Inhibition of rat heart mitochondrial respiration by cadmium chloride.
Mitochondria were isolated from hearts obtained from adult male Sprague-Dawley rats by two-part differential centrifugation of heart homogenates. Time-dependent (0-120 sec) and concentration-dependent (0-10 microM CdCl2) effects of cadmium on pyruvate-malate-supported state 3 and state 4 respiration were measured in a constant temperature reaction chamber at 37 degrees C, according to established procedures. The ID50 for cadmium chloride on state 3 respiration was determined to be 4.2 microM. The inhibition produced by cadmium chloride in heart mitochondria was compared, using identical procedures, to the effects induced by two compounds, sodium atractyloside and potassium cyanide, which are known to alter mitochondrial respiration at specific sites. The calculated ID50 values for these agents in heart mitochondria were 1.8 and 16 microM, respectively. The concentration-dependent inhibition of mitochondrial respiration induced by either cadmium chloride or potassium cyanide was maintained in the presence of 50 microM carbonyl cyanide m-chlorophenylhydrazone (CCCP), a known uncoupling agent. In contrast, sodium atractyloside did not block the uncoupling effect of 50 microM CCCP. In addition cadmium chloride was also shown to inhibit CCCP-uncoupled mitochondrial respiration. The cadmium-induced inhibition of mitochondrial respiration was reversed partially by cysteine and completely by 2,3-dimercaptopropanol. The results of the present study indicate that, at all concentrations, cadmium chloride acted solely as an inhibitor of rat heart pyruvate-malate-supported mitochondrial respiration. These findings suggest a possible mechanism for the reported disturbances in myocardial metabolism and function that occur in conjunction with acute and chronic cadmium exposure in humans and experimental animals.
D000818:Animals; D001278:Atractyloside / Q000633:toxicity; D002104:Cadmium / Q000037:antagonists & inhibitors / Q000633:toxicity*; D019256:Cadmium Chloride; D003545:Cysteine / Q000494:pharmacology; D004112:Dimercaprol / Q000494:pharmacology; D066298:In Vitro Techniques; D008293:Malates / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects*; D011190:Potassium Cyanide / Q000633:toxicity; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains
D008293:Malates; D011773:Pyruvates; D002104:Cadmium; D004112:Dimercaprol; D001278:Atractyloside; C030298:malic acid; D019289:Pyruvic Acid; D019256:Cadmium Chloride; D003545:Cysteine; D011190:Potassium Cyanide