Protection of ischemic hearts perfused with an anion exchange inhibitor, DIDS, is associated with beneficial changes in substrate metabolism

Objective: Metabolic interventions that promote glucose use during ischemia have been shown to protect the myocardium and improve functional recovery on reperfusion. In this study we evaluated if cardioprotection can be accom plished by inhibiting fatty acid uptake, which would be expected to increas e glycolytic metabolism. Methods: Diisothiocyanostilbene sulfonic acid (DID S), commonly used to inhibit Band-3 mediated anion exchanger, and has also been demonstrated to inhibit fatty acid transport in adipocytes, was used t o inhibit fatty acid uptake prior to ischemia. Isolated rat hearts were per fused with buffer containing 5 mM glucose, 70 mU/l insulin, 0.4 MM palmitat e, and 0.4 mM albumin, paced at 300 beats/min, and subjected to 50 min of l ow-flow ischemia followed by 60 min of reperfusion. Results: Ischemic injur y, as assessed by creatine kinase release, was diminished in hearts perfuse d with DIDS (334 +/- 72 in DIDS vs. 565 +/- 314 IU/g dry wt in controls, P <0.04). Increases in LVEDP during ischemia were attenuated (8 +/-3 mmHg in DIDS vs. 15 +/- 18 mmHg in controls, P <0.03) and the % recovery of LV func tion with reperfusion was enhanced in DIDS-treated hearts (78 +/- 10% of ba seline in DIDS vs. 62 +/- 19% of baseline in controls, P <0.04). These bene ficial effects of DIDS were associated with increased glucose metabolism an d ATP content during ischemia and reperfusion. Furthermore, treatment with DIDS lowered the accumulation of long chain acyl carnitines. Conclusions: T his study demonstrates that DIDS protects ischemic myocardium, and is assoc iated with inhibition of fatty acid uptake, improved glucose metabolism, an d enhanced functional recovery on reperfusion. The data presented here sugg est a potential role for therapeutic agents that lower fatty acid uptake as a metabolic adjunct in the treatment of myocardial ischemia. (C) 2001 Else vier Science BY. All rights reserved.