Desipramine Pretreatment Prevents Loss of Metabolic Efficiency in Ischemia Reperfusion

Background: Desipramine prevents uncoupling and redistribution of gap-junctions. It also improves recovery in the ischemic and reperfused heart. However, the effect on substrate use during ischemia and reperfusion has not been investigated. The goal of this study was to access the effects of Desipramine on cardiac metabolism during ischemia and reperfusion.

Methods: 20 Sprague-Dawley rat hearts were perfused as isolated working hearts. The hearts were perfused for 20 minutes, subjected to 15 minutes of global ischemia and then reperfused for 40 minutes. Rats were divided into a control-group, a group with Desipramine addition prior to ischemia and a group with desipramine addition after ischemia. Glucose- and fatty acid-oxidation was measured using ¹⁴C-Glucose and 3H-Oleat as radioactive tracers.

Results: In untreated hearts, ischemia and reperfusion led to an increase in both glucose oxidation (before ischemia: 12.97 ± 6.32 ;after ischemia: 15.81 ± 8.58 µ/min/W) and oleate oxidation (before ischemia: 18.30 ± 1.40 ;after ischemia: 24.82 ± 3.59 µ/min/W). Efficiency in cardiac substrate use was reduced (before ischemia:2.62 ± 0.23; after ischemia: 3.40 ± 0.79 calculated ATP/W). Desipramine reduced cardiac power prior to ischemia (untreated vs. desipramine: 45.05 ± 7.78 vs. 39.50 ± 3.45 W/gdry) and resulted in an increase in glucose oxidation (untreated vs. desipramine: 0.52 ± 0.20 vs. 0.88 ± 0.26 µmol/min). Pretreatment led to reduced glucose oxidation after ischemia (before ischemia: 22.36 ± 6.58; after ischemia: 17.98 ± 4.78 µ/min/W) and prevented the reduction in efficiency of substrate use (before ischemia: 3.03 ± 0.22 ATP/W; after ischemia: 3.09 ± 0.20 ATP/W). In control hearts, ischemia reperfusion led to reduced cardiac power. Cardiac power of pretreated hearts was preserved after ischemia (pretreated: 30.06 ± 5.71 W/gdry). In addition, Desipramine added during reperfusion was not able to prevent reduction in cardiac power (21.89 ± 8.90 W/gdry) and impaired substrate efficacy (4.34 ± 1.46 ATP/W).

Conclusion: Loss of function and reduced substrate efficacy after ischemia reperfusion could be prevented by preischemic application of desipramine. Improved substrate efficacy may be a cause for desipramine's protective effect.