atractyloside and Coronary-Disease

Adenine nucleotide efflux from isolated rat heart mitochondria was studied. Inorganic phosphate induced efflux of adenine nucleotides from the mitochondria. This efflux was inhibited by carboxyatractyloside and atractyloside. The rate of efflux showed saturation kinetics with respect to extramitochondrial phosphate (Km, 9.5 mM). Lowering the pH from 7.4 to 6.8 had little or no effect on the rate of efflux. Deenergizing the mitochondria enhanced carboxyatractyloside-insensitive efflux, but it did not affect carboxyatractyloside-sensitive efflux. Extramitochondrial ATP (200 microM) or AMP (200 microM) prevented efflux when the phosphate concentration was 10 mM. AMP (200 microM) did not inhibit efflux when the phosphate concentration was 40 mM. Atractyloside inhibited efflux noncompetitively with respect to inorganic phosphate. Mersalyl (10 nmol/mg protein) did not inhibit efflux. Phenylsuccinate (20 mM) totally inhibited phosphate-induced efflux. The results of this study indicate that under conditions found in the ischemic heart cell (low ATP, high phosphate), adenine nucleotides may be lost from the mitochondria via the adenine nucleotide translocase. Phosphate does not induce this efflux by interacting with the translocase or the phosphate-hydroxyl carrier. The site of action of phosphate may be the dicarboxylate carrier.

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Atractyloside; Coronary Disease; Male; Mersalyl; Mitochondria, Heart; Phosphates; Rats; Rats, Inbred Strains; Succinates

It has been proposed that electrophysiological changes following coronary artery occlusion result from inhibition of the adenine nucleotide translocase and that these changes can be reduced by carnitine infusion or reproduced by infusion of K+-atractyloside. In the present study, we recorded bipolar electrograms during serial 3- to 5-min occlusions of the left anterior descending coronary artery in open-chest, anesthetized dogs. DL-Carnitine (100-200 mg/kg iv) prior to coronary artery occlusion did not significantly alter ischemia-induced electrogram changes. L-Carnitine (100 mg/min ia) distal to the site of occlusion during coronary artery occlusion partially reversed ischemia-induced electrogram changes, but these effects resembled those produced by intra-arterial infusion of NaCl. During normal perfusion, intra-arterial infusion of K+-atractyloside (750 mumol/10 min) or equimolar KCl produced similar reversible flattening of perfused zone electrograms. Sodium atractyloside (750 mumol/10 min ia) did not produce electrogram changes. We conclude that 1) carnitine does not attenuate ischemia-induced electrogram changes in this model and 2) K+-atractyloside-induced electrogram changes are primarily due to K+.

Topics: Animals; Atractyloside; Carnitine; Coronary Disease; Dogs; Electrocardiography; Electrophysiology; Female; Glycosides; Heart; Male; Mitochondria, Heart; Oxidation-Reduction; Potassium

Topics: Acetyl Coenzyme A; Acyl Coenzyme A; Angina Pectoris; Atractyloside; Biological Transport; Carnitine; Carnitine Acyltransferases; Carnitine O-Acetyltransferase; Coenzyme A; Coronary Disease; Diptera; Doxorubicin; Fatty Acids; Glycolysis; Heart; Lipid Metabolism; Mitochondria, Muscle; Mitochondrial ADP, ATP Translocases; Myocarditis; Myocardium; Oxidation-Reduction; Triglycerides

Topics: Adenosine Triphosphate; Animals; Atractyloside; Blood Pressure; Cardiac Output; Coronary Circulation; Coronary Disease; Dogs; Electrocardiography; Glycosides; Heart; Heart Rate; Lactates; Mitochondrial ADP, ATP Translocases; Myocardium; Phosphocreatine

The myocardial cellular response to the cardiac glycoside atractylate, a known inhibitor of mitochondrial adenine nucleotide translocation, was examined physiologically, morphologically, and morphometrically in eight dogs. An isolated in situ segment of left ventricular tissue was employed in these experiments to eliminate collateral flow and the potential for large sampling error. It was found that atractylate infusion rapidly induced physiological and morphological changes suggestive of a loss of membrane regulation of ion flux in the arteriole, capillary endothelium, and myocardial cell. Also mitochondrial changes suggestive of adenine nucleotide translocase inhibition were observed. As these responses are similar to those induced by acute myocardial ischaemia, it is suggested that ischaemia and atractylate induce cell injury by similar mechanisms.

Topics: Animals; Atractyloside; Capillary Permeability; Coronary Circulation; Coronary Disease; Dogs; Glycosides; Heart; Mitochondria, Heart; Myocardium

Inhibition of adenine nucleotide translocase by elevated levels of long chain acyl-CoA esters has been shown to occur during the onset of ischemia in experiments conducted on dogs. Other findings indicate that, as a consequence of translocase inhibition, the production of mitochondrial creatine phosphate was abolished and, in this manner, respiration was slowed to state 4 or an ischemic-like condition. A variety of biochemical, hemodynamic, and ultrastructural evidence further suggest that this inhibition of adenine nucleotide transport in and out of the heart mitochondria may be the initial and key disturbance which "triggers" the more drastic metabolic changes known to occur as the degree of ischemia becomes more severe. The mitochondrial "damage" caused by long chain acyl-CoA ester inhibition of adenine nucleotide translocase appears to be reversible by carnitine.

Topics: Adenosine Diphosphate; Animals; Atractyloside; Carnitine; Cattle; Coenzyme A; Coronary Disease; Dogs; Hemodynamics; Mitochondria, Muscle; Mitochondrial ADP, ATP Translocases; Nucleotidyltransferases; Oleic Acids; Oxygen Consumption; Phosphocreatine; Time Factors