Adenosine A(3)-receptor stimulation attenuates postischemic dysfunction through K(ATP) channels.

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.

Duke Scholars

Author Jerrold Henry Levy Anesthesiology, Cardiothoracic