ryanodine and triphenyltin

A direct peripheral myopathy has been found in organotin intoxication and suggested to be a significant factor in the development of muscle weakness following exposure. In this study, by using the isolated sarcoplasmic reticulum membrane vesicles, we have shown that triphenyltin dose-dependently induced Ca2+ release from the actively and passively loaded sarcoplasmic reticulum vesicles. Triphenyltin induced Ca2+ release in ruthenium red-sensitive and insensitive ways with EC50 values of 75 and 270 microM, respectively. The Ca2+-ATPase activity and Ca2+ uptake of sarcoplasmic reticulum were also inhibited by triphenyltin. Triphenyltin exerted dual effects on the apparent [3H]ryanodine binding. Triphenyltin (0.5-10 microM) dose-dependently potentiated the [3H]ryanodine binding; however, the [3H]ryanodine binding decreased as the concentration of triphenyltin increased. The dissociation of bound [3H]ryanodine was facilitated by triphenyltin. The present study suggested that the internal Ca2+ store of skeletal muscle could be depleted by triphenyltin through the inhibition of the Ca2+ uptake and the induction of Ca2+ release by acting on the Ca2+-ATPase and Ca2+ release channel, also known as the ryanodine receptor, of sarcoplasmic reticulum, respectively. These results could partly explain the development of muscle weakness in organotin intoxication; however, their relevance to the development of peripheral myopathy requires further examination.

Topics: Animals; Calcium; Calcium Channels; Calcium-Transporting ATPases; Cell Membrane; Dose-Response Relationship, Drug; Muscle Proteins; Organotin Compounds; Rabbits; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Silver

Triphenyltin induces a contracture of the mouse phrenic nerve-diaphragm preparation. This contracture was not inhibited by (+)-tubocurarine, high magnesium or the absence of electrical stimulation. Triphenyltin (0.1 mM) reduced the muscle membrane potential, the amplitude of the muscle action potential and the muscle membrane input resistance. Pretreatment with high K+ (25 mM) or veratridine (1.5 microM; a Na+ channel activator) briefly shortened the onset of the contracture and increased the peak tension of the contracture. Pretreatment with tetrodotoxin (0.3 microM; a Na+ channel blocker) or glycerol (a T tubule uncoupler) however, significantly reduced the triphenyltin-induced contracture. Removing Ca2+ from external solution and prolonged treatment with either caffeine (20 mM) or ryanodine (2 microM) inhibited the triphenyltin-induced contracture. However, a brief treatment with a lower concentration of caffeine (10 mM) potentiated the contracture. 45Ca2+ uptake studies showed that triphenyltin caused the muscle to accumulate Ca2+ which entered from external solution. Pretreatment with trypsin and dithiothreitol (a sulfhydryl-containing reducing agent) blocked the contracture induced by triphenyltin. These results suggest that triphenyltin initially interacts with the sulfhydryl groups of membrane bound proteins (possibly the Na+ channel) to cause depolarization of the muscle fibres. This depolarization triggers the release of Ca2+ from sarcoplasmic reticulum through the mechanism of Ca2+ inducing Ca2+ release, activates the contractile filaments and causes the muscle to contract.

Topics: Action Potentials; Animals; Caffeine; Calcium; Calcium Radioisotopes; Diaphragm; Dithiothreitol; Drug Interactions; Egtazic Acid; Female; Glycerol; In Vitro Techniques; Male; Membrane Potentials; Mice; Mice, Inbred ICR; Muscle Contraction; Neuromuscular Junction; Organotin Compounds; Potassium; Ryanodine; Tetrodotoxin; Trypsin; Veratridine