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At least 19 recordsLinked to original sources
PubMed1987

Ichthyosis induced by cholesterol-lowering drugs. Implications for epidermal cholesterol homeostasis.

Ichthyosis and other disorders of cornification may occur as side effects of treatment with several hypocholesterolemic agents. Recent progress in understanding of the functional role of lipids in stratum corneum provides a new pathophysiologic basis for these earlier clinical observations. In stratum corneum, lipids are segregated within intercellular membranes, where they appear to regulate permeability barrier function and desquamation. Cholesterol is an important constituent of these membranes and may be essential to both of these functions. Perturbation of barrier function induces cholesterologenesis locally within the epidermis. Polar sterol metabolites, such as cholesterol sulfate, may also regulate epidermal sterologenesis under normal or pathologic circumstances. Cholesterol homeostasis may also modulate desquamation. For example, hairless mice fed azacosterol hydrochloride (20,25-diazacholesterol) develop a generalized scaling disorder without loss of barrier function. In these mice, total stratum corneum sterol content is markedly decreased, and topical or systemic repletion with cholesterol can correct the scaling abnormalities.

Animals↗
PubMed1978

The effect of pharmacologic acetylcholine receptor on fibrillation and myotonia in rat skeletal muscle.

Myotonic discharges in rats given 20, 25-diazacholesterol hydrochloride and fibrillation discharges in denervated rat muscle both were silenced by procaine hydrochloride, tetrodotoxin or ischemia, or potassium chloride (after initial activation). They both were activated by succinylcholine, but only the fibrillations were silenced by alpha-bungarotoxin or atropine sulfate. It is hypothesized that fibrillations and diazacholesterol-induced myotonia are mediated through mechanisms involving ionic channels, that both can be produced by activation of the junctional/nonjunctional acetylcholine receptors (or some mechanism coupled to the receptors), but that an unfettered alpha-bungarotoxin-binding portion of the acetylcholine-receptor molecule and an unblocked atropine-binding site are obligatory only for production of fibrillations.

Acetylcholine↗
PubMed1981

20,25-diazacholesterol myotonia: an electrophysiological study.

The electrophysiological characteristics of the myotonic syndrome produced in mammalian skeletal muscle by administration of 20,25-diazacholesterol (20,25-D) were studied in detail. In vivo electromyographic recordings confirmed widespread repetitive electrical activity, but delayed relaxation was evanescent and required isotonic rather than isometric conditions, with long recovery periods between stimuli, for clear demonstration. Subsequent administration of a potent inhibitor of membrane chloride conductance (GCl) induced profound delays in relaxation different from that after chronic 20,25-D alone. Intracellular passive cable analysis revealed only a small decrease in membrane GCl and none in potassium conductance. Potassium current-voltage relationships did not differ in control and treated animals. Intracellular microelectrode recordings consistently showed multiple driven action potentials during long depolarizations but no spontaneous myotonic discharges after cessation of the stimulus. Variations in temperature, buffer, and external ionic concentrations also failed to produce spontaneous activity. Anode break excitation under mild depolarizing conditions, however, did elicit repetitive membrane electrical activity. The myotonia induced by 20,25-D is not due to low membrane GCl. The relationship between delayed mechanical relaxation and membrane repetitive electrical activity remains to be clearly established in this myotonic syndrome.

Action Potentials↗
PubMed1982

Effects of 20,25-diazacholesterol on cholesterol synthesis in cultured chick muscle cells: a radiogas chromatographic and mass spectrometric study of the post-squalene sector.

Radiogas chromatography, used in conjunction with mass spectrometry, has been used to analyze the sterol content of cultured chick muscle cells. Seven sterols, plus lanosterol, were detected. These sterols conformed to a linear biosynthetic pathway linking lanosterol and cholesterol. The reaction sequence is: C-14 demethylation, C-4 demethylation, delta 8 leads to delta 5 double bond rearrangement, delta 24 double bond reduction. When chick cells were treated with increasing concentrations of 20,25-diazacholesterol, components of this pathway and aberrant products accumulated. These accumulations suggest that diazacholesterol affects reductases, double bond isomerases and the C-14 demethylation enzymes of sterol biosynthesis.

