Dipropionylcysteine ethyl ester compensates for the leakage of citric acid cycle intermediates in the pig heart with ischemia/reperfusion.

Abstract

During post-ischemic reperfusion uncompensated cataplerosis disrupts the proper operation of citric acid cycle and impairs energy production. Conventional anti-oxidative therapy utilizing N-acetylcysteine has limited success in organ reperfusion injury. To synergize an anti-oxidative capacity of cysteine with anaplerotic propionate, we synthesized a novel bi-functional compound, namely N,S-dipropionyl cysteine ethyl ester (DPrNCE). We tested DPrNCE on an anesthetized, open-chest low-flow-ischemia pig model, which was induced by 70%-reduction in LAD coronary artery flow for 1 hour, followed by 1 hour of reperfusion. Animals were either untreated (n=8), or treated with intravenous DPrNCE (1.5 mg/kg−1min−1, n=8) after 30 min. of flow reduction and continued throughout reperfusion. The treated animals had elevated propionate arterial levels and increased myocardial concentrations of succinate, fumarate, and malate, compared to untreated control. No difference was observed between the 2 groups with regards to blood pressure, heart rate, regional wall motion, and total glutathione concentration. In conclusion, an intravenous infusion of DPrNCE safely increases myocardial tissue contents of citric acid cycle intermediates and arterial concentration of propionate without any effect on cardiac mechanical function. Supported by NIH Roadmap Grant R33DK070291, and AHA Grant # 0465221.