4-Aminopyridine antagonizes saxitoxin-and tetrodotoxin-induced cardiorespiratory depression.
Antagonism of saxitoxin-and tetrodotoxin-induced lethality by 4-aminopyridine was studied in urethane-anesthetized guinea pigs instrumented for the concurrent recordings of medullary respiratory-related unit activities (Bötzinger complex and Nu. para-Ambiguus), diaphragmatic electromyogram, electrocorticogram, Lead II electrocardiogram, blood pressure, end-tidal CO2 and arterial O2/CO2/pH. The toxin (either saxitoxin or tetrodotoxin) was infused at a dose rate of 0.3 microgram/kg/min (i.v.) to produce a state of progressive cardiorespiratory depression. The animals were artificially ventilated when the magnitude of integrated diaphragm activities was reduced to 50% of control. Immediately after the disappearance of the diaphragm electromyogram, the toxin infusion was terminated, and 4-aminopyridine (2 mg/kg, i.v.) was administered. The therapeutic effect of 4-aminopyridine was striking in that the toxin-induced blockade of diaphragmatic neurotransmission, vascular hypotension, myocardial anomalies, bradycardia and aberrant discharge patterns of medullary respiratory-related neurons could all be promptly restored to a level comparable to that of control condition. The animals were typically able to breathe spontaneously within minutes after 4-aminopyridine. At the dose level used to achieve the desired therapeutic responses, 4-aminopyridine produced no sign of seizure and convulsion. Although less serious side-effects such as cortical excitant/arousal and transient periods of fascicular twitch could be observed, these events were of minor concern, in our opinion, particularly in view of the remarkable therapeutic effects of 4-aminopyridine.
Chang
F C
FC
Neurotoxicology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
Bauer
R M
RM
Benton
B J
BJ
Keller
S A
SA
Capacio
B R
BR
D015761:4-Aminopyridine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy; D002245:Carbon Dioxide / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000473:pathology; D004562:Electrocardiography; D004576:Electromyography / Q000187:drug effects; D004594:Electrophysiology; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy; D007262:Infusions, Intravenous; D008297:Male; D009474:Neurons / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D012530:Saxitoxin / Q000008:administration & dosage / Q000633:toxicity*; D009435:Synaptic Transmission / Q000187:drug effects*; D013779:Tetrodotoxin / Q000008:administration & dosage / Q000633:toxicity*
D002245:Carbon Dioxide; D012530:Saxitoxin; D013779:Tetrodotoxin; D015761:4-Aminopyridine