Accession Number : ADP008879

Title :   Reversal of Saxitoxin (STX) and Tetrodotoxin (TTX) Induced Cardio-Respiratory Failure with 4-Aminopyridine (4-AP).

Corporate Author : ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD

Personal Author(s) : Chang, F. C. ; Bauer, R. M. ; Benton, B. J. ; Moore, E. L.

Report Date : 13 MAY 1993

Pagination or Media Count : 10

Abstract : Reversal of STX and TTX induced cardio-respiratory failure with 4-AP was studied in urethane-anesthetized guinea pigs instrumented for the recordings of medullary respiratory activities, diaphragm EMG, ECoG, ECG, blood pressure, end-tidal CO(2), and arterial O(2)/CO2/pH. The toxin (STX or TTX) was infused at a dose rate of 0.3 ug/kg/min (i.v.) to produce a state of cardio-respiratory depression. Animals were maintained with artificial ventilation when the magnitude of diaphragm activity was reduced by 50%. Seconds after the disappearance of the diaphragm activity, the toxin infusion was terminated, and 4-AP (2 mg/kg; i.v.) was administered. The therapeutic effect of 4-AP was striking in that the toxin-induced functional blockade of the diaphragm, vascular hypotension and bradycardia could all be promptly returned to a level comparable to, and in many cases surpassing, that of control condition. The animals were typically able to breathe spontaneously within minutes after 4-AP. Despite an auspicious return of ventilatory function and cardiovascular performance, a variety of other 4-AP induced central and peripheral effects were also observed. The most notable ones are (1) a cortical excitant/arousal effect as indicated by the emergence of an 8-30 Hz EEG power spectral complex, (2) an increase in the magnitude of skeletal muscle (neck) background activities, and (3) a cardio-respiratory performance decrement noted in some animals attributable to an acid-base homeostatic imbalance which was readily reversible by sodium bicarbonate solution. Side effects at higher intravenous dose levels (viz., 4, 6, and 8 mg/kg) are of some concern in that 4-AP not only can cause muscle fasciculations, but also becomes seizurogenic and proconvulsant.

Descriptors :   *BLOOD PRESSURE, *MUSCLES, *TOXINS AND ANTITOXINS, *CARDIOVASCULAR SYSTEM, ACIDS, ANIMALS, BACKGROUND, BICARBONATES, BLOOD, BRADYCARDIA, CONTROL, DOSE RATE, FAILURE, FUNCTIONS, GUINEA PIGS, HYPOTENSION, INFUSIONS, MANAGEMENT, POWER, PRESSURE, RATES, REVERSIBLE, SODIUM, SWINE, URETHANES, VENTILATION, ELECTROENCEPHALOGRAPHY, IN VITRO ANALYSIS, MONOCLONAL ANTIBODIES, CHOLINESTERASE INHIBITORS, NEUROMUSCULAR TRANSMISSION.

Subject Categories : Anatomy and Physiology
      Pharmacology

Distribution Statement : APPROVED FOR PUBLIC RELEASE