L-cysteine stimulates hydrogen sulfide synthesis in myocardium associated with attenuation of ischemia-reperfusion injury.
Hydrogen sulfide (H( 2)S) is a biological mediator produced by enzyme-regulated pathways from L-cysteine, which is a substrate for cystathionine-gamma-lyase (CSE). In myocardium, endogenously and exogenously administered H(2)S has been shown to protect against ischemia-reperfusion injury. We hypothesized that L-cysteine exerts its protective action through stimulation of H(2)S production. Rat isolated hearts were Langendorff-perfused and underwent 35-minute regional ischemia and 120-minute reperfusion. L-cysteine perfusion from 10 minutes before ischemia until 10 minutes after reperfusion limited infarct size in a concentration-dependent manner, maximal at 1 mmol/L (control 36.4% +/- 2.4% vs L-cysteine 24.3% +/- 3.4%, P < .05). This protective action was attenuated by the CSE inhibitor, DL-propargylglycine (PAG) 1 mmol/L (31.4 +/- 5.9%, not significant vs control) but administration of the CSE cofactor pyridoxal-5'-phosphate (PLP) 50 mumol/L did not enhance the effect of L-cysteine. Ten minutes normoxic perfusion with L-cysteine 1 mmol/L caused a 3-fold increase in myocardial H(2)S concentration (0.64 +/- 0.16 vs 2.01 +/- 0.07 mumol/g protein, P < .01), an effect that was significantly attenuated by PAG (1.17 +/- 0.15 mumol/g protein). These data provide evidence that exogenous L-cysteine administration limits ischemia-reperfusion injury through a mechanism that appears to be at least partially dependent on H(2)S synthesis.
Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom, Royal Veterinary College, University of London, London, United Kingdom.
David J
DJ
Elsey
Robert C
RC
Fowkes
Gary F
GF
Baxter
D000480:Alkynes / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003545:Cysteine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000032:analysis / Q000378:metabolism*; D008297:Male; D017202:Myocardial Ischemia; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D011732:Pyridoxal Phosphate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014803:Vitamin B Complex / Q000494:pharmacology
D000480:Alkynes; D004791:Enzyme Inhibitors; D014803:Vitamin B Complex; D011732:Pyridoxal Phosphate; C009055:propargylglycine; D003545:Cysteine; D005998:Glycine; D006862:Hydrogen Sulfide