dihydrotachysterol and Cardiomyopathies

Topics: Animals; Calcium; Cardiomyopathies; Dihydrotachysterol; Heart Rate; Hydralazine; Male; Necrosis; Propranolol; Rats

Seven diphosphonate analogs were treated for their effects on myocardial and cardiovascular degeneration and calcification in an experimental model of cardiac calciphylaxis. A single oral dose of dihydrotachysterol (DHT) administered to rats induced myocardial and vascular degeneration, focal myocarditis and vasculitis, and myocardial and vascular mineralization. The results demonstrated a considerable variation among the various diphosphonates in their ability to block the pathological changes observed in this model. Ethane-1-hydroxy-1,1-diphosphonate (EHDP) was the most effective diphosphonate in reducing myocardial and vascular degeneration and calcification, whereas diphosphonates such as ethane-1-amino-1,1-diphosphonate (EADP) and hydroxymethylene diphosphonate (HMDP) had little or no effect compared to saline controls. For those diphosphonates which were effective, e.g., EHDP, the tissue-protective effects were observed whether the rats were treated with drug prior to the administration of DHT, or whether drug treatment commenced after DHT administration. The results are discussed in terms of the known biological properties of the diphosphonate drugs.

Topics: Animals; Calciphylaxis; Cardiomyopathies; Chemical Phenomena; Chemistry; Dihydrotachysterol; Diphosphonates; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Myocardium; Rats

Topics: Ammonium Chloride; Animals; Biological Transport; Calcitonin; Calcium; Cardiomyopathies; Dihydrotachysterol; Dose-Response Relationship, Drug; Drug Synergism; Guinea Pigs; Heart; Hydrogen-Ion Concentration; Isoproterenol; Magnesium; Myocardium; Necrosis; Phosphates; Potassium; Prenylamine; Rats; Verapamil

Experimentally induced calcification within mitochondria has been studied electron rnicroscopically. Cells investigated comprise hepatic cells damaged by CCl(4) intoxication, myocardial cells damaged by prolonged dihydrotachysterol (DHT) administration, and cells from skeletal muscle (gastrocnemius) damaged by DHT sensibilization and local injury. Cells from a human bowel carcinoma were studied too. Two types of intramitochondrial inorganic inclusion have been found. The first consists of clusters of apatite-like, needle-shaped crystals (crystalline aggregates), the second of clusters of very fine granules (granular aggregates). The former have been found mainly in mitochondria in apparently normal myocardial and muscular cells, the latter in mitochondria of degenerated hepatic, neoplastic, and myocardial cells. Crystalline aggregates are closely related to the membranes of cristae at first, but they later spread to occupy the whole mitochondrial matrix. Granular aggregates are initially found in the mitochondrial matrix near, but perhaps not touching, cristae; by growing they come into close contact with cristal membranes. Both types of aggregate show intrinsic electron opacity, which disappears after formic acid decalcification. Only the crystalline aggregates give an electron diffraction pattern of crystallinity. Uranium and lead staining of decalcified sections shows that both types of aggregate are intimately connected with an organic substrate. The substrate of crystalline aggregates consists of very thin, elongated structures shaped like the inorganic crystals. The substrate of granular aggregates consists of amorphous material gathered in clusters, with the same roundish shape and intercristal position as the inorganic granules. Both types of substrate are stained by phosphotungstic acid at low pH and by silver nitrate-methenamine after periodic acid oxidation. These results show that the organic content of the substrates includes glycoproteins; they have been confirmed by the periodic acid-Schiff (PAS) method under the optical microscope. These findings have been discussed in relation to the recent discovery of organic Ca(2+)-binding sites in mitochondria and to the general problems of soft tissue calcification.

Topics: Animals; Calcinosis; Calcium; Carbon Tetrachloride Poisoning; Cardiomyopathies; Cytological Techniques; Dihydrotachysterol; Glycoproteins; Humans; Inclusion Bodies; Intestinal Neoplasms; Lead; Liver; Microscopy, Electron; Mitochondria, Liver; Mitochondria, Muscle; Muscles; Muscular Diseases; Myocardium; Rats; Staining and Labeling; Uranium

Focal areas of calcification are frequent in rat myocardium 30 and 60 days after administration of dihydrotachysterol. These areas are PAS-positive, stain deeply with alcian blue and show high affinity for colloidal iron. Calcification is almost completely confined to intracellular structures. Small clusters of needle-shaped crystals are first found in apparently undamaged mitochondria in undamaged myocardial cells. When all the mitochondria are calcified, the cell degenerates, and inorganic crystals are laid down in relationship with its myofilaments. In other myocardial cells, clusters of amorphous or finely granular inorganic substance are found in both mitochondria and myofibrils. Both structures show signs of advanced degeneration. Inorganic substance has only occasionally been found within the structures of the sarcoplasmic reticulum. These structures do not seem to be involved in myocardial calcification under the present experimental conditions. Calcification of myocardial cells gives rise to a cellular reaction. Many macrophagic cells surround the calcified areas, which are rapidly reabsorbed. The present results show that myocardial mitochondria are actively engaged in controlling the intracellular concentration and movement of calcium ions. Their role in the myocardial contraction-relaxation cycle and the possible mechanism of myocardial calcification are discussed.

Topics: Animals; Calcinosis; Cardiomyopathies; Dihydrotachysterol; Disease Models, Animal; Edetic Acid; Female; Hypercalcemia; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Rats

Topics: Adenosine Triphosphate; Animals; Calcium; Cardiomyopathies; Dihydrotachysterol; Heart; Hydrocortisone; Isoproterenol; Magnesium; Myocardium; Phosphates; Phosphocreatine; Potassium Chloride; Prenylamine; Rats; Time Factors; Verapamil