CARVEDILOL INHIBITS ACTIVATION OF STRESS-ACTIVATED PROTEIN-KINASE ANDREDUCES REPERFUSION INJURY IN PERFUSED RABBIT HEART

Stress-activated protein kinase (SAPK/JNK) has been implicated in the signaling pathway that leads to cell death. Carvedilol, a new vasodila ting beta-adrenoceptor antagonist with potent antioxidant activity, ha s been shown to convey a high degree of cardioprotection in a variety of experimental models of myocardial ischemia as well as in patients w ith congestive heart failure. The present study was designed to explor e whether the cardioprotective effects of carvedilol involve inhibitio n of SAPK activation. Ex vivo ischemia (30 min)-reperfusion (60-120 mi n) of the rabbit heart resulted in 67% reduction of pressure-rate prod uct, 45% necrosis of left ventricular tissue and 62% loss of myocardia l creatine kinase (P < 0.01 vs. basal). SAPK levels in the perfused he arts increased markedly following reperfusion (5.6-fold increase, P < 0.01 vs. basal). Carvedilol. at 10 mu M, administered at time of reper fusion, enhanced recovery of pressure-rate product by 61%. reduced nec rotic size by 65% and decreased myocardial creatine kinase loss by 62% (P < 0.01 vs. vehicle). Carvedilol also inhibited reperfusion-induced activation of SAPK by 61% (P < 0.01 vs. vehicle). Carvedilol, at 1 mu M, displayed a trend of cardioprotection and inhibition of SAPK activ ation. Our results suggest that SAPK may play a role in ischemia/reper fusion-induced cardiac injury and inhibition of SAPK activation by car vedilol may contribute to its cardioprotective effects. (C) 1998 Elsev ier Science B.V.