Respiratory and cardiovascular effects of tetrodotoxin in urethane-anesthetized guinea pigs

Cardiorespiratory effects of tetrodotoxin (TTX) (15 micrograms/kg, i.p.) were investigated in urethane-anesthetized guinea pigs acutely instrumented for the recording of medullary respiratory-related units (RRUs), diaphragm electromyogram (DEMG), electrocorticogram (ECoG), electrocardiogram (ECG), blood pressure (BP), endtidal CO2, and arterial O2 and CO2. Respiratory system responses showed a hyperventilatory profile during the initial stage of intoxication. This was followed by an abrupt onset of a progressive decrease in the respiratory frequency, and a respiratory rate depression-related respiratory failure. The average time to TTX-induced respiratory arrest and death was 10.3 +/- 4.2 min. Concurrently recorded inspiratory and expiratory RRU activities indicated that respiration invariably failed in an end-expiratory position as manifested by a sustained period of expiratory RRU discharge. The progressive rate depression prior to respiratory arrest was temporally correlated only to a concomitantly augmenting expiratory RRU discharge duration. Inspiratory RRU discharge duration, on the other hand, did not display any significant change throughout the course of intoxication. The asymmetry in RRU response patterns indicates either an expiratory network component's particular sensitivity to perturbation by TTX or a dissociative trend in some bulbar respiratory rhythmogenic mechanisms. Peripheral cardiorespiratory changes were also quite profound. These included a gradual and steadfast decline in BP, a steadily decreasing amplitude in DEMG oscillations, and a state of progressive hypercapnia and hypoxemia. Changes in heart rate and ECG waveform attributes prior to respiratory arrest were not appreciable. In conclusion, in addition to a variety of TTX-induced peripheral cardiorespiratory effects, findings from this study have revealed a central respiratory system component that appears to show an unusual sensitivity to perturbation by TTX. The significance of this unique phenomenon as it relates to the nature and extent of TTX-induced central respiratory depression is discussed.