P656Inhibition of hydrogen sulfide formation from L-cysteine provides cardioprotection against ischemia-reperfusion injury

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Purpose: Hydrogen sulfide (H2S) is endogenously generated from L-cysteine by cystathionine-gamma-lyase (CSE). H2S donors demonstrate cardioprotective properties, however, role of endogenous H2S is not revealed. We hypothesized that exogenous L-cysteine may stimulate H2S synthesis and mediate cardioprotection. At the same time L-cysteine might be engaged in gluthatione production. Thus, the aim of the present study was to investigate the modulation of H2S synthesis from L-cysteine in heart ischemia-reperfusion (I/R) model.

Methods: 6-month old Wistar rats were randomly assigned to one of the following groups: 1) the control (n=6); 2) L-cysteine (121 mg/kg) (n=6); 3) PAG (11.3 mg/kg)+L-cysteine (n=5); 4) PAG (n=4); 5) PAG+BSO (DL-buthionine-sulfoximine, 22.2 mg/kg)+L-cysteine (n=9). All chemicals were injected intraperitonealy. Hearts were perfused by Langendorff preparation and underwent I/R protocol (20min/40min). Left ventricle developed pressure (LVDP) and dP/dt were registered. The effectiveness of oxygen utilization by myocardium was evaluated by oxygen cost of myocardial work (OCMW) expressed as the ratio of the oxygen consumption and the heart work (the product of the LVDP and the heart rate). For analysis of heart function recovery after I/R Mann-Whitney U-test was used. P values less than 0.05 were considered to be significant.

Results: L-cysteine along, as well as PAG, did not significantly improved heart function recovery after I/R and only tendency to increase of LVDP and dP/dt was observed. However, post-ischemic myocardial contraction was lower: hearts demonstrated improved cardiac relaxation as significantly lower end diastolic pressure values during all reperfusion period in both PAG- and L-cysteine-pretreated groups. Nevertheless, the dynamic of OCMW repeated the values of control group indicating non-effective oxygen utilization by myocardium. On the contrary, combined administration of PAG and L-cysteine provided more than 90% recovery of LVDP and dP/dt during all reperfusion period (p<0.005). Other parameters showed the same pattern of recovery including OCMW which at 10th min of reperfusion averaged only 134% comparing to 239% in control (p<0.028). Pre-treatment with BSO completely abolished carioprotective effect of PAG+L-cysteine treatment and the studied parameters repeated the values of the control group.

Conclusions. Our data demonstrate that L-cysteine in combination with PAG protects hearts from I/R injury and prevents non-effective oxygen utilization by ischemic myocardium. Observed cardioprotective effect is vastly depended on glutathione pathway of L-cysteine metabolism.

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