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

Abstract

The influence of the 1,4-dihydropyridines (DHPs), water-soluble glutapyrone available as sodium, potassium and ammonium salts of 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-DHP-4-carboxamide)glutaric acid, from one side, and a lipophylic cerebrocrast, 2-propoxyethyl 2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-DHP-3,5-dicarboxylate, from the other side, on partially damaged mitochondria of the Wistar rat hindlimb muscle was also studied. The following tests were made: (1) rates of endogenous respiration and substrate (succinate) oxidation and oxidative phosphorylation; (2) rates and amplitudes of high-amplitude swelling and contraction after the addition of ATP, ADP and succinate to the previously swollen mitochondria and (3) rate of reversible self-aggregation of mitochondria isolated in salt media after ATP-induced contraction without and in the presence of azidothymidine (AZT). Cerebrocrast (10-100 microM) partially normalized the endogenous respiration rate and slightly augmented the respiration rate after the addition of succinate and to lesser extent ADP. Cerebrocrast in a concentration-dependent manner (2.5-50 microM) increased (two-fold at 20-50 microM) the active contraction amplitude of swollen mitochondria, induced by single or repeated additions of ATP. The influence of cerebrocrast on the ADP- and succinate-induced contractions was less obvious. Unlike cerebrocrast glutapyrone caused a reduction of the ATP-induced contraction amplitude (two-fold at 0.5-5.0 mM), not impairing the mitochondrial contraction ability in response to ATP or succinate. Pre-exposure to 2.5 mM glutapyrone resulted in at least a 10-fold inhibition of the reversible aggregation rate in the presence of 99 and 198 microM AZT. The results suggest the usefulness of further study of cerebrocrast and glutapyrone in preventing AZT-induced and some other mitochondrial myopathies.

Comparative effects of three 1,4-dihydropyridine derivatives [OSI-1210, OSI-1211 (etaftoron), and OSI-3802] on rat liver mitochondrial bioenergetics and on the physical properties of membrane lipid bilayers: Relevance to the length of the alkoxyl chain in positions 3 and 5 of the DHP ring

“…Thus, the calcium antagonist foridone (ryodipine, PP-1466), which possesses the same substituent in the position 4 as OSI-1212 (cerebrocrast) and its analogues studied herein, improves mitochondrial bioenergetics in the isolated rat mitochondria from the infarct zone of the heart as well as from relatively undamaged zone [14]. Moreover, we have shown OSI-1212 (cerebrocrast) ability to interact with rat skeletal, neuronal and hepatic mitochondria [15,16], to incorporate into mitochondrial membranes and to induce lipid membrane organization changes [17]. Mitochondria have also been considered as an essential intracellular target for OSI-1212 (cerebrocrast) neuroprotective actions [18,19].…”

Search for Stroke-Protecting Agents in Endothelin-1-Induced Ischemic Stroke Model in Rats

“…As to degenerative alterations in cortical neurons caused by ET-1, they were successfully (about 2.5-fold) protected by both tested drugs. Moreover, both drugs also significantly reduced the infarction size, and cerebrocrast showed about a 2-fold higher activity (reduction by about 4-fold) than mildro- drugs demonstrated mitochondria-protecting activity: cerebrocrast normalized oxidative phosphorylation, augmented the ATP-induced contraction rate and amplitude of isolated swollen mitochondria (21), and protected cerebellar granule cells against mitochondria toxin 1-methyl-4-phenylpyridine (MPP + )-induced cell death, production of reactive oxygen species, and loss of mitochondrial transmembrane potential (10). In turn, in isolated rat liver mitochondria, mildronate protected against azidothymidine-induced hydrogen peroxide generation and inhibition of uncoupled respiration, ADPto-oxygen ratio, and transmembrane potential (22).…”

Distinct Influence of Atypical 1,4‐Dihydropyridine Compounds in Azidothymidine‐Induced Neuro‐ and Cardiotoxicity in Mice Ex Vivo

“…Our previous studies demonstrated that novel atypical (non‐calcium antagonistic) dicyclic and monocyclic (or amino acid‐containing) DHP compounds showed different effects on mitochondrial processes in vitro. Particularly high activity was expressed by cerebrocrast (dicyclic structure) that normalized oxidative phosphorylation and increased ATP‐induced contraction rate and amplitude in swollen mitochondria of rat skeletal muscles [4], protected cerebellar granule cells from MPP + ‐induced cell death, production of ROS, and loss of mitochondrial membrane potential [5], blocked inner membrane anion channel and inhibited K + /H + antiporter in rat liver mitochondria [6]. Besides, cerebrocrast showed an anti‐inflammatory effect by reducing inflammation in rat paw oedema model, and inhibiting secretion of neurotoxic cytokines interleukine (IL)‐1β and IL‐6 in human monocyte (THP‐1) cell line [18].…”

“…Besides, cerebrocrast showed an anti‐inflammatory effect by reducing inflammation in rat paw oedema model, and inhibiting secretion of neurotoxic cytokines interleukine (IL)‐1β and IL‐6 in human monocyte (THP‐1) cell line [18]. Contrary to cerebrocrast, glutapyrone (glutamate‐containing DHP) reduced the ATP‐induced contraction amplitude in isolated rat skeletal muscle mitochondria, whereas it was capable to protect mitochondrial aggregation caused by anti‐HIV drug azidothymidine [4]. Interesting results were obtained with tauropyrone (taurine‐containing DHP), which even increased ROS production caused by MPP + [5].…”