USE OF CHLORIDE BLOCKERS - A NOVEL-APPROACH FOR CARDIOPROTECTION AGAINST ISCHEMIA-REPERFUSION DAMAGE

We examined whether the chloride channel blockers anthracene-9-carboxy lic acid (9-AC) and cetamide-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) exert protective effects against myocardial ischemia-repe rfusion damage. In isolated guinea pig ventricular cells, 9-AC (200 mu M), but not SITS (100 mu M), inhibited the chloride current induced b y isoproterenol. Electrical and mechanical activities and intracellula r pH of arterially perfused guinea pig right ventricular preparations were recorded with an intracellular microelectrode, a force transducer and a pH-sensitive fluorescent probe, respectively. The preparations were subjected to 30 min of no-flow ischemia, with or without 9-AC (10 0 mu M) or SITS (10 mu M), followed by reperfusion. No-flow ischemia p roduced decreases in action potential amplitude and duration, and the contractile force was completely abolished. Although the changes in el ectrical parameters were reversed upon reperfusion, the contractile fo rce recovered only to about 50% of preischemic values. 9-AC and SITS h ad no inhibitory effect on contractile force under normal conditions a nd during ischemia but significantly improved the recovery of contract ile force upon reperfusion to about 80% of preischemic values. Both 9- AC and SITS showed significant inhibition of the ischemia-induced abbr eviation of action potential duration. Other parameters were not affec ted by 9-AC or SITS. During ischemia, intracellular pH showed a transi ent small increase followed by a sustained decrease, which was complet ely recovered upon reperfusion. The decrease in pH during ischemia was attenuated by 80% in SITS-but not 9-AC-treated preparations. Thus, we demonstrated that the chloride channel blockers 9-AC and SITS, which have no cardiosuppressive effects, exert protective effects against my ocardial ischemia-reperfusion damage.