4-Aminopyridine Reverses Saxitoxin (STX)- and Tetrodotoxin (TTX)-Induced Cardiorespiratory Depression in Chronically Instrumented Guinea Pigs

• Published in: Fundamental and applied toxicology 1997-07, Vol.38 (1), p.75-88
• Main Authors: Chang, Fat-Chun T., Spriggs, David L., Benton, Bernard J., Keller, Shannon A., Capacio, Benedict R.
• Format: Article
• Language: English
• Subjects: 4-Aminopyridine - pharmacology; 4-Aminopyridine - therapeutic use; Animals; Biological and medical sciences; Bradycardia - chemically induced; Bradycardia - drug therapy; Diaphragm - drug effects; Diaphragm - physiology; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electrocardiography - drug effects; Electroencephalography - drug effects; Electromyography - drug effects; Electrophysiology; Food toxicology; Guinea Pigs; Heart Rate - drug effects; Male; Medical sciences; Neck Muscles - drug effects; Neck Muscles - physiology; Respiration - drug effects; Saxitoxin - toxicity; Tetrodotoxin - toxicity; Toxicology
• ISSN: 0272-0590; 1095-6832
• DOI: 10.1006/faat.1997.2328

The extent to which cardiorespiratory infirmity and other sublethal effects of saxitoxin (STX) and tetrodotoxin (TTX) can be reversed by 4-aminopyridine (4-AP) was investigated in guinea pigs chronically instrumented for the concurrent electrophysiological recordings of electrocorticogram (ECoG), diaphragmatic electromyogram (DEMG), Lead II electrocardiogram, and neck skeletal muscle electromyogram. Animals were intoxicated with either STX or TTX (2 and 3 μg/kg, im) to produce a state of progressive cardiorespiratory depression (depicted by decreasing DEMG amplitude, bradypnea, and bradycardia). At the point where cardiorespiratory performance was most seriously compromised (≈30 min posttoxin), 4-AP (1 or 2 mg/kg, im) was administered. The therapeutic effect of 4-AP was striking in that, within minutes, the toxin-induced diaphragmatic blockade, bradypnea, bradycardia, and depressed cortical activity were all restored to a level either comparable to, or surpassing, that of control. The optimal 4-AP dose level was determined to be 2 mg/kg (im) based on analyses of cardiorespiratory activity profiles throughout the course of intoxication and 4-AP treatment. At the dose levels (either 1 or 2 mg/kg) used to restore ventilatory function and cardiovascular performance, 4-AP produced no sign of seizures and convulsions. Although less serious secondary effects such as cortical excitant/arousal effect (indicated by ECoG power spectral analysis) and transient periods of skeletal muscle fasciculation were observed, these events were of minor concern particularly in view of the remarkable therapeutic effects of 4-AP.