The hypothermic effect of tetrodotoxin in the unanaesthetized cat.

1. The hypothermic effect on unanaesthetized cats of tetrodotoxin injected I.V. or into the lateral cerebral ventricle was examined.2. At an ambient temperature (T(a)) of 22 degrees C, tetrodotoxin given intraventricularly was over 400 times more potent in lowering body temperature (T(b)) than when given I.V. The magnitude of the hypothermia was dose-dependent for both routes. Decreases in T(b) as great as 6.8 degrees C were induced by infusions or multiple injections of tetrodotoxin into the ventricle.3. Tetrodotoxin also lowered T(b) at T(a) = 13, 30 or 35 degrees C. Tachypnoea, which lasted for longer durations and which became more intense the higher the T(a), accompanied development of hypothermia. Shivering was observed only during recovery from hypothermia at 13 degrees C.4. During the tetrodotoxin-induced hypothermia, animals were still able to regulate against environmental thermal stresses.5. EDTA disodium salt, leucocytic pyrogen and prostaglandin E(1) antagonized the hypothermic effect of tetrodotoxin when they were administered during recovery from tetrodotoxin.6. Activation of heat-loss mechanisms, and the absence of compensatory shivering during development of hypothermia after tetrodotoxin administration, plus lowering of T(b) by tetrodotoxin at T(a) above as well as below the thermoneutral temperature, indicate that lowering of the thermoregulatory set-point is the mechanism by which centrally or peripherally administered tetrodotoxin lowers T(b). Further evidence for set-point lowering after intraventricular administration of tetrodotoxin is provided by persistence of the ability to regulate against both heat and cold stresses during hypothermia. The possibility that the decrease in set-point could be due to the well known action of tetrodotoxin to block transient increases in membrane sodium ion conductance is discussed in terms of a recent hypothesis regarding ionic control of the thermoregulatory set-point.