Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Aspects of Chemical WarfareFig. 19-1. Structure of palytoxin.Illustration: Courtesy of Richard Sweeny.cells (muscle, heart, neurons), PTX affects virtually allcell types that rely on the sodium-potassium ATPaseexchanger to maintain electrolyte balance, membranepotential, and electrical/ionic gradients. The sodiumpotassiumATPase exchanger pump has been suggestedto be a major molecular target of PTX. 29 PTX leadsto contractions of striated skeletal and smooth musclecells, neurotransmitter release by nerve terminals, 30potassium release and hemolysis of red blood cells,and blood vessel vasoconstriction. PTX leads to contractionin both smooth and skeletal muscle as a resultof slow and irreversible depolarization of the plasmamembrane in these cells from an induction of an inward,sodium-dependent current. 25,30 A cardiotoniceffect in cardiac muscle and depolarization of musclemembranes occurs as a result of PTX intoxication. 30PTX causes a depolarization and a decrease in theamplitude, upstroke velocity, and duration of actionpotential in papillary muscle of the heart secondary toan increase in sodium permeability of the cardiac cellmembrane. Membrane depolarization of the plasmamembrane drives sodium into the cells, promotingcalcium influx through L-type calcium channels and bythe sodium-calcium exchanger. Evidence suggests PTXbinds to the sodium-potassium ATPase exchanger atouabain receptor sites. This active transport ion pumpis converted to an open ion channel, diminishing iongradient across the membrane. 22,29–31PTX affects adrenergic neurons and red blood cells,increasing norepinephrine and potassium release,respectively. 30 PTX also effects blood vessels throughits interactions on vascular smooth muscle, nerveterminals, and vascular endothelial cells, leading tovasoconstriction, an increase in systemic blood pressure,and massive pulmonary hypertension. In addition,depolarization of the plasma membrane opensL-type calcium channels, promoting calcium influx andcontractions. 25 Perivascular nerve terminals undergomembrane depolarization, releasing norephinephrinethat binds to alpha-1-adrenoceptors on smooth musclecells. Activation of phospholipase C by norephinephrinebinding induces mobilization of intracellularcalcium stores and activates protein kinase. 25 PTX alsoacts on vascular endothelial cells by releasing nitricoxide and induces the release of prostaglandins fromthe aorta. 25PTX is a rapid-acting, lethal neurotoxin most commonlyintroduced by ingestion. The median lethal dose618