title: Effects of a cardiotoxin from Naja naja kaouthia venom on skeletal muscle: involvement of calcium-induced calcium release, sodium ion currents and phospholipases A2 and C.
abstract: Snake venom cardiotoxin (CTX) fractions induce contractures of skeletal muscle and hemolysis of red blood cells. The fractions also contain trace amounts of venom-derived phospholipase A2 (PLA2) contamination and activate tissue phospholipase C (PLC) activity. The present study examines the mechanisms of action of a CTX fraction from Naja naja kaouthia venom in skeletal muscle. Sphingosine competitively antagonized CTX-induced red blood cell hemolysis, but not skeletal muscle contractures. CTX rapidly lowered the threshold for Ca(2+)-induced Ca2+ release in heavy sarcoplasmic reticulum fractions, as monitored with arsenazo III. There was also a slower time-dependent reduction of Na+ currents, as assessed by whole cell patch-clamp techniques. The CTX fractions elevated levels of free fatty acids and diacylglycerol for 2 hr in primary cultures of human skeletal muscle by a combined action of venom-derived PLA2 contamination in the fraction and activation of endogenous PLC activity. The activation of tissue PLC activity could be readily distinguished from the contribution of the venom PLA2 by p-bromophenacyl bromide treatment of CTX fractions. The mechanism of action involved in contractures of skeletal muscle appears to be related to the immediate and specific effect of CTX (Ca2+ release by the sarcoplasmic reticulum), while the mechanisms involved in hemolysis of red blood cells and decreased Na+ currents in skeletal muscle most likely relate to long-term effects on lipid metabolism.
authors.affiliation: Department of Anesthesiology, Hahnemann University, Philadelphia, PA 19102-1192.
authors.forename: J E
authors.initials: JE
authors.lastname: Fletcher
authors.forename: M S
authors.initials: MS
authors.lastname: Jiang
authors.forename: Q H
authors.initials: QH
authors.lastname: Gong
authors.forename: M L
authors.initials: ML
authors.lastname: Yudkowsky
authors.forename: S J
authors.initials: SJ
authors.lastname: Wieland
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D004179:Cobra Cardiotoxin Proteins / Q000032:analysis / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000187:drug effects*; D010741:Phospholipases A / Q000032:analysis / Q000633:toxicity*; D054467:Phospholipases A2; D011112:Polymyxin B / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects*; D013110:Sphingosine / Q000494:pharmacology; D010738:Type C Phospholipases / Q000032:analysis / Q000633:toxicity*
chemical_list: D004179:Cobra Cardiotoxin Proteins; D015222:Sodium Channels; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D011112:Polymyxin B; D013110:Sphingosine; D002118:Calcium