Antioxidants as Antiarrhythmic Drugs

Frolkis, V.V.; Frol'kis, R. A.; Dubur, G. Ya.; Khmelevsky, Yu.V.; Shevchuk, V.G.; Golovchenko, S F; Mkhitarjan, L.S.; Voronkov, G S; Tsyomik, V.A.; Lysenko, I.V.; Poberezkina, N.B.

doi:10.1159/000174186

Cited by 12 publications

(6 citation statements)

References 6 publications

(6 reference statements)

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“…Diludine 3, ionol 30 and some other antioxidants, which prevented and protected mitochondria against swelling and disintegration (caused either by AsA induced lipid peroxidation, or exogenic phospholipase A 2 or products of their enzymatic cleavage reaction Ð salts of unsaturated FFAs) can act as antiischaemic agents, if used in vivo prophylactically, preventing heart, kidney and other organs from ischaemic and reperfusion lesions. 10,11,34,35,37 The eect was dependent on dose, time of application and introduction mode. Using antioxidants, i.e.…”

Section: Resultsmentioning

confidence: 99%

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

Velēna

Zilbers

Дубурс

1999

Cell Biochem. Funct.

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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 five 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-phenyl-substituted 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 (deltaA(520)/t) and/or O(2) uptake rate decrease (V(0)/V) as well as prolongation of the induction period (tau/tau(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 tau/tau(0)=2) are 0.1 microM to 100 microM. At 100 microM 3,5-di-p-hydroxyphenoxycarbonyl- 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-Di-n-butyloxycarbonyl-2, 6-dimethyl-1,4-DHP at 100 microM 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-depending on 1,4-DHPs structure, concentration, the type of initiators of the swelling process and the medium composition.

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Section: Resultsmentioning

confidence: 99%

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

Velēna

Zilbers

Дубурс

1999

Cell Biochem. Funct.

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“…More importantly, our data demonstrate that ROS mediates the inhibitory effect of ceramide on I HERG and antioxidants can prevent the I HERG depression. This explains at least partly the benefits of antioxidants in preventing and suppressing arrhythmias in ischemic myocardium and failing hearts [46,47]. Indeed, Tsuji et al [25] showed I Kr , measured as E-4031-sensitive tail current, to be ∼36% smaller in rabbits with ventricular tachypacing-induced CHF than in healthy rabbits.…”

Section: Role Of Reactive Oxygen Species (Ros) In I Herg Modulation Bmentioning

confidence: 99%

Sphingolipid Metabolite Ceramide Causes Metabolic Perturbation Contributing to HERG K<sup>+</sup> Channel Dysfunction

Bai

Wang²,

Shan³

et al. 2007

Cell Physiol Biochem

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Ceramide, a sphingolipid metabolite, has emerged as a key second messenger molecule that mediates multiple cellular functions. Its de nova synthesis and accumulation in ischemic myocardium, congestive heart failure and diabetic cardiomyopathy is associated with the abnormalities such as abnormal QT prolongation and increased risk of arrhythmias. To investigate how ceramide is involved in modulating cardiac repolarization, we performed whole-cell patch-clamp studies on HERG current (I_HERG), a critical determinant of cardiac repolarization, expressed in HEK293 cells. Acute application (superfusion for 25min) of membrane permeable ceramide (C2, 5 µM) did not alter I_HERG. Prolonged incubation with C2 for 10hrs caused pronounced I_HERG inhibition in a concentration-dependent and voltage-independent fashion and positive shift of voltage-dependent HERG activation. The IC₅₀ for I_HERG suppression was 19.5 µM. C2 did not affect the inactivation property and time-dependent kinetics of I_HERG. Similar effects were observed with production of endogenous ceramide catalyzed by sphingomyelinase. Tyrosine kinase inhibitors failed to reverse C2-induced suppression of HERG function, and PKA and PKC inhibitors only slightly reversed the I_HERG depression. Western blotting and immunocytochemical analyses indicate that C2 does not alter HERG protein expression on the cytoplasmic membrane. The inhibitory effect of C2 on I_HERG was reversed by antioxidants vitamin E or MnTBAP. C2 caused considerable production of intracellular reactive oxygen species (ROS), which was prevented by vitamin E or MnTBAP. We conclude that ceramide depresses I_HERG mainly via ROS overproduction and ceramide-induced I_HERG impairment may contribute to QT prolongation in prolonged myocardial ischemia, heart failure and diabetic cardiomyopathy.

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“…The findings of these studies, together with the concept that free radicals may contribute to the genesis of reperfusion-induced arrhythmias, gained support from other investigations using a wide variety of interventions, including coenzyme Q10 [40], and several species, including the dog [36,[41][42][43][44][45][46][47][48]. Support also came from a number of electrophysiologic studies [49][50][51][52], again in several species.…”

Section: Reperfusion-induced Arrhythmiasmentioning

confidence: 85%

Reperfusion-induced injury: A possible role for oxidant stress and its manipulation

Hearse

1991

Cardiovasc Drug Ther

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While some investigators recognize "reperfusion-induced injury" as an important component of the overall injury that occurs during ischemia and reperfusion, others question its existence. Resolution of this controversy is of considerable importance, particularly in an era of thrombolysis, since reperfusion-induced injury might be amenable to treatment. Although reperfusion is an absolute prerequisite for the recovery of ischemic tissue, it undoubtedly has some unfavorable effects. The identification of four (possibly sequential) components of reperfusion-induced injury helps to clarify the situation: a) Reperfusion after brief periods of ischemia can trigger arrhythmias in tissue that is potentially salvable; there is abundant experimental and clinical evidence for this form of reperfusion injury. b) Reperfusion may also be associated with "myocardial stunning"; however, given sufficient time, this prolonged postischemic contractile and metabolic dysfunction will recover. There is good experimental evidence and some clinical evidence for the existence of this type of reperfusion-induced injury. c) Reperfusion is commonly thought to cause lethal injury in cells that, until the time of reperfusion, were potentially salvable. However, conclusive evidence that reperfusion can kill cells does not yet exist. d) Reperfusion may alter the nature of necrotic processes in tissue that has already sustained lethal injury, while not altering the number of cells that die this may change the manner in which they die; this form of reperfusion injury could lead to differences in scar formation and vulnerability to aneurysm. There is considerable evidence for the existence of this form of reperfusion-induced injury. Many candidate mechanisms have been proposed for each form of reperfusion injury. Ionic disturbances (particularly for calcium) are often cited and, most recently, free radical-induced induced injury (oxidant stress) has been suggested as important. Considerable evidence exists that oxidant stress is involved in stunning and in reperfusion-induced arrhythmias, and characterization of underlying mechanisms might lead to novel therapeutic principles, such as antioxidant therapy. However, much remains to be learned.

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Antioxidants as Antiarrhythmic Drugs

Cited by 12 publications

References 6 publications

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

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

Sphingolipid Metabolite Ceramide Causes Metabolic Perturbation Contributing to HERG K<sup>+</sup> Channel Dysfunction

Reperfusion-induced injury: A possible role for oxidant stress and its manipulation

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