Toxin detection based on action potential shape analysis using a realistic mathematical model of differentiated NG108-15 cells

The negative inotropic effect of a commonly used formulation of bradykinin (Sandoz BRS-640) was found to be due to chlorobutanol, a constituent of the preparation. Solutions containing up to 100 mug of crystalline bradykinin/ml had no effect on tension or action-potential shape. Chlorobutanol (500 mug/ml) caused a 30% decrease in contraction amplitude and a 20% increase in action-potential duration. Chlorobutanol lowered conduction velocity and induced conduction failure and automaticity within isolated ventricular muscle strips. Chlorobutanol affected neither positive nor negative treppe. We conclude that bradykinin has no direct action on toad, frog, or rat myocardium. However, chlorobutanol does have direct effects on myocardial cells, acting on the cell membrane and decreasing isometric tension produced by the heart.

Download Full-text

Hyperexcitability of Cultured Spinal Motoneurons From Presymptomatic ALS Mice

Journal of Neurophysiology ◽

10.1152/jn.00665.2003 ◽

2004 ◽

Vol 91 (1) ◽

pp. 571-575 ◽

Cited By ~ 121

Author(s):

Jason J. Kuo ◽

Martijn Schonewille ◽

Teepu Siddique ◽

Annet N. A. Schults ◽

Ronggen Fu ◽

...

Keyword(s):

Action Potential ◽

Firing Frequency ◽

Resting Potential ◽

Spinal Motoneurons ◽

Electrophysiological Properties ◽

Potential Shape ◽

Wide Range ◽

Action Potential Shape ◽

And Control ◽

The Relationship

ALS (amyotrophic lateral sclerosis) is an adult-onset and deadly neurodegenerative disease characterized by a progressive and selective loss of motoneurons. Transgenic mice overexpressing a mutated human gene (G93A) coding for the enzyme SOD1 (Cu/Zn superoxide dismutase) develop a motoneuron disease resembling ALS in humans. In this generally accepted ALS model, we tested the electrophysiological properties of individual embryonic and neonatal spinal motoneurons in culture by measuring a wide range of electrical properties influencing motoneuron excitability during current clamp. There were no differences in the motoneuron resting potential, input conductance, action potential shape, or afterhyperpolarization between G93A and control motoneurons. The relationship between the motoneuron's firing frequency and injected current (f-I relation) was altered. The slope of the f-I relation and the maximal firing rate of the G93A motoneurons were much greater than in the control motoneurons. Differences in spontaneous synaptic input were excluded as a cause of increased excitability. This finding identifies a markedly elevated intrinsic electrical excitability in cultured embryonic and neonatal mutant G93A spinal motoneurons. We conclude that the observed intrinsic motoneuron hyperexcitability is induced by the SOD1 toxic gain-of-function through an aberration in the process of action potential generation. This hyperexcitability may play a crucial role in the pathogenesis of ALS as the motoneurons were cultured from presymptomatic mice.

Download Full-text