Low affinity binding sites for 1,4-dihydropyridines in mitochondria and in guinea pig ventricular membrane

Brush, K; Perez, Margot; Hawkes, Mary Jane; Pratt, David R.; Hamilton, Susan L.

doi:10.1016/0006-2952(87)90574-0

Cited by 11 publications

(3 citation statements)

References 41 publications

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“…Additional dissociation kinetics demonstrated that verapamil is acting in a non-competitive manner, as it enhanced the dissociation kinetics constant. These results are in contrast with those of Brush et al (1987), who demonstrated no effect of verapamil on [3H]-nitrendipine binding to guinea-pig cardiac mitochondrial membranes. In line with our results, is another study in which verapamil was shown to displace completely [3H]-nitrendipine binding from guinea-pig cardiac mitochondrial membranes (Zernig & Glossmann, 1988).…”

Section: Discussioncontrasting

confidence: 99%

“…The high-affinity binding site is considered to be a part of, or closely related to plasmalemmal L-type voltage-sensitive Ca channels; this has been demonstrated through electrophysiological (Hess et al, 1984), biochemical (Flockerzi et al, 1986) or functional experiments (Artalejo et al, 1988). A low-affinity site has been recently demonstrated in guinea-pig heart mitochondria (Brush et al, 1987). Further experiments showed that the inner mitochondrial membrane was enriched in lowaffinity sites (Zernig & Glossmann, 1988).…”

Section: Introductionmentioning

confidence: 99%

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Separate [³H]‐nitrendipine binding sites in mitochondria and plasma membranes of bovine adrenal medulla

Ballesta¹,

Garcı́a²,

Gutiérrez³

et al. 1990

British J Pharmacology

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Two binding sites for the 1,4‐dihydropyridine (DHP) derivative [3H]‐nitrendipine have been found in the bovine adrenal medulla. The high‐affinity site (Kd = 0.48 nM and Bmax = 128 fmol mg−1 protein) was specifically located in purified plasma membranes. The low‐affinity site (Kd = 252nM and Bmax = 169 pmol mg−1 protein) was located only in mitochondria. Chromaffin granule membranes lacked specific binding sites for [3H]‐nitrendipine. Kinetic analysis of the rates of association and dissociation of [3H]‐nitrendipine, saturation isotherms and displacement experiments with unlabelled nitrendipine and PN200‐110 revealed single, homogeneous populations of high‐ and low‐affinity sites in plasma and mitochondrial membranes, respectively. The high affinity site was sensitive to Ca2+ deprivation and heating; it was practically unaffected by changes in ionic strength of the medium and its optimal pH was slightly alkaline. This site exhibited a strong DHP stereoselectivity; diltiazem increased and verapamil decreased the affinity of [3H]‐nitrendipine. In contrast, binding of [3H]‐nitrendipine to the low affinity site was more heat resistant and less affected by Ca2+ removal. Its optimal pH was slightly acid and the increase in ionic strength enhanced the number of available sites. The site had no DHP stereoselectivity. Verapamil decreased the dissociation constant of [3H]‐nitrendipine acting in a non‐competitive manner; diltiazem did not affect equilibrium binding parameters of [3H]‐nitrendipine. These results suggest that both binding sites reflect different receptor entities. The high‐affinity binding site corresponds to the dihydropyridine receptor associated with the L‐type calcium channel. The function of the mitochondrial, low‐affinity binding site is, at present, unknown.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Separate [³H]‐nitrendipine binding sites in mitochondria and plasma membranes of bovine adrenal medulla

Ballesta¹,

Garcı́a²,

Gutiérrez³

et al. 1990

British J Pharmacology

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“…There are low-anity binding sites for 1,4-DHPs in lipid bilayers and mitochondria. 3,17 The combination of electrostatic and hydrophobic binding between charged 1,4-DHP (amlodipine) and membrane phospholipid may explain the high anity of this drug for the membrane bilayer. The mitochondrial inner membrane contains speci®c binding sites for dihydropyridine Ca 2 -antagonists, which are associated with an inner mitochondrial anion channel.…”

Section: Introductionmentioning

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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Altered muscle calcium channel binding kinetics in autoimmune motoneuron disease

Smith¹,

Kimura²,

Harati³

et al. 1995

Muscle and Nerve

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While skeletal muscle is not apparently affected directly in amyotrophic lateral sclerosis (ALS), immunoglobulin G fractions purified from patients with ALS (ALS IgG) bind dihydropyridine (DHP)-sensitive L-type voltage-gated calcium channel (VGCC) antigen isolated from skeletal muscle in ELISA and Western immunoblot, and alter VGCC function in vitro. To determine whether muscle VGCC properties are altered in ALS, VGCC-enriched subsarcolemmal membrane fractions were prepared from biopsied quadriceps muscle of patients with ALS, with other neurologic diseases, or without apparent muscle disease, and tested for DHP binding with [3H]PN200-110. ALS muscle VGCCs possessed eightfold higher binding affinities for [3H]PN200-110 than did VGCCs from muscle fractions of most other patients, independent of denervation-induced increases in DHP binding site number. Similarly elevated DHP binding affinities were observed in specimens from patients with autoimmune motor neuropathies, suggesting that ALS and immune mediated motoneuron disease share skeletal muscle L-type VGCC alterations.

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Low affinity binding sites for 1,4-dihydropyridines in mitochondria and in guinea pig ventricular membrane

Cited by 11 publications

References 41 publications

Separate [³H]‐nitrendipine binding sites in mitochondria and plasma membranes of bovine adrenal medulla

Separate [³H]‐nitrendipine binding sites in mitochondria and plasma membranes of bovine adrenal medulla

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

Altered muscle calcium channel binding kinetics in autoimmune motoneuron disease

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Low affinity binding sites for 1,4-dihydropyridines in mitochondria and in guinea pig ventricular membrane

Cited by 11 publications

References 41 publications

Separate [3H]‐nitrendipine binding sites in mitochondria and plasma membranes of bovine adrenal medulla

Separate [3H]‐nitrendipine binding sites in mitochondria and plasma membranes of bovine adrenal medulla

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

Altered muscle calcium channel binding kinetics in autoimmune motoneuron disease

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Separate [³H]‐nitrendipine binding sites in mitochondria and plasma membranes of bovine adrenal medulla

Separate [³H]‐nitrendipine binding sites in mitochondria and plasma membranes of bovine adrenal medulla