TAN-67, A DELTA(1)-OPIOID RECEPTOR AGONIST, REDUCES INFARCT SIZE VIA ACTIVATION OF G(I O) PROTEINS AND K-ATP CHANNELS/

We have previously shown that delta (delta)-opioid receptors, most not ably delta(1), are involved in the cardioprotective effect of ischemic preconditioning (PC) in rats; however, the mechanism by which delta-o pioid receptor-induced cardioprotection is mediated remains unknown. T herefore, we hypothesized that several of the known mediators of ische mic PC such as the ATP-sensitive potassium (K-ATP) channel and G(i/o) proteins are involved in the cardioprotective effect produced by delta (1)-opioid receptor activation. To address these possibilities, anesth etized, open-chest Wistar rats were randomly assigned to five groups. Control animals were subjected to 30 min of coronary artery occlusion and 2 h of reperfusion. To demonstrate that stimulating delta(1)-opioi d receptors produces cardioprotection, TAN-67, a new selective delta(1 )-agonist, was infused for 15 min before the long occlusion and reperf usion periods. In addition, one group received 7-benzylidenenaltrexone (BNTX), a selective delta(1)-antagonist, before TAN-67. To study the involvement of K-ATP channels or G(i/o) proteins in delta(1)-opioid re ceptor-induced cardioprotection, glibenclamide (Glib), a K-ATP channel antagonist, or pertussis toxin (PTX), an inhibitor of G(i/o) proteins , was administered before TAN-67. Infarct size (IS) as a percentage of the area at risk (IS/AAR) was determined by tetrazolium stain. TAN-67 significantly reduced IS/AAR as compared with control (56 +/- 2 to 27 +/- 5%, n = 5, P < 0.05). The cardioprotective effect of TAN-67 was c ompletely abolished by BNTX, Glib, and PTX (51 +/- 3, 53 +/- 5, and 61 +/- 4%, n = 6 for each group, respectively). These results are the fi rst to suggest that stimulating the delta(1)-opioid receptor elicits a cardioprotective effect that is mediated via G(i/o) proteins and K-AT P channels in the intact rat heart.