Animals↗
PubMedDate not supplied

Effects of diazacholesterol dihydrochloride (SC-12937), an avian antifertility agent, on rat testis.

The present study was undertaken to evaluate the effectiveness of an avian chemosterilant, 20, 25-diazacholesterol dihydrochloride (SC-12937), on the rat testis. Adult male rats were injected intraperitoneally with 10 mg (Group 1) or 30 mg (Group 2) of SC-12937/kg/d or with vehicle alone (Group 3) for 10 days, and were killed 24 hours after the last injection. A wide range of variation in the appearance of affected seminiferous tubules was observed in the testis of SC-12937-treated rats at both dose levels. This ranged from apparently normal-looking seminiferous tubules to almost completely atrophied tubules with no cells. Affected tubules exhibited intraepithelial vacuoles of varying size, multinucleated giant cells, germ cell exfoliation, and tubular atrophy. The presence of severely damaged and entirely normal seminiferous tubules adjacent to one another in the same section was noteworthy. The changes appeared to be dose-related. A greater number (34.6%) of affected tubules were observed in rats receiving 30 mg of SC-12937 compared with the ones receiving 10 mg of this compound (19.6%). The Sertoli cells also were affected by this drug and exhibited cytoplasmic vacuolation, a marked increase in the accumulation of lipid droplets and myeloid bodies. Necrotic Sertoli cells also were observed in the severely affected tubules. The possible mechanism of antispermatogenic action of SC-12937 in rats has been discussed briefly.

Animals↗
PubMed1982

Sarcolemmal desmosterol accumulation and membrane physical properties in 20,25-diazacholesterol myotonia.

In rats treated biweekly with 20,25-diazacholesterol (200 mg/kg orally), the desmosterol level in skeletal muscle sarcolemma increased progressively to about 80% of membrane sterol while total sterol levels remained constant. Following a single oral dose of 20,25-D, the kinetics of desmosterol accumulation and subsequent loss in sarcolemma were more rapid than in whole muscle homogenates. The anisotropy of diphenylhexatriene fluorescence and the calculated microviscosity of the probe's microenvironment decreased significantly with increasing desmosterol levels in a temperature-dependent manner, although fluorescent lifetimes were not altered. Fluorescent probes which localize in more superficial regions of the membrane detected no change. Studies with erythrocyte ghost membranes yielded results comparable to sarcolemma. Replacement of membrane yielded results comparable to sarcolemma. Replacement of membrane cholesterol with desmosterol reduced the local microviscosity of membrane cholesterol with desmosterol reduced the local microviscosity of the membrane hydrophobic region associated with phospholipid acyl chains and sterol side chains, but had little apparent effect on more superficial, polar regions. These observations can be correlated with the membrane location of the unsaturated side chain in desmosterol.

Animals↗
PubMed1979

A histological and histochemical study of changes of fiber types in experimental myotonia.

In both fast and slow muscles of rats treated with 20--25 diazacholesterol there were qualitative alterations, such as changes of fiber outlines, numerous moth-eaten fibers and rare ring fibers. In addition there were generally larger groups of Type I and intermediate fibers than in normal controls ("type-grouping" tendency) in the preparations for oxidative enzymes in the extensor digitorum longus (EDL) of myotonic animals. Quantitative evaluations of EDL and soleus of myotonic rats revealed moderate hypothrophy of Type I and Type II fibers with an increase in the numbers of Type I and of Type III fibers in the EDL and a significant decrease of the nondominant fibers in the soleus muscle. The data are discussed in the light of a neurally mediated and/or direct action of the drug on the muscle fiber.

Animals↗
PubMed1986

Fast to slow transition induced by experimental myotonia in rat EDL muscle.

Experimental myotonia was induced by feeding rats with 20,25-diazacholesterol for up to 8 months. Histochemical analysis of myotonic extensor digitorum longus (EDL) muscle showed a progressive decrease of type IIB fibres and a concomitant increase of type IIA and type I fibres. A transient hypertrophy of type IIA fibres was observed 6 months after beginning the treatment. Analysis of the pattern of myosin light chains of single fibres from EDL showed that myotonia caused a progressive decrease of fibres showing a pure fast myosin light chain pattern and an increase of fibres showing coexistence of fast and slow myosin light chains (intermediate fibres). Only a small percentage of intermediate fibres showed coexistence of fast and slow myosin heavy chains. Myotonic fibres presented an increased sensitivity to caffeine which approached that of normal soleus fibres. Furthermore, sarcoplasmic reticulum (SR) vesicles isolated from hind limb fast muscles of myotonic rats demonstrated a decrease of Ca2+-dependent ATPase and Ca2+-transport activities as well as a decrease of immunoreactivity with anti-rabbit SR fast Ca2+-ATPase antibody. These results suggest that the increased electrical activity brought about by 20,25-diazacholesterol-induced myotonia, caused a fast to slow transition in the phenotypic expression of myosin and sarcoplasmic reticulum proteins.

Adenosine Triphosphatases↗
PubMed1978

Alteration of developing and adult rat muscle membranes by zuclomiphene and other hypocholesterolemic agents.

The present study presents evidence for a third hypocholesterolemic drug, zuclomiphene, being able to induce an experimental myotonic condition. Other drugs used singly or in combination were AY-9944, Triparanol and 20, 25-diazacholesterol. It has also been demonstrated for the first time that experimental myotonia can be induced in developing rats as well as adults. Developing rats received the initial intraperitoneal injections of drug at 5 days of age and were examined at 50 days of age. Adult rats were treated for 5 weeks. Two injections were given per week. Positive electromyography findings were observed in the developing and adult animals receiving 20, 25-diazacholesterol and zuclomiphene. The electromyography data of the other regimens of treatment were equivocal with regard to myotonia. Histological, histochemical, and electron microscopic examination of the muscle demonstrated no important changes. estimation of sterol composition showed that desmosterol was a major sterol in muscle after 20, 25-diazacholesterol or zuclomiphene treatment, thus furthering the concept that it is desmosterol in the muscle membrane, and not the drug, that is responsible for the myotonic condition.

Animals↗
PubMed1984

Membrane fluidity and myotonia: effects of cholesterol and desmosterol on erythrocyte membrane fluidity in rats with 20,25-diazacholesterol-induced myotonia and on phospholipid liposomes.

Previous spin-label and electromyographic experiments with rats fed 20,25-diazacholesterol, an inhibitor of the biosynthetic conversion of desmosterol to cholesterol, demonstrated an increased erythrocyte membrane fluidity and myotonia, a prolonged muscle contraction upon stimulation. The current studies with rats showed normal erythrocyte fluidity in animals fed 20,25-diazacholesterol but maintained on a high-cholesterol diet and no myotonia. Studies of model membrane systems composed of phospholipid vesicles containing desmosterol, cholesterol, or both demonstrated that desmosterol increased membrane lipid fluidity relative to cholesterol, suggesting that in 20,25-diazacholesterol-induced myotonia, in which desmosterol accounts for 85% of the plasma sterol, the increased membrane fluidity previously observed in erythrocytes and sarcolemma in this animal model of human congenital myotonia may be due to desmosterol.

Animals↗
PubMed1977

Cholesterol in muscle membranes.

The composition of skeletal muscle microsomes is reviewed. Evidence for the involvement of cholesterol in the transport of calcium by vesicles derived from the sarcoplasmic reticulum is considered. Results obtained by non aqueous extractions of skeletal muscle microsomes, and by use of the cholesterol analogue 20, 25 diazacholesterol indicate that cholesterol is not involved in calcium transport by vesicles of sarcoplasmic reticulum origin. Use of density perturbation procedures indicating that cholesterol is present in muscle membranes other than those of the sarcoplasmic reticulum involved in calcium transport is discussed. The distribution of membranal cholesterol in muscle is compared to that in other tissues.

Adenosine Triphosphatases↗
PubMed1977

Effect of extended hypocholesterolemic drug treatment on peripheral and central nervous system sterol content of the rat.

Extended treatment of developing or adult rats with a variety of hypocholesterolemic drugs has shown that both the central nervous system (CNS) and peripheral nervous system (PNS) sterol content could be affected in both age groups by this type of treatment. Treatment of developing animals was begun at 5 days of age and continued for 45 days. Adult rats, 300 g at onset, were treated for 35 days. The influence of these drugs on PNS sterol composition has not been previously examined. Diazacholesterol administration caused an accumulation of desmosterol in the CNS and 7-dehydrodesmosterol and desmosterol in the PNS. Zuclomiphene induced a build-up of desmosterol in either tissue. Both of these drugs had a more pronounced effect on developing CNS and PNS than on adult CNS and PNS. Addition of AY-9944 or Triparanol to the zuclomiphene treatment of the developing animals reduced desmosterol accumulation but brought about a build-up of 7-dehydrocholesterol and 7-dehydrodesmosterol.

Animals↗
PubMed1986

Sterol composition and biosynthesis in mouse salivary glands.

Sterol components of mouse submandibular, sublingual and parotid glands were studied by thin-layer and gas-liquid chromatography. The major sterol was cholesterol (5-cholesten-3 beta-ol; 26.7, 28.0, 18.8 micrograms/mg protein respectively), with minor amounts of squalene, lathosterol (5 alpha-cholest-7-en-3 beta-ol), desmosterol (cholesta-5,24-dien-3 beta-ol), lanosterol (4,4',14-trimethyl-5 alpha-cholesta-8,24-dien-3 beta-ol), dihydrolanosterol (4,4',14-trimethyl-5 alpha-cholest-8-en-3 beta-ol) and methylstenol. Chromatograms of salivary sterols were similar to those of liver, and different from those of skin in which the amount of lathosterol was much higher. Administration of the anticholesterolaemic agent, 20,25-diazacholesterol, resulted in accumulation of desmosterol in all tissues tested, and additional sterols also accumulated in skin. The gas-liquid chromatographic profiles of salivary sterols from the treated animals were similar to those of liver, but different from those of skin. Thus sterols were synthesized in salivary glands and the biosynthetic pathway was via C24-unsaturated side-chain intermediates, as in liver. This was verified by showing that [2-14C]-mevalonate was incorporated into sterols in vitro when it was incubated with homogenates of these glands.

Animals↗
PubMed1982

Biochemical and morphological effects of 20,25-diazacholesterol on cultured muscle cells.

Effects of 20,25-diazacholesterol (DAC), a myotonia-inducing drug, were evaluated on certain biochemical and morphological properties of embryonic rat muscle cells grown in tissue culture. During DAC treatment, muscle fibers exhibited spontaneous contractions that changed from coarse twitches to finer fibrillation movements, The ultrastructural alterations produced by DAC were smeared Z-lines, disorganized myofibrils, occasional honeycomb appearance of membranes and large vacuoles connected to zipper-like structures. Biochemically, a microsomal fraction prepared from DAC-treated cells (compared to that of normal cells) showed a 30-45 per cent decrease in the isoproterenol-enhanced and the NaF-enhanced adenylate cyclase activity. however, the beta-adrenergic receptors, through which isoproterenol activates the enzyme, showed no change in density or affinity as judged by the binding of [125I]iodohydroxybenzylpindolol. That indicated that DAC treatment caused an uncoupling of beta-receptor-adenylate cyclase interaction. Guanylate cyclase and cyclic GMP-phosphodiesterase were both markedly increased in DAC-treated cells, indicating a greater turnover of cyclic GMP. Binding of [3H]concanavalin A to DAC-treated muscle membranes was decreased 20-40 per cent. The data indicate that DAC exert a direct influence on muscle fibers, affecting their functional, biochemical and morphological properties.

Animals↗