K. E. Cooper

Evidence supporting a role for endogenous vasopressin in natural suppression of fever in the sheep.

1. The antipyretic effect of arginine vasopressin (AVP) introduced into the brain by push‐pull perfusion was investigated in the sheep. 2. Control perfusions with sucrose solutions had no effect on fevers induced by a bacterial endotoxin. Sucrose solutions containing AVP (4.0 microgram/ml.) perfused at 40 microliter./min had significant antipyretic activity, reducing the two peaks of the fever but had no effect on resting body temperature. 3. Loci in which AVP induced antipyresis were limited to the septal region about 2‐3 mm anterior to the anterior commissure. 4. The amounts of AVP in perfusates from the septal region correlated negatively with changes in body temperature. 5. AVP administered I.V. did not lower fever. 6. AVP plasma levels correlated negatively with fever magnitude following premature birth induced by dexamethasone.

Antipyresis following perfusion of brain sites with vasopressin.

Vasopressin was found to be an effective antipyretic when it was perfused through discrete regions of the brain of the sheep.

Antipyresis: Its Effect on Mortality Rate of Bacterially Infected Rabbits

The effect of an antipyretic drug administered directly into the preoptic-anterior hypothalamus was measured in order to investigate the role of fever on mortality of bacterially infected mammals. New Zealand white rabbits (Oryctolagus cuniculus) were injected intravenously with Pasteurella multocida and either sodium salicylate or a control solution was infused directly into the preoptic-anterior hypothalamus. Both groups developed fevers, but the fever of the rabbits infused with the antipyretic was reduced by 50% during the initial stage of infection. Hypothalamic sodium salicylate infusions produced a lower average fever than control infusions over an initial 5 hour period of infection, reducing average 5 hour fevers from 1.56 degrees C to 0.72 degrees C. All of the infected rabbits infused with sodium salicylate died whereas only 29% of the infected control rabbits died. Rabbits receiving sodium salicylate alone did not die. The increased mortality could possibly be the result of a fulminating infection caused by rapidly multiplying bacteria during the initial, attenuated phase of the febrile course in the salicylate-treated rabbits.

Evidence supporting a role for endogenous vasopressin in fever suppression in the rat.

1. Infusion of human purified interleukin‐1 into a lateral cerebral ventricle of the rat evoked a rise in core temperature which was abolished by heating the interleukin‐1. 2. When the intracerebroventricular infusion of interleukin‐1 was preceded by a bilateral injection of saline into the ventral septal area, the resulting febrile response was not different from that induced by interleukin‐1 alone. However, when the vasopressin V1 antagonist, d(CH2)5Tyr(Me)AVP, was injected into the ventral septal area prior to interleukin‐1, a fever was evoked which was significantly greater in magnitude and duration. This enhancement of fever by the V1 antagonist was dose related. 3. Injection of either saline or the V1 antagonist into the ventral septal area, in the absence of interleukin‐1, did not evoke any consistent alteration in the core temperature of the rats. 4. The vasopressin V2 antagonist, d(CH2)5‐D‐ValVAVP, was injected into the ventral septal area to determine the effect of another vasopressin analogue on the fever evoked by interleukin‐1. The V2 antagonist did not alter the time course of interleukin‐1‐induced fever or alter core temperature in the afebrile rat. 5. These data are consistent with the hypothesis that endogenous vasopressin, released in the ventral septal area, may be involved in limiting fever. In addition, these results indicate that the central receptor mediating the antipyretic action of vasopressin may resemble the V1 subtype of peripheral vasopressin receptor.

Vasopressin may mediate febrile convulsions

The possibility that arginine vasopressin (AVP) is involved in the etiology of febrile convulsions was investigated by experiments on hyperthermia-induced convulsions in rats. Homozygous Brattleboro rats, which genetically lack AVP, and Long Evans rats, which were passively immunized by intracerebroventricular anti-AVP antiserum, either convulsed at higher body temperatures than untreated Long Evans rats or did not convulse at all. This indicates that a lack of AVP increases the threshold for the convulsions. High blood levels of AVP in hyperthermic convulsing rats compared to hyperthermic non-convulsive rats support the hypothesis that AVP may mediate febrile convulsions.

