azacosterol and Myotonia

Topics: Animals; Azacosterol; Carboxylic Acids; Chlorides; Clofibrate; Desmosterol; Humans; Iodides; Membrane Potentials; Muscles; Myotonia; Rats

We report the occurrence of neurologic complications in 23 patients who underwent gastric restriction surgery for the treatment of morbid obesity. Complications occurred 3 to 20 months after surgery. All the patients had had protracted vomiting for the first 3 months after the operation. The following syndromes were found: chronic or subacute symmetric polyneuropathy (12 patients), acute severe polyneuropathy (1 patient), burning feet syndrome (2 patients), meralgia paresthetica (3 patients), myotonic syndrome (1 patient), posterolateral myelopathy (2 patients), and Wernicke-Korsakoff encephalopathy (2 patients). The patients suffering from burning feet syndrome and those with Wernicke-Korsakoff encephalopathy showed a clear improvement after parenteral thiamine treatment. As to the rest of the patients, the occurrence of the complications seems to be linked to nutritional causes, although no such deficiencies were detected.

Topics: Adult; Azacosterol; Female; Humans; Male; Middle Aged; Myotonia; Obesity, Morbid; Peripheral Nervous System Diseases; Postoperative Complications; Stomach; Wernicke Encephalopathy

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.

Topics: Adenosine Triphosphatases; Animals; Azacosterol; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Histocytochemistry; Male; Muscles; Myofibrils; Myosins; Myotonia; Rats; Rats, Inbred Strains; Sarcoplasmic Reticulum

An abnormality in myoplasmic Ca2+ regulation has frequently been proposed in 20,25-diazacholesterol (20,25-D) myotonia. We report here the results of several studies of transmembrane Ca2+ movement in this animal model. (i) Physiologic Ca2+ release by intact sarcoplasmic reticulum (SR) was examined in chemically skinned single muscle fibers preloaded in EGTA-buffered Ca2+ solutions (pCa2+7.0 to 6.4). Isometric tension development and Ca2+ release thresholds in response to Cl- or caffeine showed no differences between control and 20,25-D fibers at any pCa2+. (ii) The kinetics of energy-dependent Ca2+ accumulation in purified SR vesicles were followed spectrophotometrically using Ca2+-sensitive dyes. The apparent rate for ATP-dependent Ca2+ uptake and Ca2+ sequestering capacity were unchanged in SR from 20,25-D animals vs. controls. (iii) Surface membrane Ca2+ATPase activity was measured in red blood cell ghosts and sarcolemma. Enzyme Vmax was decreased by 25 to 50% in both membranes in the 20,25-D-treated animals with a compensatory increase in the number of Ca2+ATPase molecules. In general, the SR handling of Ca2+ appears normal in 20,25-D myotonia, although the activity of Ca2+ATPase in membranes with high sterol content may be altered in response to changes in the lipid environment in this model.

Topics: Adenosine Triphosphate; Animals; Azacosterol; Caffeine; Calcium; Calcium-Transporting ATPases; Cell Membrane; Chlorides; Cholesterol; Egtazic Acid; Erythrocyte Membrane; Kinetics; Male; Myotonia; Rats; Rats, Inbred Strains; Sarcolemma; Sarcoplasmic Reticulum

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.

Topics: Animals; Azacosterol; Cholesterol, Dietary; Desmosterol; Disease Models, Animal; Erythrocyte Membrane; Liposomes; Male; Membrane Fluidity; Myotonia; Rats; Rats, Inbred Strains

Topics: Animals; Azacosterol; Cell Membrane; Cholesterol; Desmosterol; Kinetics; Male; Membrane Lipids; Muscles; Myotonia; Ouabain; Phosphorylation; Rats; Rats, Inbred Strains; Sarcolemma; Sodium-Potassium-Exchanging ATPase; Thermodynamics

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.

Topics: Animals; Azacosterol; Cell Membrane; Cholesterol; Desmosterol; Male; Membrane Lipids; Muscles; Myotonia; Rats; Rats, Inbred Strains; Sarcolemma; Viscosity

Topics: Action Potentials; Animals; Azacosterol; Cholesterol; Male; Membrane Potentials; Muscle Contraction; Muscles; Myotonia; Ouabain; Potassium; Rats; Rats, Inbred Strains; Sodium; Tetrodotoxin

Topics: Action Potentials; Animals; Azacosterol; Biomechanical Phenomena; Disease Susceptibility; Leg; Male; Membrane Potentials; Muscles; Myotonia; Nerve Regeneration; Rats; Rats, Inbred Strains

Topics: Action Potentials; Animals; Azacosterol; Chlorides; Cholesterol; Desmosterol; Electromyography; Male; Muscle Contraction; Muscles; Myotonia; Rats; Rats, Inbred Strains; Sarcolemma

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.

Topics: Action Potentials; Animals; Azacosterol; Electric Conductivity; Electromyography; Electrophysiology; In Vitro Techniques; Male; Membrane Potentials; Muscle Contraction; Muscles; Myotonia; Rats; Rats, Inbred Strains

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.

Topics: Animals; Azacosterol; Female; Mitochondria, Muscle; Muscles; Myotonia; Peripheral Nervous System Diseases; Rats; Staining and Labeling

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.

Topics: Animals; Anticholesteremic Agents; Azacosterol; Electromyography; Female; Male; Muscles; Myotonia; Rats; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride

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.

Topics: Acetylcholine; Animals; Atropine; Azacosterol; Bungarotoxins; Evoked Potentials; Ischemia; Male; Muscle Denervation; Muscle Spasticity; Muscles; Myotonia; Potassium Chloride; Procaine; Pyridostigmine Bromide; Rats; Receptors, Cholinergic; Succinylcholine; Tetrodotoxin; Tubocurarine

A new inhibitor of cholesterol synthesis, 20,25 diazachlestenol, produced myotonia in 31 persons; and, in six of these, a keratoderma which resembles the natural disease, keratoderma climactericum. These observations further emphasize the importance of normal lipid synthesis in orderly cornification.

Topics: Azacosterol; Female; Humans; Keratoderma, Palmoplantar; Middle Aged; Myotonia