Myocardial glutathione depletion impairs recovery of isolated blood-perfused hearts after global ischaemia.
This study was performed to determine whether depletion of myocardial glutathione would impair recovery of left ventricular function of blood-perfused, isolated hearts after reversible ischaemic injury. Cats were treated with either vehicle or buthionine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the synthesis of glutathione. The feline isolated hearts were perfused with the blood of normal donor cats before and after 40 min of global myocardial ischaemia. The myocardial concentration of glutathione of the BSO group, 178 +/- 38 ng/mg tissue, was significantly less than that of the control group, 292 +/- 38 ng/mg tissue (P < 0.05). The peak left ventricular developed pressure (LVDP) 1 h after reperfusion, expressed as a fraction of the peak LVDP before ischaemia, was 0.87 +/- 0.10 for the control group and 0.64 +/- 0.08 for the BSO group (P = 0.05 vs. control). The peak left ventricular dP/dt after reperfusion, expressed as a fraction of the peak dP/dt before ischaemia, was 1.08 +/- 0.14 for the control group and 0.78 +/- 0.09 for the BSO group (P = 0.05 vs. control). The myocardial creatine kinase activity of the BSO group, 1046 +/- 46 U/g tissue, was not significantly different from that of the control group, 1038 +/- 17 U/g tissue (P = 0.87). Thus, depletion of myocardial glutathione resulted in impaired post-ischaemic contractile function that cannot be attributed to a greater extent of irreversible cell injury.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
S W
SW
Werns
J C
JC
Fantone
A
A
Ventura
B R
BR
Lucchesi
D000818:Animals; D019328:Buthionine Sulfoximine; D002415:Cats; D003402:Creatine Kinase / Q000378:metabolism; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D003402:Creatine Kinase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione