MODIFICATION OF SWELLING-CONTRACTION-AGGREGATION PROCESSES IN RAT MUSCLE MITOCHONDRIA BY THE 1,4-DIHYDROPYRIDINES, CEREBROCRAST AND GLUTAPYRONE, THEMSELVES AND IN THE PRESENCE OF AZIDOTHYMIDINE

The influence of the 1,4-dihydropyridines (DHPs), water-soluble glutap yrone available as sodium, potassium and ammonium salts of ,5-diethoxy carbonyl-1,4-DHP-4-carboxamide)glutaric acid, from one side, and a lip ophylic cerebrocrast, 2-propoxyethyl -difluoromethoxyphenyl)-1,4-DHP-3 ,5-dicarboxylate, from the other side, on partially damaged mitochondr ia of the Wistar rat hindlimb muscle was also studied. The following t ests were made: (1) rates of endogenous respiration and substrate (suc cinate) oxidation and oxidative phosphorylation; (2) rates and amplitu des of high-amplitude swelling and contraction after the addition of A TP, ADP and succinate to the previously swollen mitochondria and (3) r ate of reversible self-aggregation of mitochondria isolated in salt me dia after ATP-induced contraction without and in the presence of azido thymidine (AZT). Cerebrocrast (10-100 mu M) partially normalized the e ndogenous respiration rate and slightly augmented the respiration rate after the addition of succinate and to lesser extent ADP. Cerebrocras t in a concentration-dependent manner (2.5-50 mu M) increased (two-fol d at 20-50 mu M) the active contraction amplitude of swollen mitochond ria, induced by single or repeated additions of ATP. The influence of cerebrocrast on the ADP-and succinate-induced contractions was less ob vious. Unlike cerebrocrast glutapyrone caused a reduction of the ATP-i nduced contraction amplitude (two-fold at 0.5-5.0 mM), not impairing t he mitochondrial contraction ability in response to ATP or succinate. Pre-exposure to 2.5 mM glutapyrone resulted in at least a 10-fold inhi bition of the reversible aggregation rate in the presence of 99 and 19 8 mu M AZT. The results suggest the usefulness of further study of cer ebrocrast and glutapyrone in preventing AZT-induced and some other mit ochondrial myopathies. (C) 1997 John Wiley & Sons, Ltd.