Derivatives of 1,4-dihydropyridines as modulators of ascorbate-induced lipid peroxidation and high-amplitude swelling of mitochondria, caused by ascorbate, sodium linoleate and sodium pyrophosphate
✍ Scribed by Astrīda Velēna; Juris Zilbers; Gunārs Duburs
- Book ID
- 101281935
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 242 KB
- Volume
- 17
- Category
- Article
- ISSN
- 0263-6484
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✦ Synopsis
A group of 26 2,6-dimethyl-3,5-disubstituted and 2,6-dimethyl-3,4,5-trisubstituted-1,4-dihydropyridines (1,4-H 2 Py 1,4-DHPs) and ®ve related pyridines were studied as inhibitors of rat liver mitochondrial swelling and O 2 uptake by ascorbic acid-dependent lipid peroxidation (LP) and as modulators of mitochondrial swelling induced by Na -linoleate or Na -pyrophosphate. 1,4-DHPs studied include 4-unsubstituted and 4-methyl-and 4-phenylsubstituted 3,5-dialkoxycarbonylderivatives of 2,6-dimethyl-1,4-DHP with variations in alkoxy chain length and composition, 4-unsubstituted and 4-methyl-, 4-aryl-and 4-pyridyl-substituted 3,5-dianilidocarbonylderivatives, and a structurally related group of 3,5-dipyridylamidocarbonylderivatives. Many 1,4-DHPs possess marked antioxidant (AO) and membrane stabilizing activity, expressed as the mitochondrial swelling (DA 520 /t) and/or O 2 uptake rate decrease (V 0 /V) as well as prolongation of the induction period (t/t 0 ) of mitochondrial swelling and/or O 2 uptake at ascorbic acid-dependent LP of rat liver mitochondria. 4-Unsubstituted 3,5-dialkoxycarbonyl-2,6-dimethyl-1,4-DHPs, as well as 4-unsubstituted or those possessing lipophylic 4-aryl-groups 3,5-diamido-2,6-dimethyl-1,4-DHPs, reveal marked AO and membrane stabilizing properties. Oxidized (heteroaromatized) derivatives have minimal activity. Perhaps 1,4-DHPs preferably act as antioxidants on stages of initiation and prolongation of LP chain reactions at low concentrations: IC 50 (when V 0 /V or t/t 0 2) are 0 . 1 mM to 100 mM. At 100 mM 3,5-di-phydroxyphenoxycarbonyl-and 3,5-di-p-tolyloxycarbonyl-2,6-dimethyl-1,4-DHPs, as well as 3,5-diethoxycarbonyl-2,6-dimethylpyridine (oxidized form of Hantzsch ester) and 3,5-diamyloxycarbonyl-2,6-dimethylpyridine, alter the mitochondrial swelling rate in the presence of natural protonophore Na -linoleate (0 . 063 mM and 0 . 125 mM). 3,5-Din-butyloxycarbonyl-2,6-dimethyl-1,4-DHP at 100 mM completely stops mitochondrial swelling in the presence of 0 . 8 mM Na -pyrophosphate. In the presence of many of the 1,4-DHPs, the lipid peroxidation process was inhibited. However, the swelling process could be prolonged, promoted, accelerated or inhibited Ð depending on 1,4-DHPs structure, concentration, the type of initiators of the swelling process and the medium composition. Copyright