W.L. Veale

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.

Perfusion of vasopressin within the rat brain suppresses prostaglandin E-hyperthermia

These experiments were undertaken to determine whether arginine vasopressin (AVP) could suppress a prostaglandin hyperthermia and to localize sites of these actions in the rat. Prostaglandin E2 (PGE2) sensitive sites were localized in the ventral-septal area by microinjecting 200 ng/0.5 microliter of prostaglandin E2. During perfusion with an artificial CSF, PGE2 injected into the lateral cerebral ventricle evoked a hyperthermia of more than 1 degree C. Perfusion of 6.5 micrograms/ml of AVP markedly attenuated the PGE2-induced hyperthermia. These results suggest that AVP suppresses PGE2-induced hyperthermia in sites in which PGE2 evokes an increase in core temperature.

Perfusion of vasopressin within the ventral septum of the rabbit suppresses endotoxin fever

The antipyretic action of arginine vasopressin (AVP), administered into a lateral cerebral ventricle or directly into the brain tissue via push-pull perfusion, was investigated in conscious New Zealand White rabbits. Administration of AVP into a lateral cerebral ventricle (ICV) was ineffective in reducing an endotoxin-induced fever and did not alter body temperature in the afebrile rabbit. Control push-pull perfusions with the carrier vehicle were without effect on endotoxin fevers or normal body temperature. Perfusion of the vehicle containing AVP provided significant antipyretic activity against both intravenous (IV) and ICV endotoxin without affecting normal body temperature. Both the maximum fever height and the fever index were significantly reduced during AVP perfusion. Tissue sites in which AVP was found to be antipyretic were located in the rostroventral parts of the septal region, at sites similar to those where perfusion of the peptide caused antipyresis in the sheep and rat. These results support the hypothesis that AVP, or a closely related molecule, may modulate fever within the central nervous system.

Stimulation of vasopressin release in the ventral septum of the rat brain suppresses prostaglandin E1 fever.

1. Infusion of prostaglandin E1 (PGE1) into a lateral cerebral ventricle of the rat evoked a rise in core temperature which could be attenuated by electrical stimulation of the bed nucleus of the stria terminalis (BST). Electrical stimulation of the BST in the absence of PGE1 did not alter body temperature in the afebrile rat. 2. When the intracerebroventricular (I.C.V.) infusion of PGE1 was preceded by a bilateral injection of saline or vasopressin V2 antagonist d(CH2)5D‐ValVAVP into the ventral septal area (VSA), electrical stimulation of the BST suppressed the PGE1 hyperthermia. However, when the vasopressin V1 antagonist d(CH2)5Tyr(Me)AVP was injected into the VSA prior to I.C.V. infusion of PGE1, electrical stimulation of the BST did not alter the hyperthermic response to PGE1. 3. These actions were site specific in that the suppression of PGE1 hyperthermia was observed only when the electrode tips were located in the area of the BST. Similarly, the V1 antagonist only blocked the effect of electrical stimulation when injected into the VSA. 4. When the vasopressin V1 antagonist was injected into the VSA, the PGE1 fever was prolonged when compared to the controls with saline. 5. Injection of saline, vasopressin V1 and V2 antagonist into the VSA, without PGE1 or BST stimulation, did not evoke any significant change in the core temperature of the rats. 6. These data are consistent with the hypothesis that vasopressin may function within the brain as an endogenous antipyretic and that vasopressin may act in a BST‐VSA neuronal pathway concerned with endogenous antipyresis.

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.

Injection of neuropeptide Y into the paraventricular nucleus of the hypothalamus inhibits gastric acid secretion in the rat

Neuropeptide Y (NPY) was injected into the paraventricular nucleus (PVN) of the hypothalamus of anesthetized rats in order to assess its effect on gastric acid secretion. NPY evoked a dose-dependent decrease of interdigestive gastric acid output when injected directly into the PVN or immediately ventral to it. Intracerebroventricular NPY and saline injections did not alter acid output. Injection of NPY into adjacent non-PVN hypothalamic areas resulted in either an elevated acid output or had no effect depending on the site of injection. Mean arterial blood pressure and heart rate were not consistently affected by NPY. These results show that injection of NPY into the PVN of anesthetized rats inhibits interdigestive gastric acid output in a dose-dependent manner.