张末压（LVDP，相对于基线的百分比）降至34±2%。在用Cl-IB-MECA预处理的心脏中，LVDP有统计学显著升高（50±6%），而与Glib共同给药后则逆转（37±1%）。对照组心脏的左心室压力峰值正变化率（dP/dt）也有类似下降。因此，与对照组相比，A(3)激动剂显著减轻了缺血后心脏动力学损伤，而Glib可逆转这种损伤。累积肌酸激酶（CK，单位为U/分钟）活性在对照组中最为明显（10.4±0.6），而Cl-IB-MECA使其显著降低（7.5±0.4），与Glib共同给药后则逆转（9.4±0.2）。腺苷输注期间冠状动脉血流量增加（为基线的160%），但Cl-IB-MECA输注期间未增加。Cl-IB-MECA的作用未被特异性A(1)拮抗剂KW-3902逆转。我们得出结论，A(3)受体刺激所提供的心脏保护作用可能部分由K(ATP)通道介导。Cl-IB-MECA可能是一种有效的预处理药物，可减轻缺血后心脏动力学功能障碍和CK释放，而没有其他腺苷激动剂的血管舒张副作用。