Vasopressin: A homeostatic effector in the febrile process

This review compares the physiological changes which accompany infection and fever with the effects of the peptide, arginine vasopressin (AVP). AVP may act as a neuromodulator, a releasing factor, or a hormone to induce responses which are opposite to those homeostatic changes accompanying fever. Since AVP is released into blood and brain during fever, it is hypothesized that AVP contributes to the maintenance of homeostasis in the infected organism.

Role of Prostaglandins in Fever and Temperature Regulation

The remarkable ability of a warm-blooded animal to regulate its body temperature makes it relatively independent of the thermal conditions of the external environment. Every living organism produces heat which may be stored or given off to the environment. This condition allows an animal to reach a “steady state” of thermal exchange with its surroundings. In the homeothermic animal, heat production and heat loss are regulated to maintain internal body temperature within narrow limits over a wide range of environmental conditions. This thermohomeostasis is achieved in animals by two principal systems, namely behavioral and autonomic. In man these include regulation of heat loss, and of heat production. The heat loss regulation involves the choice of clothing, artificial environments, alterations in the skin blood flow, and variation in the level of evaporative heat loss by sweating. Heat production can be modified by altering the level of basal heat production by shivering or nonshivering thermogenesis, and by voluntary muscular activity. Deviations of about 2°C in central body temperature from the normal level, in general, do not seriously impair body function in man. Increases above this range can lead to convulsions, particularly in infants, and a further increase may cause death. If body temperature falls below normal limits (hypothermia), nervous system function is depressed, leading to a loss of consciousness and impairment of thermoregulation itself. As temperature falls even further, the coordinated contraction of heart muscle is disrupted.

Modification of thermoregulatory responses in rabbits reared at elevated environmental temperatures.

1. Pregnant New Zealand white rabbits were kept from 14 days pre‐partum at an environmental temperature of 33 degrees C, and their offspring were reared at this temperature. 2. In response to a 4 hr cold exposure, animals (aged 90‐180 days) raised in this way showed significant drops in colonic temperature (‐2.7 +/‐ 0.5 degrees C) while control animals reared at 20 degrees C did not (+0.05 +/‐ 0.1 degrees C). 3. A reduced, monophasic endotoxin fever was observed in animals reared at 33 degrees C, while a normal biphasic fever was seen in rabbits originally reared at 20 degrees C and subsequently acclimated to 33 degrees C. 4. A greatly reduced temperature response to intravenous infusion of noradrenaline was also found in animals raised at 33 degrees C. 5. It is proposed that thermal afferent input during early life may play an important role in the development of the thermoregulatory system.

Vasopressin: Its role in antipyresis and febrile convulsion

When pyrogenic substances are injected intravenously into experimental animals, a sequence of events is set in motion which involves the hypothalamus and perhaps other portions of the diencephalon to produce a febrile response. We now present evidence that the brain produces its own endogenous antipyretic which may serve as a means of controlling the extent of the fever. When arginine vasopressin is perfused through the lateral septal area of the hypothalamus of the sheep, fever is suppressed. Vasopressin alone does not lower normal body temperature when perfused through this region of the brain. In addition, evidence is provided to indicate that vasopressin is released within the lateral septal area during the febrile response. It is concluded that, in fever, arginine vasopressin may be released in the lateral septal area of the brain and serve as an endogenous antipyretic. Results indicate that, following an initial application of vasopressin into the brain itself, a subsequent similar administration of vasopressin produces seizure-like activity. Therefore, it is suggested that this release of arginine vasopressin may contribute to the production of febrile convulsion.

The effect of noradrenaline, injected into the hypothalamus, on thermoregulation in the cat.

1. Noradrenaline (NA) was microinjected into the anterior hypothalamic/preoptic area(AH/POA) of unanaesthetized cats held at ambient temperatures of 10, 22 or 35 degrees C. Loci in which injection of NA caused body temperature changes were also found to be sensitive to the febrile action of PGE1. 2. At all ambient temperatures, NA caused a dose‐dependent fall in body temperature. However the mechanisms by which these temperature changes were brought about varied at different ambient temperatures. In cats maintained at the higher ambient temperature, NA activated heat loss mechanisms whereas in the cats maintained in the 10degrees C environment, the major effect of NA injection was an inhibition of heat conservation and heat production mechanisms. 3. We conclude that NA acts in cats not only as an inhibitor of heat conservation and production, but also acts in an excitatory manner on an active heat loss pathway within the AH/POA.